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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/m 2 , 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/m 2 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/m 2 . For all women with BMI ≥30 kg/m 2 , 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/m 2 . 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/m 2 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/m 2 , 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/m 2 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/m 2 in early pregnancy, without taking previous child's birthweight into account, remain difficult., (© 2019 Nordic Federation of Societies of Obstetrics and Gynecology.)

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.

Maternal microchimerism may arise in the offspring during pregnancy, and may be favorable or unfavorable. Additionally, maternal cells present in umbilical cord blood used for stem cell transplantation may affect the outcome after transplantation. The aim of this study was to evaluate the cellular subset and frequency of maternal cells in umbilical cord blood following vaginal deliveries and elective Cesarean sections where the umbilical cord clamping time was measured. A total of 44 healthy women with normal pregnancies were included in the study. Of these, 24 delivered vaginally and 20 by elective Cesarean sections. In the fresh umbilical cord blood, cellular subsets of CD3+ (T-cells), CD19+ (B-cells), CD33+ (myeloid cells), CD34+ (hematopoietic progenitor cells) and CD56+ (natural killer cells) cells were isolated and DNA extracted. A single-nucleotide polymorphism unique to the mother was identified and maternal microchimerism in the different cellular fractions was detected using quantitative real-time polymerase chain reaction with a sensitivity of 0.01%. Overall, 5 out of the 44 (11%) umbilical cord blood samples contained maternal microchimerism. The positive fractions were total DNA (whole blood, n = 3), CD34+ ( n = 1), CD56+ ( n = 1) and CD34+/CD56+ ( n = 1). Overall, four of the five (80%) positive samples were from Cesarean sections and one was from a vaginal delivery. The conclusion from this study is that maternal microchimerism in umbilical cord blood is not a common phenomenon but includes both lymphoid and hematopoietic progenitor lineages.

Here, we present a method for in-depth human plasma proteome analysis based on high-resolution isoelectric focusing HiRIEF LC-MS/MS, demonstrating high proteome coverage, reproducibility and the potential for liquid biopsy protein profiling. By integrating genomic sequence information to the MS-based plasma proteome analysis, we enable detection of single amino acid variants and for the first time demonstrate transfer of multiple protein variants between mother and fetus across the placenta. We further show that our method has the ability to detect both low abundance tissue-annotated proteins and phosphorylated proteins in plasma, as well as quantitate differences in plasma proteomes between the mother and the newborn as well as changes related to pregnancy., Competing Interests: MP, AS, YZ, JB, DT, JS, AB, MW, HÅ, CÖ, MW, JL No competing interests declared, (© 2019, Pernemalm et al.)

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.

Objectives: Color tissue Doppler imaging (cTDI) is a promising tool for the assessment of fetal cardiac function. However, the analysis of myocardial velocity traces is cumbersome and time-consuming, limiting its application in clinical practice. The aim of this study was to evaluate fetal cardiac function during the second half of pregnancy and to develop reference ranges using an automated method to analyze cTDI recordings from a cardiac four-chamber view., Methods: This was a cross-sectional study including 201 normal singleton pregnancies between 18 and 42 weeks of gestation. During fetal echocardiography, a four-chamber view of the heart was visualized and cTDI was performed. Regions of interest were positioned at the level of the atrioventricular plane in the left ventricular (LV), right ventricular (RV) and septal walls of the fetal heart, to obtain myocardial velocity traces that were analyzed offline using the automated algorithm. Peak myocardial velocities during atrial contraction (Am), ventricular ejection (Sm) and rapid ventricular filling, i.e. early diastole (Em), as well as the Em/Am ratio, mechanical cardiac time intervals and myocardial performance index (cMPI) were evaluated, and gestational age-specific reference ranges were constructed., Results: At 18 weeks of gestation, the peak myocardial velocities, presented as fitted mean with 95% CI, were: LV Am, 3.39 (3.09-3.70) cm/s; LV Sm, 1.62 (1.46-1.79) cm/s; LV Em, 1.95 (1.75-2.15) cm/s; septal Am, 3.07 (2.80-3.36) cm/s; septal Sm, 1.93 (1.81-2.06) cm/s; septal Em, 2.57 (2.32-2.84) cm/s; RV Am, 4.89 (4.59-5.20) cm/s; RV Sm, 2.31 (2.16-2.46) cm/s; and RV Em, 2.94 (2.69-3.21) cm/s. At 42 weeks of gestation, the peak myocardial velocities had increased to: LV Am, 4.25 (3.87-4.65) cm/s; LV Sm, 3.53 (3.19-3.89) cm/s; LV Em, 4.55 (4.18-4.94) cm/s; septal Am, 4.49 (4.17-4.82) cm/s; septal Sm, 3.36 (3.17-3.55) cm/s; septal Em, 3.76 (3.51-4.03) cm/s; RV Am, 6.52 (6.09-6.96) cm/s; RV Sm, 4.95 (4.59-5.32) cm/s; and RV Em, 5.42 (4.99-5.88) cm/s. The mechanical cardiac time intervals generally remained more stable throughout the second half of pregnancy, although, with increased gestational age, there was an increase in duration of septal and RV atrial contraction, LV pre-ejection and septal and RV ventricular ejection, while there was a decrease in duration of septal postejection. Regression equations used for the construction of gestational age-specific reference ranges for peak myocardial velocities, Em/Am ratios, mechanical cardiac time intervals and cMPI are presented., Conclusion: Peak myocardial velocities increase with gestational age, while the mechanical time intervals remain more stable throughout the second half of pregnancy. Using an automated method to analyze cTDI-derived myocardial velocity traces, it was possible to construct reference ranges, which could be used in distinguishing between normal and abnormal fetal cardiac function. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.)

Objectives: The aim of this study was to investigate if occupational exposure to inorganic particles or welding fumes during pregnancy is associated with negative birth outcomes., Design: A prospective national cohort study., Setting: All single births from 1994 to 2012 in Sweden. Information on birth weight, preterm birth, small for gestational age, smoking habits, nationality, age, occupation, absence from work and education was obtained from nationwide registers. Exposure to inorganic particles (mg/m 3 ) was assessed from a job exposure matrix., Participants: This study included all single births by occupationally active mothers (995 843)., Outcome Measures: Associations between occupational exposures and negative birth outcomes in the form of low birth weight, preterm birth and small for gestational age., Results: Mothers who had high exposure to inorganic particles and had less than 50 days (median) of absence from work during pregnancy showed an increased risk of preterm birth (OR 1.18; 95% CI 1.07 to 1.30), low birth weight (OR 1.32; 95% CI 1.18 to 1.48) as well as small for gestational age (OR 1.20; 95% CI 1.04 to 1.39). The increased risks were driven by exposure to iron particles. No increased risks were found in association with exposure to stone and concrete particles. High exposure to welding fumes was associated with an increased risk of low birth weight (OR 1.22; 95% CI 1.02 to 1.45) and preterm birth (OR 1.24; 95% CI 1.07 to 1.42)., Conclusions: The results indicate that pregnant women should not be exposed to high levels of iron particles or welding fumes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To develop a model for prediction of stillbirth after the 28th gestational week in singleton pregnancies of women with overweight or obesity., Method: This is a register-based cohort study. The first trimester screening database including data from 2006 until 2015 was cross-linked with the Swedish Medical Birth Register and the Swedish Register of Total Population. The final study cohort comprised 145,319 pregnancies, out of which 45,859 pregnancies were complicated by overweight or obesity and without pre-gestational diabetes. There were in total 282 stillbirths. Prediction models for stillbirth in pregnancies with overweight or obesity were constructed based on maternal characteristics, pregnancy complications and biochemical markers. Receiver Operating Characteristic (ROC) and area under curve (AUC) were calculated, based on logistic regression analyses., Results: The prevalence of stillbirth was 1.6/1000 births and 2.6/1000 births in normal weight and overweight/obese women, respectively. The final predictive model had an AUC of 0.69 (95% CI: 0.64-0.74) with a sensitivity of 28% at a 90% fixed specificity., Conclusions: It is possible to predict 28% of stillbirths in overweight or obese women, at a false positive rate of 10%. In particular, growth-restricted fetuses are at increased risk of stillbirth., Competing Interests: The authors have declared that no competing interests exist.

Objective: To evaluate the feasibility of automated analysis of fetal myocardial velocity recordings obtained by color tissue Doppler imaging (cTDI)., Methods: This was a prospective cross-sectional observational study of 107 singleton pregnancies ≥ 41 weeks of gestation. Myocardial velocity recordings were obtained by cTDI in a long-axis four-chamber view of the fetal heart. Regions of interest were placed in the septum and the right (RV) and left (LV) ventricular walls at the level of the atrioventricular plane. Peak myocardial velocities and mechanical cardiac time intervals were measured both manually and by an automated algorithm and agreement between the two methods was evaluated., Results: In total, 321 myocardial velocity traces were analyzed using each method. It was possible to analyze all velocity traces obtained from the LV, RV and septal walls with the automated algorithm, and myocardial velocities and cardiac mechanical time intervals could be measured in 96% of all traces. The same results were obtained when the algorithm was run repeatedly. The myocardial velocities measured using the automated method correlated significantly with those measured manually. The agreement between methods was not consistent and some cTDI parameters had considerable bias and poor precision., Conclusions: Automated analysis of myocardial velocity recordings obtained by cTDI was feasible, suggesting that this technique could simplify and facilitate the use of cTDI in the evaluation of fetal cardiac function, both in research and in clinical practice. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.)

Major congenital malformations affect up to 3% of newborns. Infants with prenatally diagnosed soft tissue defects should benefit from having autologous tissue readily available for surgical implantation in the perinatal period. In this study, we investigate fetal subcutaneous cells as cellular source for tissue engineering. Fetal subcutaneous biopsies were collected from elective terminations at gestational Week 20-21. Cells were isolated, expanded, and characterized in vitro. To determine cell coverage, localization, viability, and proliferation in different constructs, the cells were seeded onto a matrix (small intestine submucosa) or in collagen gel with or without poly(ε-caprolactone) mesh and were kept in culture for up to 8 weeks before analysis. Angiogenesis was analysed through a tube-forming assay. Fetal subcutaneous cells could be expanded until 43 ± 3 population doublings, expressed mesenchymal markers, and readily differentiate into adipogenic and osteogenic lineages. The cells showed low adherence to small intestine submucosa and did not migrate deep into the matrix. However, in collagen gels, the cells migrated into the gel and proliferated with sustained viability for up to 8 weeks. The cells in the matrices expressed Ki67, CD73, and α-smooth muscle actin but not cytokeratin or CD31. Fetal cells derived from subcutaneous tissue demonstrated favourable characteristics for preparation of autologous tissue transplants before birth. Our study supports the theory that cells could be obtained from the fetus during pregnancy for tissue engineering purposes after birth. In a future clinical situation, autologous transplants could be used for reconstructive surgery in severe congenital malformations., (Copyright © 2018 John Wiley & Sons, Ltd.)

Severe acute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). The placenta protects the fetus from the mother's immune system. We evaluated placenta-derived decidua stromal cells (DSCs), which differ from bone marrow mesenchymal stromal cells (BM-MSCs), as a treatment for severe acute GVHD. DSCs were obtained from term placentas. The DSCs were given to 38 patients with severe acute GVHD; 25 were steroid refractory (SR). DSCs were thawed and infused in buffer supplemented with either 10% AB plasma (group 1, n = 17), or 5% albumin (group 2, n = 21). The viability of cells was higher when thawed in albumin rather than AB plasma (p < .001). Group 1 received a higher cell dose (p < .001), cells of lower passage number (p < .001), and fewer infusions (p = .002) than group 2. The GVHD response (no/partial/complete) was 7/5/5 in group 1 and 0/10/11 in group 2 (p = .01). One-year survival in the two groups was 47% (95% confidence interval [CI] 23-68) and 76% (95% CI 51-89), respectively (p = .016). For the SR patients, 1-year survival was 73% (95% CI 37-90) in SR group 2 (n = 11), which was better than 31% (95% CI 11-54) in SR group 1 (n = 13; p = .02), 20% (95% CI 5-42) in BM-MSC treated (n = 15; p = .0015), and 3% (95% CI 0-14) in historic controls (n = 32; p < .001). DSCs are a promising new treatment for severe acute GVHD. Prospective randomized trials are needed for evaluation of efficacy. (Clinical trial NCT-02172937.) Stem Cells Translational Medicine 2018;7:325-332., (© 2018 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Cell-free DNA analysis is becoming adopted for first line aneuploidy screening, however for most healthcare programs, cost and workflow complexity is limiting adoption of the test. We report a novel cost effective method, the Vanadis NIPT assay, designed for high precision digitally-enabled measurement of chromosomal aneuploidies in maternal plasma. Reducing NIPT assay complexity is achieved by using novel molecular probe technology that specifically label target chromosomes combined with a new readout format using a nanofilter to enrich single molecules for imaging and counting without DNA amplification, microarrays or sequencing. The primary objective of this study was to assess the Vanadis NIPT assay with respect to analytical precision and clinical feasibility. Analysis of reference DNA samples indicate that samples which are challenging to analyze with low fetal-fraction can be readily detected with a limit of detection determined at <2% fetal-fraction. In total of 286 clinical samples were analysed and 30 out of 30 pregnancies affected by trisomy 21 were classified correctly. This method has the potential to make cost effective NIPT more widely available with more women benefiting from superior detection and false positive rates.

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 × 10 9 /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., (© 2017 AABB.)

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., (© 2017 Nordic Federation of Societies of Obstetrics and Gynecology.)

Purpose of Review: The aim of the study is to provide an overview on the possibility of treating congenital disorders prenatally with mesenchymal stromal cells (MSCs)., Recent Findings: MSCs have multilineage potential and a low immunogenic profile and are immunomodulatory and more easy to expand in culture. Their ability to migrate, engraft and differentiate, or act via a paracrine effect on target tissues makes MSCs candidates for clinical therapies. Fetal and extra-fetal MSCs offer higher therapeutic potential compared to MSCs derived from adult sources., Summary: MSCs may be safely transplanted prenatally via ultrasound-guided injection into the umbilical cord. Due to these characteristics, fetal MSCs are of great interest in the field of in utero stem cell transplantation for treatment of congenital disease., Competing Interests: Compliance with Ethical StandardsRachel Sagar, Lilian Walther-Jallow, Anna L. David, Cecilia Götherström, and Magnus Westgren are members of the BOOSTB4 consortium. Cecilia Götherström is the consortium leader for the study Boost Brittle Bones Before Birth (BOOSTB4). Magnus Westgren and Cecilia Götherström are shareholders in a company Cellprotect AB working on different stem cell therapies.This article does not contain any studies with human or animal subjects performed by any of the authors.

Background and Objective: Umbilical cord blood (UCB) is a valuable stem cell source used for transplantation. Immediate umbilical cord (UC) clamping is widely practised, but delayed UC clamping is increasingly advocated to reduce possible infant anaemia. The aim of this study was to investigate an intermediate UC clamping time point and to evaluate iron status at the age of 4 months in infants who had the UC clamped after 60 s and compare the results with immediate and late UC clamping., Design: Prospective observational study with two historical controls., Setting: A university hospital in Stockholm, Sweden, and a county hospital in Halland, Sweden., Methods: Iron status was assessed at 4 months in 200 prospectively recruited term infants whose UC was clamped 60 s after birth. The newborn baby was held below the uterine level for the first 30 s before placing the infant on the mother's abdomen for additional 30 s. The results were compared with data from a previously conducted randomised controlled trial including infants subjected to UC clamping at ≤10 s (n=200) or ≥180 s (n=200) after delivery., Results: After adjustment for age differences at the time of follow-up, serum ferritin concentrations were 77, 103 and 114 µg/L in the 10, 60 and 180 s groups, respectively. The adjusted ferritin concentration was significantly higher in the 60 s group compared with the 10 s group (P=0.002), while the difference between the 60 and 180 s groups was not significant (P=0.29)., Conclusion: In this study of healthy term infants, 60 s UC clamping with 30 s lowering of the baby below the uterine level resulted in higher serum ferritin concentrations at 4 months compared with 10 s UC clamping. The results suggest that delaying the UC clamping for 60 s reduces the risk for iron deficiency., Trial Registration Number: NCT01245296., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Cardiovascular events (CVEs) are prevalent in patients with systemic lupus erythematosus (SLE), and it is the young women who are disproportionately at risk. The risk factors for accelerated cardiovascular disease remain unclear, with multiple studies producing conflicting results. In this paper, we aim to address both traditional and SLE-specific risk factors postulated to drive the accelerated vascular disease in this cohort. We also discuss the more recent hypothesis that adverse pregnancy outcomes in the form of maternal-placental syndrome and resultant preterm delivery could potentially contribute to the CVEs seen in young women with SLE who have fewer traditional cardiovascular risk factors. The pathophysiology of how placental-mediated vascular insufficiency and hypoxia (with the secretion of placenta-like growth factor (PlGF) and soluble fms-tyrosine-like kinase-1 (sFlt-1), soluble endoglin (sEng) and other placental factors) work synergistically to damage the vascular endothelium is discussed. Adverse pregnancy outcomes ultimately are a small contributing factor to the complex pathophysiological process of cardiovascular disease in patients with SLE. Future collaborative studies between cardiologists, obstetricians, obstetric physicians and rheumatologists may pave the way for a better understanding of a likely multifactorial aetiological process.

Objectives: Placenta or placental chorangioma could be the origin site of infantile haemangioma since they share various histochemical and genetic characteristics with placental vascular tissue. The aim of the current study was to investigate the association between chorangiomas and infantile haemangiomas in singleton and multiple pregnancies., Materials and Methods: An informative questionnaire enquiring about the presence or not of infantile haemangioma and including illustrative photos of haemangioma was sent to 469 (153 cases with chorangioma and 316 controls) mothers of 323 singleton (104 cases and 219 controls) and 146 multiple (49 cases and 97 controls) liveborn neonates registered in Sweden. Overall, 310 mothers (66.1%) from 216 singleton and 94 multiple pregnancies (96 cases and 214 controls) provided feedback and their consent to participate in the current case-control study., Results: The incidence of infantile haemangioma showed no statistically significant differences between cases and controls (18.8% vs 18.2%) or between singleton and multiple pregnancies (18.9% vs 17.0%). The frequency of pre-eclampsia was significantly higher in cases with chorangioma compared with controls (41.7% vs 24.3%, OR=2.22, 95% CI 1.33 to 3.71, p=0.0022) and in singleton compared with multiple pregnancies (33.3% vs 21.3%, OR=1.85, 95% CI 1.04 to 3.26, p=0.034), whereas there were no significant differences in the incidence of infantile haemangioma in neonates of mothers with or without pre-eclampsia or in neonates of mothers with multiple compared with singleton pregnancies., Conclusion: There was no association between placental chorangiomas and infantile haemangiomas. Multiple pregnancies or pre-eclampsia were not significantly related to higher incidence of infantile haemangioma., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Mesenchymal stromal cells (MSCs) are increasingly used in regenerate medicine. Placenta-derived decidual stromal cells (DSCs) are a novel therapy for acute graft-versus-host-disease (GVHD) and hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (HSCT). DSCs are more immunosuppressive than MSCs. We assessed adverse events and safety using DSCs among 44 treated patients and 40 controls. The median dose of infused cells was 1.5 (range 0.9-2.9) × 10 6 DSCs/kg. The patients were given 2 (1-5) doses, with a total of 82 infusions. Monitoring ended 3 months after the last DSC infusion. Three patients had transient reactions during DSC infusion. Laboratory values, hemorrhages, and transfusions were similar in the two groups. The frequency of leukemic relapse (2/2, DSC/controls) and invasive fungal infections (6/6) were the same in the two groups. Causes of death were those seen in HSCT patients: infections (5/3), respiratory failure (1/1), circulatory failure (3/1), thromboembolism (1/0), multiorgan failure (0/1), and GVHD and others (2/7). One-year survival for the DSC patients with GVHD was 67%, which was significantly better than achieved previously at our center. One-year survival was 90% in the DSC-treated HC group. DSC infusions appear safe. Randomized studies are required to prove efficacy.

Objective: To enable early prediction of strong traction force vacuum extraction., Design: Observational cohort., Setting: Karolinska University Hospital delivery ward, tertiary unit., Population and Sample Size: Term mid and low metal cup vacuum extraction deliveries June 2012-February 2015, n = 277., Methods: Traction forces during vacuum extraction were collected prospectively using an intelligent handle. Levels of traction force were analysed pairwise by subjective category strong versus non-strong extraction, in order to define an objective predictive value for strong extraction., Statistical Analysis: A logistic regression model based on the shrinkage and selection method lasso was used to identify the predictive capacity of the different traction force variables., Predictors: Total (time force integral, Newton minutes) and peak traction (Newton) force in the first to third pull; difference in traction force between the second and first pull, as well as the third and first pull respectively. Accumulated traction force at the second and third pull., Outcome: Subjectively categorized extraction as strong versus non-strong., Results: The prevalence of strong extraction was 26%. Prediction including the first and second pull: AUC 0,85 (CI 0,80-0,90); specificity 0,76; sensitivity 0,87; PPV 0,56; NPV 0,94. Prediction including the first to third pull: AUC 0,86 (CI 0,80-0,91); specificity 0,87; sensitivity 0,70; PPV 0,65; NPV 0,89., Conclusion: Traction force measurement during vacuum extraction can help exclude strong category extraction from the second pull. From the third pull, two-thirds of strong extractions can be predicted.

Uterine natural killer (NK) cells are abundantly present in endometrium and decidua. Their function is governed by interactions between killer cell immunoglobulin-like receptors (KIRs) and cognate human leukocyte antigen (HLA) class I ligands. These interactions have implications for reproductive success. Whereas most uterine NK cells are known to express KIRs, little information is available about KIR repertoire formation and stability over time. This is primarily due to inherent difficulties in gaining access to human uterine tissue. As endometrial immune cells are shed during menstruation, menstrual blood may serve as a source for studies of KIRs on uterine NK cells. Here, we performed a combined assessment of six inhibitory and activating KIRs on uterine NK cells from paired menstrual and peripheral blood. Menstrual blood contained a high frequency of uterine NK cells expressing KIRs. The uterine NK cell KIR repertoires were markedly different from those in peripheral blood NK cells, biased toward KIR2D-receptor expression, and formed independently of selection conferred by cognate HLA class I molecules. Moreover, uterine NKG2C + self-KIR + NK cell expansions were detected. Finally, the distinct KIR repertoires of uterine NK cells were stable over multiple menstrual cycles. Our results provide novel insight into KIR repertoire formation on human uterine NK cells.

Objectives: To investigate the specificities and level of HLA class I antibodies in selected cases referred for suspected foetal and neonatal alloimmune thrombocytopenia (FNAIT)., Background: FNAIT occurs in 1 : 1-2000 live births, whereas maternal immunisation against human leukocyte antigen (HLA) class I is common. Whether HLA class I antibodies alone can cause FNAIT is debatable., Material and Methods: A total of 260 patient samples were referred between 2007 and 2012. Referrals with maternal HLA class I antibodies and no other cause for the neonatal thrombocytopenia were included for analysis (cases, n = 23). HPA-1a negative mothers were excluded. Control groups were screened positive mothers of healthy neonates (controls, n = 33) and female blood donors (blood donors, n = 19). LABScreen single antigen HLA class I beads was used for antibody analysis. Clinical records were reviewed for cases., Results: All groups had broad antibody reactivity. Cases had more antibodies with high SFI levels compared with the controls (SFI>9999; medians 26, 6 and 0; P < 0·05) and higher overall median HLA-ABC and HLA-B SFI (P < 0·05). Many of the antibodies were reactive with rare alleles. When reviewing the clinical records, several of the cases had other contributing factors to the thrombocytopenia. There was no correlation between foetal platelet count and antibody levels., Conclusion: Mothers of thrombocytopenic neonates had higher levels of HLA class I antibodies compared with control groups of women with healthy children and female blood donors. However, clinical outcome and antibody response correlated poorly in the heterogeneous case group, indicating a multifactorial cause to the thrombocytopenia in the majority of cases., (© 2016 British Blood Transfusion Society.)

Objective: To evaluate the management and outcome of a large international cohort of cases of pregnancies complicated by fetal and neonatal alloimmune thrombocytopenia (FNAIT)., Methods: This was an observational prospective and retrospective cohort study of all cases of FNAIT entered into the international multicentre No IntraCranial Haemorrhage (NOICH) registry during the period of 2001-2010. We evaluated human platelet antigen (HPA) specificity, the antenatal and postnatal interventions performed, and clinical outcome., Results: A total of 615 pregnancies complicated by FNAIT from 10 countries were included. Anti-HPA-1a was the most commonly implicated antibody. Antenatal treatment was administered in 273 pregnancies (44%), varying from intrauterine platelet transfusion to maternal administration of immunoglobulins, steroids, or a combination of those. Intracranial haemorrhage was diagnosed in 23 fetuses or neonates (3.7%). Overall perinatal mortality was 1.14% (n = 7)., Conclusion: This study presents the largest cohort of cases of FNAIT published. Our data show that antenatal treatment for FNAIT results in favourable perinatal outcome. Over time, in most centres, treatment for FNAIT changed from an invasive to a complete non-invasive procedure., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

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., (© The Authors 2016. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please journals.permissions@oup.com.)

Introduction: Chorangiomas (CAs) are the most common non-trophoblastic tumor-like-lesions of the placenta. Although the clinical significance of small CAs is unknown, the large lesions are often associated with maternal and fetal complications. The aim of our study was to assess the maternal clinical characteristics and neonatal outcome in singleton and multiple pregnancies with placental CA., Materials and Methods: Among 15742 selected placentas 170 CAs were diagnosed. Pregnancy and neonatal outcomes were analyzed in singleton (n = 121) and multiple (n = 49) pregnancy groups including 121 and 100 neonates, respectively., Results: The frequency of APGAR score <7 at 5 minutes (p = 0,012), abnormal pulsatility index (p = 0,034), and abnormal blood flow class (p = 0,011) were significantly higher in neonates from singleton compared to multiple pregnancies. Significantly smaller CAs in singleton pregnancies were related to small for gestational age neonates (p = 0,00040) and neonates admitted to the neonatal care unit (p = 0,028). In singleton pregnancies, significantly smaller CAs were associated to maternal preeclampsia (p = 0,039) and larger CAs to multiparity (p = 0,005) and smoking (p = 0,001) groups. The frequency of preeclampsia was high in both singleton and multiple pregnancy groups (41,32% vs 26,53%, respectively), however, the difference did not reach the level of statistical significance., Discussion: A high incidence of preeclampsia in cohort of placental CA might lead to a possible recognition of CAs as potential morphologic indicator of placental hypoxia., Conclusion: A more favorable pregnancy outcome in multiple gestations compared to the singleton gestations with CAs might reflect an adaptive mechanism for increased demand of oxygen and associated placental tissue hypoxia in this group., Competing Interests: The authors have declared that no competing interests exist.

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., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Background: Intravenous immunoglobulins (IVIGs) are the cornerstone in the treatment of pregnancies at risk for fetal and neonatal alloimmune thrombocytopenia (FNAIT). The most commonly used dose is 1.0 g/kg/week, not based on any dose-finding study. IVIG is an expensive multidonor human blood product with dose-related side effects. Our aim was to describe the amount of severe thrombocytopenia according to two different doses of IVIG., Study Design and Methods: We performed a cohort study, where two dosage regimes of IVIG were evaluated in the treatment of pregnant women suffering from FNAIT with a previous affected child without intracranial hemorrhage (ICH). Cases, treated with 0.5 or 1.0 g/kg/week, were selected from the international multicenter No IntraCranial Hemorrhage (NOICH) registry. Outcome was neonatal platelet (PLT) count at birth and amount of severe thrombocytopenia. Furthermore the appearance of ICH was analyzed., Results: A total of 109 women were included in the study, 46 in the 0.5 IVIG group and 63 in the 1.0 IVIG group. There was no difference in PLT count at birth (mean, 112 vs. 119; crude difference, 7; confidence interval [CI], -37.4 to 23.7]) and incidence of severe thrombocytopenia (<30 × 10(9) /L; n = 7/46 vs. n = 7/63; odds ratio, 1.43 [CI, 0.46-4.42]). No ICH occurred., Conclusion: In pregnancies with FNAIT with a previous affected child without ICH, treatment with IVIG in a weekly dose of 0.5 or 1.0 g/kg results in comparable neonatal PLT count at birth and degree of thrombocytopenia., (© 2016 AABB.)

Objective: To analyze whether the frequency of autism spectrum disorder (ASD) in a cohort of Swedish children differs between those exposed to ultrasound in the 12(th) week and those exposed to ultrasound in the 18(th) week of gestation., Methods: The study cohort consisted of approximately 30 000 children born between 1999 and 2003 to mothers who had been randomized to a prenatal ultrasound examination at either 12 or 18 weeks' gestation as part of the framework for a study on nuchal translucency screening. The outcome measure in the present study was the rate of ASD diagnoses among the children. Information on ASD diagnoses was based on data from the Swedish social insurance agency concerning childcare allowance granted for ASD., Results: Between 1999 and 2003, a total of 14 726 children were born to women who underwent a 12-week ultrasound examination and 14 596 to women who underwent an 18-week ultrasound examination. Of these, 181 (1.2%) and 176 (1.2%) children, respectively, had been diagnosed with ASD. There was no difference in ASD frequency between the early and late ultrasound groups., Conclusions: Women subjected to at least one prenatal ultrasound examination at either 12 or 18 weeks' gestation had children with similar rates of ASD. However, this result reflects routine care 10-15 years ago in Sweden. Today, higher intensity ultrasound scans are performed more frequently, at earlier stages during pregnancy and for non-medical purposes, implying longer exposure time for the fetus. This change in the use of ultrasound necessitates further follow-up study of the possible effects that high exposure to ultrasound during the gestational period has on the developing brain. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To estimate the cost-effectiveness of first trimester non-invasive fetal RHD screening for targeted antenatal versus no routine antenatal anti-D prophylaxis (RAADP) or versus non-targeted RAADP., Design: Model based on a population-based cohort study., Setting: The Swedish health service., Population: Intervention subjects in the underlying cohort study were RhD-negative pregnant women receiving first trimester fetal RHD screening followed by targeted anti-D in 2010-2011 (n = 6723). Historical comparators were RhD-negative women who delivered in 2008-2009 when standard care did not include RAADP (n = 7099)., Methods: Healthcare costs for the three strategies were included for the first and subsequent pregnancies. For the comparison with non-targeted RAADP, the immunisation rate was based on the observed rate for targeted therapy and adjusted downwards by removing the influence of false negatives., Main Outcome Measure: Additional cost per RhD immunisation averted., Results: Compared with RAADP, targeted prophylaxis was associated with fewer immunisations (0.19 versus 0.46% per pregnancy) and lower costs (cost-savings of €32 per RhD-negative woman). The savings were from lower costs during pregnancy and delivery, and lower costs of future pregnancies through fewer immunisations. Non-targeted anti-D was estimated to result in 0.06% fewer immunisations and an additional €16 in cost-savings per mother, compared with targeted anti-D., Conclusion: Based on effect data from a population-based cohort study, targeted prophylaxis was associated with lower immunisation risk and costs versus no RAADP. Based on effect data from theoretical calculations, non-targeted RAADP was predicted to result in lower costs and immunisation risk compared with targeted prophylaxis., Tweetable Abstract: Fetal RHD screening and targeted prophylaxis resulted in lower immunisation risk and costs compared with no RAADP., (© 2015 Royal College of Obstetricians and Gynaecologists.)

Objectives: Women with SLE are at increased risk of cardiovascular events (CVEs), but a relationship with traditional cardiovascular and SLE-specific risk factors has not been established. In unselected populations, adverse pregnancy outcomes linked to maternal-placental syndrome (MPS) are associated with an increased risk of CVEs. However, the effect of MPS on CVEs is unknown in women with SLE. The aim of this study was to determine if MPS increased the risk and accelerated the development of CVEs in women with SLE., Methods: Utilizing Swedish population registries, parous women with SLE were identified. Exposures were the following: MPS defined as hypertensive disorders of pregnancy; small-for-gestational-age; placental abruption and stillbirth; and preterm delivery <34 weeks. Outcomes were CVE encompassing cardiovascular morbidity and mortality. Risk of an event was modelled using Cox proportional hazards adjusted for year of delivery, age at CVE, severity of SLE and cardiovascular risk factors. Time-to-CVE was estimated using Kaplan-Meier methods., Results: Over the 38-year study period, there were 3977 women with 7410 pregnancies, of whom 413 (10.2%) suffered a CVE. Hazard of CVE was higher in those with MPS, particularly when MPS (adjusted HR = 1.64; 95% CI: 1.31, 2.05) was combined with preterm delivery < 34 weeks' gestation (adjusted HR 1.99; 95% CI 1.39, 2.84). There was accelerated development of CVEs in women with MPS of 10.5% (vs 7.3% in uncomplicated pregnancies) over the 38-year interval (P < 0.05)., Conclusion: Pregnancy complicated by MPS and preterm delivery exerts an independent effect to increase the risk and accelerate the development of CVEs in parous women with SLE., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The intrinsic regenerative capacity of human fetal cardiac mesenchymal stromal cells (MSCs) has not been fully characterized. Here we demonstrate that we can expand cells with characteristics of cardiovascular progenitor cells from the MSC population of human fetal hearts. Cells cultured on cardiac muscle laminin (LN)-based substrata in combination with stimulation of the canonical Wnt/β-catenin pathway showed increased gene expression of ISL1, OCT4, KDR, and NKX2.5. The majority of cells stained positive for PDGFR-α, ISL1, and NKX2.5, and subpopulations also expressed the progenitor markers TBX18, KDR, c-KIT, and SSEA-1. Upon culture of the cardiac MSCs in differentiation media and on relevant LNs, portions of the cells differentiated into spontaneously beating cardiomyocytes, and endothelial and smooth muscle-like cells. Our protocol for large-scale culture of human fetal cardiac MSCs enables future exploration of the regenerative functions of these cells in the context of myocardial injury in vitro and in vivo., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Chorangiomas (CAs) are the most frequent non-trophoblastic tumor-like-lesions of the placenta, and since they occur with an unusual frequency in pregnancies at high altitude, they are considered as a part of a spectrum of hypoxia-related vascular lesions of the placenta. The aim of our study is to describe the morphological features of the CAs and to show associations between CAs and other hypoxia related morphological changes in placentas of singleton and multiple pregnancies., Materials and Methods: Placentas from singleton (121 vs 242) and multiple (49 vs 98) pregnancies, with and without CAs, respectively, were selected from a cohort of 15,742 placentas and enrolled into a case control study., Results: Singleton placentas with CAs showed increased incidence of hypoxia-related placental changes including accelerated maturation of chorionic villi (OR = 2.40, p < 0.001), infarction (OR = 2.89, p < 0.001), decidual arteriopathy (OR = 3.24, p < 0.001), fetal thrombosis (OR = 4.05, p < 0.001) and hypercoiled umbilical cords (OR = 5.55, p < 0.001). The incidence of CAs in multiple placentas was higher in our studied cohort and a significant associated change was shown with fetal thrombosis (OR = 4.58, p = 0.017). There were no significant morphological changes between CAs in singleton compared to multiple pregnancies., Discussion: In singleton placentas, CA is associated with several placental changes related to hypoxia, whereas in multiple pregnancies this relationship is not present. We speculate that CAs in multiple pregnancies might reflect an adaptive mechanism for relative hypoxia per se in these pregnancies., Conclusion: Our study provides evidence that CAs are associated with an increased rate of hypoxia related changes in singleton placentas., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: To investigate the traction force employed during vacuum extractions., Design: Observational cross-sectional study., Setting: Obstetric Department, Karolinska University Hospital, Sweden, and the Swedish National Congress of Obstetrics and Gynaecology, 2013., Population: Two hundred women with vacuum extraction at term and 130 obstetricians participating in a simulated setting., Methods: In a normal clinical setting, we used a specially adapted device to measure and record the force used to undertake vacuum extraction. In a subsequent part of the study, the force employed for vacuum extraction by a group of obstetricians in a fictive setting was estimated and objectively measured., Main Outcome Measures: Applied force during vacuum extraction in relation to the estimated level of difficulty in the delivery; perinatal diagnoses of asphyxia or head trauma; estimated force compared with objectively measured force employed in the fictive setting., Results: The median (minimum-maximum) peak forces for minimum, average and excessive vacuum extraction in the clinical setting were 176 N (5-360 N), 225 N (115-436 N), and 241 N (164-452 N), respectively. In 34% of cases a force in excess of 216 N was employed. There was no correlation between the umbilical arterial pH at delivery and the traction force employed during extraction. Four cases of mild hypoxic ischaemic encephalopathy were observed, three of which were associated with a delivery whereby excessive traction force was employed during the vacuum extraction. In the fictive setting, the actual exerted force was twice the quantitative estimation. The measured forces in the clinical setting were four times higher than that estimated in the fictive setting., Conclusions: Higher than expected levels of traction force were used for vacuum extraction delivery. As obstetricians tend to underestimate the force applied during vacuum extraction, objective measurement with instantaneous feedback may be valuable in raising awareness., (© 2015 Royal College of Obstetricians and Gynaecologists.)

Introduction: A population-based observational study investigated the contribution of obstetric factors to the survival and postnatal development of extremely preterm infants., Material and Methods: Mortality up to 1 year and neurodevelopment at 2.5 years (Bayley-III test, cerebral palsy, vision, hearing) were evaluated in infants born before 27 weeks of gestation in Sweden 2004-2007 (n = 1011), using logistic regression analyses of risk factors., Results: Of 844 fetuses alive at admission, 8.4% died in utero before labor, 7.8% died intrapartum. Of 707 live-born infants, 15% died within 24 h, 70% survived ≥365 days, 64% were assessed at 2.5 years. The risk of death within 24 h after birth decreased with gestational age [odds ratio (OR) 0.3; 95% CI 0.2-0.4], antenatal corticosteroids (OR 0.3; 95% CI 0.1-0.6), and cesarean section (OR 0.4; 95% CI 0.2-0.9); it increased with multiple birth (OR 3.0; 95% CI 1.5-6.0), vaginal breech delivery (OR 2.3; 95% CI 1.0-5.1), 5-min Apgar score <4 (OR 50.4; 95% CI 28.2-90.2), and birth at a level II hospital (OR 2.6; 95% CI 1.2-5.3). The risk of death between 1 and 365 days remained significantly decreased for gestational age and corticosteroids. The risk of mental developmental delay at 2.5 years decreased with gestational age, birthweight and fetal growth; it increased with vaginal breech delivery (OR 2.0; 95% CI 1.2-7.4), male gender, low Apgar score and high Clinical Risk Index for Babies score., Conclusion: Several obstetric factors, including abdominal delivery, influenced the risk of death within the first day of life, but not later. Antenatal corticosteroids and gestational age decreased the mortality up to 1 year. Mental developmental delay was related to vaginal breech delivery., (© 2015 Nordic Federation of Societies of Obstetrics and Gynecology.)

Osteogenesis imperfecta (OI) is characterized by severe bone deformities, growth retardation and bones that break easily, often from little or no apparent cause. OI is a genetic disorder primarily with defective type I collagen with a wide spectrum of clinical expression. In the more severe cases, it can be diagnosed before birth. Transplantation of mesenchymal stem cells (MSC) has the potential to improve the bone structure and stability, growth and fracture healing. Prenatal and postnatal cell transplantation has been investigated in preclinical and clinical studies of OI and suggests that this procedure is safe and has positive effects. Cell transplantation resulted in improved linear growth, mobility and reduced fracture incidence. However, the effect is transient and for this reason re-transplantation may be needed. So far there is limited experience in this area, and proper studies are required to accurately determine if MSC transplantation is of clinical benefit in the treatment of OI. In this review, we summarize what is currently known in this field., (© 2015 John Wiley & Sons, Ltd.)

Introduction: Previously, cerebral palsy has been associated with placental infarctions diagnosed macroscopically by midwifes. However, the risk of misclassification of infarctionsis is high without a histological verification. Therefore, the objective of this study was to study placental histopathology in relation to developmental outcome at 2.5 years corrected age in a population born extremely preterm., Material and Methods: A prospective cohort study was carried out at Karolinska University Hospital, Stockholm, Sweden on a population of 139 live born infants delivered <27 gestational weeks during 2004-2007. A senior perinatal pathologist, who was blinded to outcome data, evaluated all placental slides microscopically. Neuromotor and sensory functions of the children were evaluated. Bayley Scales of Infant and Toddler Development-III (Bayley-III) were used to assess development at corrected age 2.5 years. The outcome data were evaluated without reference to obstetrical and pathology data. The primary outcome measure was neurological and developmental status at 2.5 years of corrected age. This was measured as diagnosis of cerebral palsy, visual impairment, hearing impairment as well as performance on Bayley-III scales evaluating cognitive, language and motor functions., Results: Two out of seven children with placental infarction were diagnosed with cerebral palsy compared with one child of 51 without placental infarction (p = 0.036). For developmental outcome according to Bayley-III at 2.5 years no statistically significant associations with placental pathology were found., Conclusion: A possible association between placental infarction, verified by microscopic examination, and cerebral palsy has been identified in this extremely preterm population., (© 2015 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: To determine if maternal placental syndromes (MPS) are associated with an increased risk of death from cardiovascular causes in women with systemic lupus erythematosus (SLE)., Methods: Between 1973 and 2011, women with SLE and a history of pregnancy were identified using linked Swedish population registries. The outcome was death from primarily cardiovascular causes, defined as death from acute coronary syndrome or coronary artery disease, stroke, or peripheral vascular disease. The exposure was MPS, defined as any hypertensive disorders in pregnancy, stillbirth, placental abruption, or delivery of a small-for-gestational-age infant. The association of preterm delivery (delivery at <34 weeks of gestation) with death from cardiovascular causes was also explored. Risk of death from cardiovascular causes was determined using logistic regression, adjusting for the year of first delivery, duration of SLE, number of inpatient admissions, and cardiovascular risk factors., Results: A total of 3,977 women with SLE had 7,410 pregnancies during the study interval. Death from primarily cardiovascular causes occurred in 44 of the 325 women who died (13.5%). The median age at death from cardiovascular causes was 54 years (interquartile range 48-58 years), and these women were more likely to have had hypertension and renal disease. MPS was associated with an increased risk of death from primarily cardiovascular causes (adjusted odds ratio [OR] 2.19 [95% confidence interval (95% CI) 1.14-4.22]), specifically, a history of placental abruption (adjusted OR 5.78 [95% CI 1.61-20.72]). Delivery at <34 weeks of gestation, particularly when combined with MPS, was also associated with an increased risk of death from primarily cardiovascular causes (adjusted OR 2.49 [95% CI 1.06-5.85])., Conclusion: MPS in pregnancy is associated with a higher risk of death from primarily cardiovascular causes in women with SLE., (© 2015, American College of Rheumatology.)

Background: Tissue Doppler imaging (TDI) can be used to assess fetal cardiac function and it has been shown to detect changes associated with hypoxia in animal models. However, the analysis is cumbersome and time consuming. The main objective of this study was to evaluate the feasibility of a new algorithm developed for the automated analysis of color TDI velocity recordings of the fetal myocardium. Furthermore, we wanted to assess the effect of different sizes of region of interests (ROI) on the measurement of cardiac cycle time intervals and myocardial velocities at different gestations., Methods: This study included analysis of 261 TDI velocity traces obtained from 17 fetal echocardiographic examinations performed longitudinally on five pregnant women. Cine-loops of fetal cardiac four chamber view were recorded with color overlay in TDI mode and stored for off-line analysis. ROIs of different sizes were placed at the level of the atrioventricular plane in the septum and in the right and left ventricular walls of the fetal heart. An automated algorithm was then used for the analysis of velocity traces., Results: Out of the total 261 velocity traces, it was possible to analyze 203 (78 %) traces with the automated algorithm. It was possible to analyze 93 % (81/87) of traces recorded from the right ventricular wall, 82 % (71/87) from the left ventricular wall and 59 % (51/87) from the septum. There was a trend towards decreasing myocardial velocities with increasing ROI length. However, the cardiac cycle time intervals were similar irrespective of which ROI size was used., Conclusions: An automated analysis of color TDI fetal myocardial velocity traces seems feasible, especially for measuring cardiac cycle time intervals, and has the potential for clinical application.

Congenital malformations are the leading cause of deaths during the neonatal period. Infants with prenatally diagnosed soft tissue defects may benefit from readily available autologous tissue for surgical implantation perinatally. In this study we investigated the cell content of amniotic fluid (AF) and its suitability for isolation and expansion of autologous cells for clinical use. Second trimester AF was obtained at routine amniocentesis at mean gestational week+day 16+2 (n=54). To investigate the cell content, freshly harvested AF cells (AFC) were analyzed for different cell lineages by flow cytometry. To evaluate the isolation and expansion potential of AFC, isolation by plastic adherence was evaluated with three cell culture media and positive selection of CD117, CD133, CD271, and fibroblast cells were evaluated with minimum essential medium alpha culture media. Both the positive (+) and the negative (-) fractions were analyzed. Surface expression, senescence, immunogenicity, colony forming, proliferation, and differentiation capacity was examined. In the nonhematopoietic, nonendothelial fraction of freshly harvested AF (n=17), 0.13% cells were CD73(+)/CD117(+) and 0.12% CD73(+)/CD271(+). AF displayed large donor variability with varying isolation and expansion success (n=30). The proliferative, differentiative, colony forming capacity and time before senescence also showed high variance. AFC had a preference for osteogenic rather than adipogenic lineages. Most culture-expanded AFC expressed mesenchymal but not hematopoietic surface epitopes. AFC expanded in Dulbecco's modified Eagle's medium showed higher immunogenic characteristics. This study shows that AF is a heterogeneous cell source, with high donor variation. Therefore, it may not be the best source for autologous cell therapy.

Objective: To study associations between placental histopathology and stillbirth as well as neonatal outcome in a population born extremely preterm., Design: Prospective cohort study., Setting: Stockholm, Sweden., Population: 167 infants born <27 gestational weeks during 2004-2007., Methods: One senior perinatal pathologist, blinded to outcome data, evaluated all placental slides., Main Outcome Measures: Intrauterine fetal death, small-for-gestational age, major neonatal morbidity (intraventricular hemorrhage ≥grade 3, retinopathy of prematurity ≥grade 3, necrotizing enterocolitis, cystic periventricular leukomalacia or severe bronchopulmonary dysplasia) and neonatal mortality. Additional outcome variables were Apgar score at 5 min, sepsis, and treated patent ductus arteriosus., Results: Accelerated villous maturation was associated with a decreased risk for Apgar score <7 at 5 min (p = 0.041). Fetal thrombosis and low placental weight were associated with an increased risk for both intrauterine fetal death (p < 0.001 and p = 0.011, respectively) and small-for-gestational age (p < 0.001 and p < 0.001, respectively)., Conclusion: Placental histology may have prognostic value as it appears to be associated with intrauterine fetal death, as well as with being small-for-gestational age and assignment of a low Apgar score at birth., (© 2015 Nordic Federation of Societies of Obstetrics and Gynecology.)

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., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Cell-free DNA has been used for fetal rhesus factor and sex determination, fetal aneuploidy screening, cancer diagnostics and monitoring, and other applications. However current methods of using cell free DNA require amplification, which leads to allelic dropout and bias especially when starting with small amounts of DNA. Here we describe an amplification-free method for sequencing of cell-free DNA, even from low levels of starting material. We evaluated this method in the context of prenatal diagnosis of fetal aneuploidy and compared it with a PCR-based library preparation method as well as a recently described method using unique molecular identifiers (UMI). All methods performed well, however coverage was increased by the amplification-free method and GC-induced bias was reduced by both the amplification-free method and the UMI method. Future diagnostic applications including whole genome sequencing of cell-free DNA will benefit from amplification-free sequencing., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Pregnancies at risk of fetal and neonatal alloimmune thrombocytopenia (FNAIT) are commonly treated using weekly intravenous immunoglobulin (IVIG) at 1 g/kg maternal weight. IVIG is an expensive multidonor human blood product with dose-related side effects. Our aim was to evaluate the effectiveness of IVIG at a lower dose, i.e., 0.5 g/kg., Methods: This was a randomized controlled multicenter trial conducted in Sweden, the Netherlands and Australia. Pregnant women with human platelet antigen alloantibodies and an affected previous child without intracranial hemorrhage (ICH) were enrolled. The participants were randomized to IVIG at 0.5 or 1 g/kg per week. The analyses were per intention to treat. The primary outcome was fetal or neonatal ICH. Secondary outcomes were platelet count at birth, maternal and neonatal IgG levels, neonatal treatment and bleeding other than ICH., Results: A total of 23 women were randomized into two groups (low dose: n = 12; standard dose: n = 11). The trial was stopped early due to poor recruitment. No ICH occurred. The median newborn platelet count was 81 × 10(9)/l (range 8-269) in the 0.5 g/kg group versus 110 × 10(9)/l (range 11-279) in the 1 g/kg group (p = 0.644)., Conclusion: The risk of adverse outcomes in FNAIT pregnancies treated with IVIG at 0.5 g/kg is very low, similar to that using 1 g/kg, although our uncompleted trial lacked the power to conclusively prove the noninferiority of using the low dose.

Objective: To study associations between placental histopathology and neonatal outcome in preeclampsia (PE)., Study Design: The cohort consisted of 544 singleton pregnancies complicated by PE and managed at Karolinska University Hospital, Stockholm, Sweden during 2000-2009. Evaluation of placental histopathology was made by one senior perinatal pathologist, blinded to outcome. Clinical outcome was obtained from prospectively collected medical registry data and medical records. Main outcome measures were intrauterine fetal death, smallness for gestational age, admission to neonatal unit, major neonatal morbidity (defined as presence of intraventricular hemorrhage ≥ grade 3, retinopathy of prematurity ≥ grade 3, necrotizing enterocolitis, cystic periventricular leucomalacia and/or severe bronchopulmonary dysplasia) and neonatal mortality. Logistic regression analyses including gestational age were performed., Results: Abnormal placental weight, both low (adjusted odds ratio (OR) [95% confidence interval] 5.2 [1.1-24], p = 0.03) and high (adjusted OR 1048 [21-51 663], p < 0.001) for gestational age, was associated with major neonatal morbidity in preterm infants. Accelerated villous maturation was less prevalent in intrauterine fetal death pregnancies (adjusted OR 0.18 [0.04-0.77], p = 0.02). Decidual arteriopathy increased the odds for admission to neonatal care (adjusted OR 2.7 [1.1-6.5], p = 0.03). Infarction involving ≥5% of the placenta was associated with intrauterine fetal death and small for gestational age infants (adjusted OR's 75 [5.5-1011], p = 0.001 and 3.2 [1.7-5.9], p < 0.001; respectively). No relations between histological variables and neonatal mortality could be found., Conclusion: Placental pathology in PE reflects adverse perinatal events and deviant placental weight predicts adverse neonatal outcome in preeclamptic women delivering preterm. Placental investigation without delay can contribute to neonatal risk assessment.