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Purpose To evaluate the independent factors associated with the success of a trial of vaginal birth (TVB) in women with type 1 diabetes. Despite all therapeutic efforts and technological innovations, rates of caesarean sections (CS) in pregnant women with type 1 diabetes remain unchanged above 60%. Our aim was to point out influencing factors to improve the quality of antepartum counseling. Methods We performed a retrospective cohort study of 195 pregnancies with type 1 diabetes treated between 2000 and 2019. After exclusions, 118 women with near-term singleton pregnancies intended vaginal birth (TVB). Group differences between CS and successful vaginal delivery were analyzed. Multivariate logistic regression was performed by including clinical and metabolic variables to determine the independent effects on a successful vaginal delivery. Subgroup analysis for nulliparous women. Results Of 118 women with TVB, 67 (56.8%) were delivered vaginally. History of previous vaginal delivery (OR 10.29; CI 2.39; 44.30), HbA1c changes during pregnancy (per % increase; OR 0.59; CI 0.36; 0.96) and gestational weight gain (per kg; OR 0.87; CI 0.80; 0.96) were independent predictors for a successful vaginal delivery. In nulliparous women, the duration of diabetes was independently and negatively associated with vaginal delivery. Conclusion Provided data can help to improve antepartum counseling in type 1 diabetic patients. It seems that women with type 1 diabetes should avoid postponing pregnancy and childbirth.

Background Labor pain is difficult to measure. The aim of this proof-of-concept study is to implement and test a questionnaire assessing pain sensation during and after vaginal deliveries. Its key aspect is a highly standardized survey of patient-reported outcome (PRO) by staff not involved in routine care. Methods Between January and November 2015 339 women were assessed 24–48 h after spontaneous or operative-vaginal delivery of a singleton. German language skills were a prerequisite to participate. The test–retest reliability was calculated in 38 women 24–36 and 48–72 h postpartum between July and October 2017. Primiparae after spontaneous delivery and multiparae with no history of operative deliveries were compared in a subgroup analysis. Results Maximum labor pain and post-partum pain were reported a median of 9 [8–10] and 4 [3–6]. Higher ratings were associated with younger age, higher gestational ages, infant’s biometrics, and the duration of laboring. Only regional analgesia tended to reduce pain perception (NRS 8 vs. 9). Higher-degree injuries were associated with less pain postpartum. The questionnaire proved to be reliable in most aspects (Cronbach's α > 0.6 for 19/21 questions) and showed an acceptable content and criterion validity (Cohen correlation > ± 0.3, interrelation between items). Conclusion Labor is a very painful experience, irrespective of previous obstetric history. Ratings indicate inadequateness of treatment except for patients receiving preventive postoperative pain management. Systematic postpartum pain assessment, hence, is still a pending issue. Adjustments will be made concerning language skills and specific questions on effectiveness of analgesia otherwise good reliability and validity of the questionnaire were proven.

Diagnostic imaging plays a key role in the evaluation of non-accidental consequences of injuries in childhood. Fractures are the second most common consequence of child abuse, after skin lesions such as abrasions or bleeding. With the evidence of radiological criteria, non-accidental fractures can be differentiated from accidental fractures. Special types of fractures such as the classic metaphyseal lesion can only be differentiated if the image quality is high.The goal of this prospective study was to assess adherence to guidelines and quality assurance of radiological diagnostics in the event of suspected abuse in Germany. For this purpose, the quantity and diagnostic quality in university and non-university hospitals as well as the existence of a pediatric radiology department were analyzed.In all, 958 X‑ray examinations of 114 suspected abuse cases (46 girls, 68 boys) were evaluated; 42 cases from university, 42 from maximum care and 30 from regular care clinics with a median age of 6 months (3 weeks-3 years of age) were assessed as DICOM data by 3 pediatric radiologists in a consensus procedure with regard to adherence to guidelines and various quality parameters. An accompanying questionnaire was used to compare the theoretical knowledge with the respective practical implementation.A mean of 8.4 X‑rays (range 1-22) were made per case. In 12 of 114 assessed cases (10%) there was a complete skeletal status according to the S1 guideline. A babygram was performed in 13 cases (10.5%). Departments with focus on pediatric radiology produced significantly more X‑rays per skeletal status than facilities without this specialization (p 0.04). Significantly higher qualitative implementation was recorded in university hospitals (p 0.001). Regardless of the type of institution, there was only marginal agreement between the questionnaire response and the available image material.In Germany, a guideline-compliant procedure in the event of suspected child abuse is largely lacking. It remains to be seen whether this will change in the future with the broader implementation of child protection groups and the S3+ child protection guideline adopted in 2019 (AWMF register 027-069). The establishment of reference centers for a second diagnosis and recommendations for imaging technology can also improve the quality of care over the long term.HINTERGRUND: Die bildgebende Diagnostik nimmt in der Evaluation nichtakzidentieller Verletzungsfolgen im Kindesalter eine Schlüsselrolle ein. Frakturen sind nach Hautläsionen wie Abschürfungen oder Hämatomen die zweithäufigste Folge körperlicher Kindesmisshandlung. Mit Hilfe radiologischer Kriterien können nichtakzidentielle von akzidentiellen Frakturen differenziert werden. Spezielle Frakturtypen wie die klassische metaphysäre Läsion können nur bei hoher Bildqualität differenziert werden.In einer prospektiven Analyse sollten Leitlinientreue und Qualitätssicherung der radiologischen Diagnostik bei Misshandlungsverdacht in Deutschland erfasst werden. Dazu wurden Quantität und diagnostische Qualität in der universitären und nichtuniversitären Versorgung sowie in Abhängigkeit einer vorhandenen kinderradiologischen Fachabteilung analysiert.Es wurden 958 Röntgenuntersuchungen von 114 vermuteten Misshandlungsfällen (46 Mädchen, 68 Jungen) bewertet. Insgesamt 42 Fälle aus universitären, 42 aus maximalversorgenden und 30 aus regelversorgenden Kliniken mit einem medianen Alter von 6 Monaten (3 Wochen – 3. Lebensjahr) wurden als DICOM-Daten von 3 Kinderradiologen im Konsensverfahren hinsichtlich Leitlinientreue und verschiedener Qualitätsparameter beurteilt. Ein Begleitfragebogen sollte die theoretischen Kenntnisse mit der jeweiligen praktischen Umsetzung vergleichen.Je Fall wurden im Mittel 8,4 Röntgenaufnahmen (1–22) angefertigt. In 12 von 114 beurteilten Fällen (10 %) lag ein vollständiger Skelettstatus nach S1-Leitlinie GPR vor. In 13 Fällen (10,5 %) wurde ein Babygramm durchgeführt. Abteilungen mit kinderradiologischem Schwerpunkt fertigten signifikant mehr Röntgenaufnahmen je Skelettstatus an als Einrichtungen ohne Schwerpunkt (p 0,05). Eine signifikant höhere qualitative Umsetzung wurde in Universitätskliniken verzeichnet (p 0,001). Eine Übereinstimmung von Fragebogenantwort und vorliegendem Bildmaterial zeigte sich unabhängig der Institutionsart nur marginal.In Deutschland fehlt bislang mehrheitlich ein leitliniengerechtes Vorgehen bei Misshandlungsverdacht. Es bleibt abzuwarten, ob sich dies mit der breiteren Implementierung von Kinderschutzgruppen und der 2019 verabschiedeten S3-Kinderschutzleitlinie (AWMF-Registrierungsnummer: 027-069) zukünftig ändern wird. Die Etablierung von Referenzzentren für Zweitbefundung und Empfehlungen zur Aufnahmetechnik können zusätzlich die Versorgungsqualität nachhaltig verbessern.

Objectives (A) To introduce a new technique for vaginal fluid sampling (biocompatible synthetic fiber sponge) and (B) evaluate the collected vaginal fluid interleukine-6 (IL-6vag)-concentration as a new diagnostic tool for daily monitoring of intrauterine inflammation after preterm premature rupture of membranes (PPROM). Secondary objectives were to compare the potential to predict an intrauterine inflammation with established inflammation parameters (e.g., maternal white blood cell count). Methods This prospective clinical case-control diagnostic accuracy multicenter study was performed with women after PPROM (gestational age 24.0/7 – 34.0/7 weeks). Sampling of vaginal fluid was performed once daily. IL-6vag was determined by electrochemiluminescence-immunoassay-kit. Neonatal outcome and placental histology results were used to retrospectively allocate the cohort into two subgroups: 1) inflammation and 2) no inflammation (controls). Results A total of 37 cases were included in the final analysis. (A): Measurement of IL-6 was successful in 86% of 172 vaginal fluid samples. (B): Median concentration of IL-6vag in the last vaginal fluid sample before delivery was significantly higher within the inflammation group (17,085 pg/mL) compared to the controls (1,888 pg/mL; p=0.01). By Youden’s index an optimal cut-off for prediction an intrauterine inflammation was: 6,417 pg/mL. Two days before delivery, in contrast to all other parameters IL-6vag remained the only parameter with a sufficient AUC of 0.877, p Conclusions This study established a new technique for vaginal fluid sampling, which permits assessment of IL-6vag concentration noninvasively in clinical daily routine monitoring.

Purpose Several roles are attributed to the myometrium including sperm and embryo transport, menstrual discharge, control of uterine blood flow, and labor. Although being a target of diabetes complications, the influence of high glucose on this compartment has been poorly investigated. Both miRNAs and IGF1R are associated with diabetic complications in different tissues. Herein, we examined the effects of high glucose on the expression of miRNAs and IGF1R signaling pathway in the human myometrium. Methods Human myometrial explants were cultivated for 48 h under either high or low glucose conditions. Thereafter, the conditioned medium was collected for biochemical analyses and the myometrial samples were processed for histological examination as well as miRNA and mRNA expression profiling by qPCR. Results Myometrial structure and morphology were well preserved after 48 h of cultivation in both high and low glucose conditions. Levels of lactate, creatinine, LDH and estrogen in the supernatant were similar between groups. An explorative screening by qPCR arrays revealed that 6 out of 754 investigated miRNAs were differentially expressed in the high glucose group. Data validation by single qPCR assays confirmed diminished expression of miR-215-5p and miR-296-5p, and also revealed reduced miR-497-3p levels. Accordingly, mRNA levels of IGF1R and its downstream mediators FOXO3 and PDCD4, which are potentially targeted by miR-497-3p, were elevated under high glucose conditions. In contrast, mRNA expression of IGF1, PTEN, and GLUT1 was unchanged. Conclusions The human myometrium responds to short-term exposure (48 h) to high glucose concentrations by regulating the expression of miRNAs, IGF1R and its downstream targets.

Glucocorticoid (GC) -induced fetal programming of the activity of the hypothalamus-pituitary-adrenal axis (HPAA) and its associated cognitive and behavioral consequences in later life have been well characterized in several animal species. However, information on humans is scarce. In this study, we examined HPAA activity markers and associated outcomes at 8 to 9 years of age among children prenatally exposed to GC for suspected preterm birth. Our hypothesis was that antenatal exposure to the betamethasone (BM) is associated with exacerbation of HPAA activity in childhood.Prospective observational study in 31 children whose mothers received single (n = 19) or multiple (n = 12) courses of BM for threatened preterm birth but born with normal weight appropriate for the gestational age (median 37+There was no statistically significant difference in HPAA activity markers between antenatal BM exposed and unexposed groups. ANS activity in BM-exposed children shifted towards a higher parasympathetic tone reflected by a higher overall high-frequency band power of heart rate variability. IQ scores were within normal limits for both groups; however, BM-exposed children had lower IQ scores than the unexposed group. BM-exposed group had marginally more ADHD core symptoms and increased electrocortical activity in the occipital brain region compared with controls. A monotonic dose-response relation between BM exposure and activity of the ANS and IQ was estimated in post-hoc analyses.Antenatal exposure to BM in the context of threatened preterm birth was not associated with changes in HPAA activity in childhood. However, BM exposure may be associated with changes in ANS activity. Antenatal GC prophylaxis is a valuable and often life-saving therapy, but its prescription may warrant a well-balanced risk-benefit assessment.

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease of unknown cause, which mainly affects women of childbearing age, especially between 15 and 55 years of age. During pregnancy, SLE is associated with a high risk of perinatal morbidity and mortality. Among the most frequent complications are spontaneous abortion, fetal death, prematurity, intrauterine Fetal growth restriction (FGR), and preeclampsia (PE). The pathophysiology underlying obstetric mortality and morbidity in SLE is still under investigation, but several studies in recent years have suggested that placental dysfunction may play a crucial role. Understanding this association will contribute to developing therapeutic options and improving patient management thus reducing the occurrence of adverse pregnancy outcomes in this group of women. In this review, we will focus on the relationship between SLE and placental insufficiency leading to adverse pregnancy outcomes.

With begin of the SARS-CoV-2 pandemic the german obstetric, peri-/neonatological and pediatric professional societies published recommendations for care of pregnant and newborn, as well as for necessary staff protection in March 2020 [1-3]. Because of the rapid emerging increase of knowledge an update is required. This work therefore perceives as prosecution of the existing recommendations [1-3].Worldwide national recommendations were recently compared and published in a consensual review [4]. In methodological dependence this update of recommendations comments on key questions of pre-, peri- and postnatal care at SARS-CoV-2 and COVID-19, based on publications up to 30.05.2020. Statements represent a carefully concerned expert consensus and can change contemporary as new knowledge appears.The responsibility for concrete management remains at the local medical team, decisions should be supported by these recommendations.Mit Beginn der SARS-CoV-2 Pandemie haben die deutschen geburtshilflichen und pädiatrischen Fachgesellschaften im März 2020 Empfehlungen zur Versorgung infizierter Schwangerer und deren Neugeborener, wie auch notwendige Schutzmaßnahmen für das Personal veröffentlicht [1–3]. Eine Aktualisierung ist aufgrund des rasanten Wissenszuwachses notwendig. Die vorliegende Empfehlung versteht sich daher als Fortschreibung der bereits vorliegenden Publikationen [1–3].Von der Cochrane Pregnancy and Childbirth Group wurden weltweit nationale Empfehlungen verglichen und als Review veröffentlicht [4]. In methodischer Anlehnung hieran nehmen die vorliegenden aktualisierten Empfehlungen Stellung zu den Kernfragen der prä-, peri- und postnatalen Betreuung bei SARS-CoV-2 und COVID-19, auf der Grundlage der bis zum 30.05.2020 verfügbaren Publikationen. Die Stellungnahmen basieren auf einem sorgfältig abgestimmten ExpertInnenkonsens und können sich – insofern neue Erkenntnisse veröffentlicht werden – zeitnah ändern.Die Verantwortung für das konkrete Vorgehen bleibt bei dem vor Ort medizinisch betreuenden Team, dessen Entscheidungen durch diese Empfehlung unterstützt werden sollen.

Since the onset of the SARS-CoV-2 pandemic, the German Society of Gynecology and Obstetrics and the Society for Peri-/Neonatal Medicine have published and repeatedly updated recommendations for the management of SARS-CoV-2 positive pregnancies and neonates. As a continuation of existing recommendations, the current update addresses key issues related to the prenatal, perinatal, and postnatal care of pregnant women, women who have recently given birth, women who are breastfeeding with SARS-CoV-2 and COVID-19, and their unborn or newborn infants, based on publications through September 2021. Recommendations and opinions were carefully derived from currently available scientific data and subsequently adopted by expert consensus. This guideline - here available in the short version - is intended to be an aid to clinical decision making. Interpretation and therapeutic responsibility remain with the supervising local medical team, whose decisions should be supported by these recommendations. Adjustments may be necessary due to the rapid dynamics of new evidence. The recommendations are supported by the endorsement of the professional societies: German Society for Perinatal Medicine (DGPM), German Society of Gynecology and Obstetrics (DGGG), German Society for Prenatal and Obstetric Medicine (DGPGM), German Society for Pediatric Infectiology (DGPI), Society for Neonatology and Pediatric Intensive Care Medicine (GNPI).Seit Beginn der SARS-CoV-2-Pandemie haben die Deutsche Gesellschaft für Gynäkologie und Geburtshilfe und die Gesellschaft für Peri-/Neonatalmedizin Empfehlungen zum Umgang mit SARS-CoV-2-positiven Schwangerschaften und Neugeborenen veröffentlicht und wiederholt aktualisiert. Als Weiterführung der bestehenden Empfehlungen werden in dem aktuellen Update Schlüsselfragen zur prä-, peri- und postnatalen Versorgung von Schwangeren, Gebärenden, Wöchnerinnen, Stillenden mit SARS-CoV-2 und COVID-19 sowie deren Un- oder Neugeborenen auf der Grundlage von Veröffentlichungen bis zum September 2021 behandelt. Die Empfehlungen und Stellungnahmen wurden sorgfältig aus den aktuell verfügbaren wissenschaftlichen Daten abgeleitet und anschließend im Expertenkonsens verabschiedet. Dieser Leitfaden – hier in der Kurzfassung vorliegend – soll eine Hilfe für die klinische Entscheidungsfindung darstellen. Die Auslegung und therapeutische Verantwortung obliegen weiterhin dem betreuenden medizinischen Team vor Ort, dessen Entscheidungen durch diese Empfehlungen unterstützt werden sollen. Aufgrund der raschen Dynamik neuer Erkenntnisse kann eine Anpassung erforderlich sein. Die Empfehlungen werden durch die Zustimmung der Fachgesellschaften getragen: Deutsche Gesellschaft für Perinatale Medizin (DGPM), Deutsche Gesellschaft für Gynäkologie und Geburtshilfe (DGGG), Deutsche Gesellschaft für Pränatal- und Geburtsmedizin (DGPGM), Deutsche Gesellschaft für Pädiatrische Infektiologie (DGPI), Gesellschaft für Neonatologie und Pädiatrische Intensivmedizin (GNPI).

Since the onset of the SARS-CoV-2 pandemic, the German Society of Gynecology and Obstetrics and the Society for Peri-/Neonatal Medicine have published and repeatedly updated recommendations for the management of SARS-CoV-2 positive pregnancies and neonates. As a continuation of existing recommendations, the current update addresses key issues related to the prenatal, perinatal, and postnatal care of pregnant women, women who have given birth, women who have recently given birth, women who are breastfeeding with SARS-CoV-2 and COVID-19, and their unborn or newborn infants, based on publications through September 2021. Recommendations and opinions were carefully derived from currently available scientific data and subsequently adopted by expert consensus. This guideline - here available in the long version - is intended to be an aid to clinical decision making. Interpretation and therapeutic responsibility remain with the supervising local medical team, whose decisions should be supported by these recommendations. Adjustments may be necessary due to the rapid dynamics of new evidence. The recommendations are supported by the endorsement of the professional societies: German Society for Perinatal Medicine (DGPM), German Society of Gynecology and Obstetrics (DGGG), German Society for Prenatal and Obstetric Medicine (DGPGM), German Society for Pediatric Infectiology (DGPI), Society for Neonatology and Pediatric Intensive Care Medicine (GNPI).Seit Beginn der SARS-CoV-2-Pandemie haben die Deutsche Gesellschaft für Gynäkologie und Geburtshilfe und die Gesellschaft für Peri-/Neonatalmedizin Empfehlungen zum Umgang mit SARS-CoV-2-positiven Schwangerschaften und Neugeborenen veröffentlicht und wiederholt aktualisiert. Als Weiterführung der bestehenden Empfehlungen werden in dem aktuellen Update Schlüsselfragen zur prä-, peri- und postnatalen Versorgung von Schwangeren, Gebärenden, Wöchnerinnen, Stillenden mit SARS-CoV-2 und COVID-19 sowie deren Un- oder Neugeborenen auf der Grundlage von Veröffentlichungen bis zum September 2021 behandelt. Die Empfehlungen und Stellungnahmen wurden sorgfältig aus den aktuell verfügbaren wissenschaftlichen Daten abgeleitet und anschließend im Expertenkonsens verabschiedet. Dieser Leitfaden – hier in der Langfassung vorliegend – soll eine Hilfe für die klinische Entscheidungsfindung darstellen. Die Auslegung und therapeutische Verantwortung obliegen weiterhin dem betreuenden medizinischen Team vor Ort, dessen Entscheidungen durch diese Empfehlungen unterstützt werden sollen. Aufgrund der raschen Dynamik neuer Erkenntnisse kann eine Anpassung erforderlich sein. Die Empfehlungen werden durch die Zustimmung der Fachgesellschaften getragen: Deutsche Gesellschaft für Perinatale Medizin (DGPM), Deutsche Gesellschaft für Gynäkologie und Geburtshilfe (DGGG), Deutsche Gesellschaft für Pränatal- und Geburtsmedizin (DGPGM), Deutsche Gesellschaft für Pädiatrische Infektiologie (DGPI), Gesellschaft für Neonatologie und Pädiatrische Intensivmedizin (GNPI).

Metagenomic sequencing is promising for clinical applications to study microbial composition concerning disease or patient outcomes. Alterations of the vaginal microbiome are associated with adverse pregnancy outcomes, like preterm premature rupture of membranes and preterm birth. Methodologically these samples often have to deal with low relative amounts of prokaryotic DNA and high amounts of host DNA ( 90%), decreasing the overall microbial resolution. Nanopore's adaptive sampling method offers selective DNA depletion or target enrichment to directly reject or accept DNA molecules during sequencing without specialized sample preparation. Here, we demonstrate how selective 'human host depletion' resulted in a 1.70 fold (± 0.27 fold) increase in total sequencing depth, providing higher taxonomic profiling sensitivity. At the same time, the microbial composition remains consistent with the control experiments. The complete removal of all human host sequences is not yet possible and should be considered as an ethical approval statement might still be necessary. Adaptive sampling increased microbial sequencing yield in all 15 sequenced clinical routine vaginal samples, making it a valuable tool for clinical surveillance and medical-based research, which can be used in addition to other host depletion methods before sequencing.

This opinion paper briefly presents arguments that support the unlikelihood of an impact on female fertility from current covid-19 vaccines.

Since the COVID-19 pandemic, the demand for online courses has increased enormously. Therefore, finding new methods to improve medical education is imperative.The aim of this study was to compare the self-reports of the individual student-centered virtual teaching techniques (seminar versus fishbowl) in a group of medical students.During the second semester of 2020, students in the clinical phase of the study (n = 144) participated in the optional subject of Sports Medicine. The students were divided into 2 groups. One group (n = 72) received the knowledge transfer in the form of a virtual seminar, the other group (n = 72) in the form of a virtual fishbowl.Virtual seminar and virtual fishbowl students gave insights into these teaching techniques. Most of the students from the virtual fishbowl group believed that the virtual fishbowl format allowed them to be more actively involved in learning. The mean quiz scores were statistically higher for students in the virtual fishbowl group than students in the virtual seminar group (p0. 001).This study concluded that virtual seminars and virtual fishbowl formats could be served as structured learning and teaching formats. At the same time, the virtual fishbowl format can promote an active exchange of knowledge from students' perspectives.

INTRODUCTION Preterm birth is a major cause of neonatal morbidity and mortality. There is an urgent need to accurately predict imminent delivery to enable necessary interventions such as tocolytic, glucocorticoid, and magnesium sulfate administration. We aimed to evaluate placental α-macroglobulin-1 as a new diagnostic marker in the prediction of preterm birth. MATERIAL AND METHODS We performed a prospective observational trial in women with intact membranes between 24+0 and 36+6 weeks of gestation. We included both women with and without threatened preterm labor symptoms. We evaluated the test performance of placental α-macroglobulin-1 measurements in cervicovaginal fluid regarding three different presentation-to-delivery intervals: ≤2, ≤7, ≤14 days. In addition, we calculated placental α-macroglobulin-1 performance in combination with other prognostic factors such as ultrasonographic cervical length measurements. RESULTS We included 126 women in the study. We detected high specificity (97%-98%) and negative predictive value (89%-97%) for placental α-macroglobulin-1 at all time intervals. We assessed placental α-macroglobulin-1 in combination with cervical length measurements (≤15 mm) in the sub-group of women presenting with threatened preterm labor symptoms (n = 63) and detected high positive predictive values (100%) for 7- and 14-day presentation-to-delivery intervals. CONCLUSIONS Our study provides evidence that placental α-macroglobulin-1 testing in cervicovaginal fluid, in combination with cervical length measurements, accurately predicts preterm birth in women with preterm labor symptoms. This novel test combination may be used clinically to triage women presenting with threatened preterm labor, avoiding overtreatment and unnecessary hospitalizations.

Zusammenfassung Ziel Offizielle Leitlinie der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG), der Österreichischen Gesellschaft für Gynäkologie und Geburtshilfe (ÖGGG) und der Schweizerischen Gesellschaft für Gynäkologie und Geburtshilfe (SGGG). Ziel der Leitlinie ist es, die Prädiktion, die Prävention und das Management der Frühgeburt anhand der aktuellen Literatur, der Erfahrung der Mitglieder der Leitlinienkommission einschließlich der Sicht der Selbsthilfe evidenzbasiert zu verbessern. Methoden Anhand der internationalen Literatur entwickelten die Mitglieder der beteiligten Fachgesellschaften und Organisationen Empfehlungen und Statements. Diese wurden in einem formalen Prozess (strukturierte Konsensuskonferenzen mit neutraler Moderation, schriftliche Delphi-Abstimmung) verabschiedet. Empfehlungen Der Teil I dieser Kurzversion der Leitlinie zeigt Statements und Empfehlungen zur Epidemiologie, Ätiologie, der Prädiktion sowie der primären und sekundären Prävention der Frühgeburt.

Background: Male sex has been reported as a risk factor for perinatal mortality. It can be hypothesized that smoking during pregnancy and low maternal pre-pregnancy body mass index (BMI) would lead to a higher proportion of growth restricted male compared to female newborns. The objective of the study was to analyze sex-specific differences in birth weight related to smoking and maternal BMI. Method: Data on maternal and newborn characteristics were obtained from the German Perinatal Survey. We analyzed data on 508,926 singleton pregnancies that had been collected in eight German federal states between 1998 and 2000. Women were classified according to the number of cigarettes smoked per day (non-smokers, 1-7, 8-14, ≥ 15) and by maternal BMI (< 18.5, 18.5-24.99, 25-29.99, ≥ 30 kg/m2) at the first obstetric consultation. Newborns were classified as small, appropriate, or large for gestational age based on birth weight below the 10th, between 10th and 90th, or above the 90th percentile, respectively. The proportional sexual dimorphism (PSD) was calculated as the female mean divided by the male mean ×100. Results: Smoking is related to a decrease in mean birth weight and an increase of in the SGA rate. Maternal BMI is positively related to the birth weight. However, the proportional sexual dimorphism for birth weight was not different with smoking or BMI. Conclusion: Smoking during pregnancy is related to lower birth weight, and high BMI is related to higher birth weight with no change in PSD.

Effective perioperative pain management is essential for optimal patient recovery after surgery and reduces the risk of chronification. However, in clinical practice, perioperative analgesic treatment still needs to be improved and data availability for evidence-based procedure specific analgesic recommendations is insufficient. We aimed to identify procedures related with high pain scores, to evaluate the effect of higher pain intensity on patients and to define patient and intervention related risk factors for increased pain after standard gynaecological and obstetrical surgery. Therefore, we performed a prospective cross-sectional study based on the German registry for quality in postoperative pain (QUIPS). A cohort of 2508 patients receiving surgery between January 2011 and February 2016 in our tertiary referral centre (university departments of gynaecology and obstetrics, respectively) answered a validated pain questionnaire on the first postoperative day. Maximal pain intensity was measured by means of a 11-point numeric rating scale (NRS) and related to procedure, perioperative care as well as patient characteristics. The interventions with the highest reported pain scores were laparoscopic removal of ovarian cysts (NRS of 6.41 ± 2.12) and caesarean section (NRS of 6.98 ± 2.08). Factors associated with higher pain intensity were younger age (OR 1.75, 95% CI 1.65–1.99), chronic pain (OR 2.08, 95% CI 1.65–2.64) and surgery performed outside the regular day shift (OR 1.67, 95% CI 1.09–2.36). Shorter duration of surgery, peridural or local analgesic and preoperative sedation reduced postoperative pain. Patients reporting high pain scores (NRS ≥ 5) showed relevant impairment of daily activities and reduced satisfaction. Caesarean section and minimal invasive procedures were associated with the highest pain scores in the present ranking. Pain management of these procedures has to be reconsidered. Younger age, receiving surgery outside of the regular shifts, chronic pain and the surgical approach itself have a relevant influence on postoperative pain intensity. When reporting pain scores of 5 or more, patients were more likely to have perioperative complications like nausea or vomiting and to be impaired in mobilisation. Registry-based data are useful to identify patients, procedures and critical situations in daily clinical routine, which increase the risk for elevated post-intervention pain. Furthermore, it provides a database for evaluation of new pain management strategies.

Objective Management of gestational diabetes (GDM) is currently changing toward a more personalized approach. There is a growing number of GDM patients requiring only a single dose of basal insulin at night to achieve glucose control. Well-known risk factors like obesity, parity and family history have been associated with GDM treatment requirements. Sleep quality and lifestyle factors interfering with the circadian rhythm are known to affect glucose metabolism. The aim of this study was to investigate the impact of such lifestyle factors on insulin requirement in GDM patients, in particular on long-acting insulin to control fasting glucose levels. Research design and methods A total of 805 patients treated for GDM between 2012 and 2016 received a study questionnaire on lifestyle conditions. Sleep quality and work condition categories were used for subgroup analysis. Independent effects on treatment approaches were evaluated using multivariate regression. Results In total, 235 (29.2%) questionnaires returned. Women reporting poor sleep conditions had higher pre-pregnancy weight and BMI, heavier newborns, more large for gestational age newborns and higher rates of hyperbilirubinemia. Treatment requirements were related to sleep and work condition categories. Multivariate regression for ‘Basal’ insulin-only treatment revealed an adjOR 3.4 (CI 1.23–9.40, p p Conclusions Our findings suggest that external stressors like unfavorable work conditions and living with children are independently associated with the necessity of long-acting insulin at night in GDM patients. Thus, fasting glucose levels of pregnant women presenting with such lifestyle conditions may be subject to close monitoring.

A primiparous pregnant woman was admitted due to preterm premature rupture of membranes (PPROM) at 27+0 week of gestational age (WGA). Conventional vaginal microbiological analysis had no pathological finding. Management decisions based on national guidelines included antenatal corticoids, tocolytics and antibiotics. Unstoppable efforts of preterm labor in 28+0 WGA and supposed amniotic infection syndrome necessitated emergency cesarean section. The preterm infant underwent NICU therapy, developed an early-onset neonatal sepsis and therapy-refractory pulmonary insufficiency with consecutive right heart failure, resulting in death on the 36th day of life. Microbiota analyses by 16Sr DNA sequencing was performed from maternal vaginal swabs and from neonatal pharyngeal swabs. Maternal antibiotic treatment resulted in depletion of physiological vaginal colonization with Lactobacillus crispatus. Ureaplasma parvum became the dominant vaginal microorganism at delivery and was detected in high relative abundance in the neonatal specimen. Progressive radiological air-space changes and interstitial pathologies associated with Ureaplasma infection (bronchopulmonary dysplasia type III) were seen early at the 3rd and distinctly from 14th day of life. This clearly demonstrates the need of vaginal colonization diagnostics in PPROM patients and awareness of the consecutive risks in the preterm. Vaginal microbiome analysis may allow individualized and targeted maternal and fetal diagnostic, prophylactic and therapeutic strategies to identify, protect and treat the high-risk neonates after PPROM.

Problem Extracellular vesicles (EVs) released by the placenta are packed with biological information and play a major role in fetomaternal communication. Here, we describe a comprehensive set-up for the enrichment and characterization of EVs from human placenta perfusion and their application in further assays. Method of study Human term placentas were used for 3 h ex vivo one-sided perfusions to simulate the intervillous circulation. Thereafter, populations of small (sEVs) and large EV (lEVs) were enriched from placental perfusate via serial ultracentrifugation. Following, EV populations were characterized regarding their size, protein concentration, RNA levels, expression of surface markers as well as their uptake and miRNA transfer to recipient cells. Results The sEV and lEV fractions from an entire perfusate yielded, respectively, 294±32 µg and 525±96 µg of protein equivalents and 2.6±0.5 µg and 3.6±0.9 µg of RNA. The sEV fraction had a mean diameter of 117±47 nm, and the lEV fraction presented 236±54 nm. CD63 was strongly detected by dot blot in sEVs, whereas only traces of this marker were found in lEVs. Both EV fractions were positive for the trophoblast marker PLAP (placental alkaline phosphatase) and annexin A1. EV internalization in immune cells was visualized by confocal microscopy, and the transfer of placental miRNAs was detected by quantitative real-time PCR (qPCR). Conclusions Enriched EV populations showed characteristic features of sEVs and lEVs. EV uptake and transfer of miRNAs to recipient cells demonstrated their functional integrity. Therefore, we advocate the ex vivo one-sided placenta perfusion as a robust approach for the collection of placental EVs.

Following an exponential increase in SARS-CoV-2 infections, the city of Jena, Thuringia, was the first in Germany to introduce mandatory mouth and nose coverings. An estimation of the SARS-CoV-2 period prevalence was achieved by screening an unselected cohort of pregnant women. Of interest was the number of unreported cases.Upon admission to hospital, patients were screened for SARS-CoV-2 by a specific real-time PCR and antibodies determined by a specific SARS-CoV-2 IgG in serum by ELISA. The SARS-CoV-2 period prevalence was estimated using the Clopper-Pearson exact method, the group comparison with Fischer's exact test.From 6 April to 13 May 2020, 234 pregnant women were admitted to the Department of Obstetrics. A total of 225 (96.2%) SARS-CoV-2 PCRs were carried out and all remained negative. Specific IgG antibodies were detected in one (0.6%) of 180 (76.9%) antibody tests performed. The interval estimate of the period prevalence thus results in a 95% confidence interval between 0-1.7%. For 96 households with children, the period prevalence is 0-3.8%, which does not differ from the 0-4.8% for 76 households without children (p=1.00).This is the first report on the SARS-CoV-2 period prevalence of an unselected sample of pregnant women in Germany. Antibody testing showed no evidence of the feared high number of unreported asymptomatic SARS-CoV-2 infections. The seroconversion rate was below 1% (0.6%).Die Stadt Jena, Thüringen, führte nach exponentiellem Anstieg der SARS-CoV-2 Infektionen bundesweit erstmalig eine Pflicht zur Bedeckung von Mund und Nase ein. Durch Screening einer unselektierten Kohorte von Schwangeren sollte eine Schätzung der SARS-CoV-2 Periodenprävalenz erfolgen. Von Interesse war die Frage nach der Dunkelziffer.Bei stationärer Aufnahme erfolgte ein Screening sowie eine Antikörperbestimmungen auf SARS-CoV-2, mittels spezifischer Real-Time-PCR und Bestimmung spezifischer SARS-CoV-2 IgG im Serum mittels ELISA. Die Schätzung der SARS-CoV2 Periodenprävalenz erfolgte nach der exakten Methode von Clopper und Pearson, der Gruppenvergleich mit Fischers exaktem Test.Vom 06.04. bis 13.05.2020 wurden 234 Schwangere stationär aufgenommen. 225 (96,2%) durchgeführte SARS-CoV2 PCR verblieben negativ. Bei einer (0,6%) von 180 (76,9%) erfolgten Antikörperbestimmungen wurden spezifische IgG-Antikörper detektiert. Die Intervallschätzung der Periodenprävalenz ergibt damit ein 95%-Konfidenzintervall zwischen 0–1,7%. Für 96 Haushalten mit Kindern ergibt sich eine Periodenprävalenz von 0–3,8%, die sich nicht von der für 76 Haushalte ohne Kinder von 0–4,8% unterscheidet (p=1,00).Erstmalig wird die SARS-CoV-2 Periodenprävalenz einer unselektierten Stichprobe Schwangerer in Deutschland erfasst. Es ergab sich kein Hinweis für eine befürchtet hohe Dunkelziffer asymptomatischer Schwangerer für unbemerkte SARS-CoV-2 Infektionen mittels Antikörpernachweis. Die messbare Serokonversionsrate lag bei unter 1% (0,6%).

Introduction The NUT midline carcinoma is a rare tumor mostly reported in the midline of upper aerodigestive tract and mediastinum. Children as well as adolescents are affected without a gender distribution. A standard treatment is not established. So far, there exists no reported case of a pregnant female suffering from NUT midline carcinoma with musculoskeletal manifestation. Case presentation A 34-year-old woman was referred to our outpatient clinic by the general practitioner during her 31st week of pregnancy suffering from shoulder pain and dyspnea. So far, dyspnea was interpreted as a typical pregnancy-related symptom. However, a chest X-ray showed a tumor mass in the right lung in close relation to the scapula. Further examinations found metastases in different areas of the body. No pregnancy-related complications were detected by obstetric examination. After an interdisciplinary perinatal case discussion, cesarean section was directly followed by an open biopsy of the right side scapula tumor lesion. A NUT midline carcinoma was diagnosed by immunohistochemistry. Due to disseminated tumor disease in multiple non-resectable locations, a palliative systemical chemotherapy was started by the oncological outpatient clinic. Conclusion This report presents the case of the very rare NUT midline carcinoma under pregnancy which made interdisciplinary case discussions indispensable for therapy planning.

Members of the placenta-specific miRNA cluster C19MC, including miR-519d, are secreted by fetal trophoblast cells within extracellular vesicles (EVs). Trophoblast-derived EVs can be internalized by the autologous trophoblast and surrounding maternal immune cells, resulting in coordination of cellular responses. The study of functions and targets of placental miRNAs in the donor and recipient cells may contribute to the understanding of the immune tolerance essential in pregnancy. Here, we report that miR-519d-3p levels correlate positively with cell proliferation and negatively with migration in trophoblastic cell lines. Inhibition of miR-519d-3p in JEG-3 cells increases caspase-3 activation and apoptosis. PDCD4 and PTEN are targeted by miR-519d-3p in a cell type-specific manner. Transfection of trophoblastic cell lines with miR-519d mimic results in secretion of EVs containing elevated levels of this miRNA (EVmiR-519d). Autologous cells enhance their proliferation and decrease their migration ability when treated with EVmiR-519d. NK92 cells incorporate EV-delivered miR-519d-3p at higher levels than Jurkat T cells. EVmiR-519d increases the proliferation of Jurkat T cells but decreases that of NK92 cells. Altogether, miR-519d-3p regulates pivotal trophoblast cell functions, can be transferred horizontally via EVs to maternal immune cells and exerts functions therein. Vesicular miRNA transfer from fetal trophoblasts to maternal immune cells may contribute to the immune tolerance in pregnancy.

Dienogest (DNG) administration is a well-established treatment for endometriosis but bleeding irregularities remain its main disadvantage. Changes in diet, mainly to vegetable consumption, are beneficial in the treatment of estrogen-related pathologies but their use for endometriosis has been poorly studied. In this study, addition of the phytochemical 3,3′-diindolylmethane (DIM) to DNG therapy has been investigated in in vitro and ex vivo models for endometriosis and in a small cohort of women with endometriosis. Endometrial Ishikawa cells were treated with DNG or DIM at dosages from 10−10 M to 10−5 M for up to 72 h. Cell proliferation was measured by assessing BrdU incorporation. Endometrial tissue from women with endometriosis and controls was incubated with DNG or a combination of DNG and DIM. Tissue viability was determined using a modified colorimetric MTS assay. 17β-estradiol secretion was quantified by an electro-chemiluminescence immunoassay. Finally, DNG as monotherapy or in combination with DIM was randomly administered to women with endometriosis (n = 8) over 3 months. Bleeding patterns and associated pelvic pain were assessed by Visual Analogue Scale (VAS). DNG and DIM significantly reduced cell proliferation in Ishikawa cells. Ex vivo, DIM reduced viability and estradiol secretion specifically in endometriotic but not in normal endometrial tissue. This effect was enhanced by combination with DNG. Endometriosis associated pelvic pain was significantly reduced in patients taking the DNG-DIM combination therapy compared to those taking DNG alone. Bleeding pattern (number and duration of episodes) was significantly improved by addition of DIM to the DNG treatment. In conclusion, addition of DIM enhances effects of DNG ex vivo and may ameliorate bleeding patterns in endometriosis patients.

Background The use of fetal bovine serum (FBS) as growth supplement for human cell and tissue culture is widely spread in basic research as well as in clinical approaches, although several limitations must be considered, such as unstable composition and availability, biosafety and ethical aspects. Regarding interspecies differences, xenogeneic growth factors may evoke incompatibilities and non-desired interactions with human cells resulting in imprecise outcome of human-relevant data. Methods In this study the functionality of human serum (HS) has been investigated in comparison to FBS by assessing proliferation, migration and invasion of the human cervical cancer cell lines SiHa and HeLa. The effects of both sera on spheroid formation were analyzed microscopically. Results Both, FBS and HS, stimulate cell proliferation and migration similarly, whereas HS significantly enhanced cell invasion. The spheroid formation assay revealed remarkable differences between both sera, especially for SiHa cells. While in FBS supplemented medium cells only formed loose aggregates, HS induced regularly shaped spheroids under all tested conditions. Conclusion We were able to demonstrate that HS and FBS differently influence behavior of cells in culture which may have an impact on experimental results, especially in 3D cultures.

Introduction: Trophoblast homing to maternal spiral arteries is mandatory for successful placentation. Cell-cell adhesion molecules regulate this process and adhesion molecule expression is altered in impaired placentation. We hypothesize that, similar to immune cell recruitment, trophoblast cell adherence and rolling are primarily mediated by adhesion molecules like, cadherins, immunoglobulins, selectins and their partnering ligands. Here, the interdependence of adhesion molecule expression in trophoblastic cell lines of diverse origin was investigated in relation to their interaction with endothelial cell networks on Matrigel® co-cultures and the effect of specific adhesion molecule knockdown analyzed. Methods: Trophoblastic cells were labeled in red and co-cultured with green HUVEC networks on Matrigel®. Association was quantified after collection of fluorescence microscopy pictures using Wimasis® internet platform and software. Expression of adhesion molecules was analyzed by PCR and Western blot, immuno-fluorescence and flow cytometry. The impact of adhesion molecules on trophoblast-endothelial-cell interaction was investigated using siRNA technique. Results: N-cadherin and CD162 were specifically expressed in the trophoblast cell line HTR-8/SVneo, which closely adhere to and actively migrate toward HUVEC networks on Matrigel®. Suppression of N-cadherin led to a significant alteration in trophoblast-endothelial cell interaction. Expression of VE-cadherin in closely interacting trophoblast cells was not confirmed in vitro. Discussion: We identified N-cadherin to mediate specific interaction between HUVEC and the migrating trophoblast cells HTR-8/SVneo in a Matrigel® co-culture model. VE-cadherin contribution could not be confirmed in vitro. Our results support the hypothesis that impaired N-cadherin but not VE-cadherin expression is involved in trophoblast recruitment to the maternal endothelium.

Proviral insertion in murine (PIM) lymphoma proteins are mainly regulated by the Janus Kinase/Signal Transducer Activator of Transcription (JAK/STAT) signaling pathway, which can be activated by members of the Interleukin-6 (IL-6) family, including Leukemia Inhibitory Factor (LIF). Aim of the study was to compare PIM1, PIM2 and PIM3 expression and potential cellular functions in human first and third trimester trophoblast cells, the immortalized first trimester extravillous trophoblast cell line HTR8/SVneo and the choriocarcinoma cell line JEG-3. Expression was analyzed by qPCR and immunochemical staining. Functions were evaluated by PIM inhibition followed by analysis of kinetics of cell viability as assessed by MTS assay, proliferation by BrdU assay, and apoptosis by Western blotting for BAD, BCL-XL, (cleaved) PARP, CASP3 and c-MYC. Apoptosis and necrosis were tested by flow cytometry (annexin V/propidium iodide staining). All analyzed PIM kinases are expressed in primary trophoblast cells and both cell lines and are regulated upon stimulation with LIF. Inhibition of PIM kinases significantly reduces viability and proliferation and induces apoptosis. Simultaneously, phosphorylation of c-MYC was reduced. These results demonstrate the involvement of PIM kinases in LIF-induced regulation in different trophoblastic cell lines which may indicate similar functions in primary cells.

Peripheral and uterine NK cells (pNK, uNK) can be distinguished according to their receptor expression. Recent studies indicate an association of elevated pNK and uNK with recurrent miscarriage (RM). This study aimed to analyze pNK and uNK in patients with RM and healthy controls. Out of n=590 RM patients screened according to a standard diagnostic protocol, n=268 couples with ≥3 consecutive RM were identified. Subgroups consisted of n=151 primary RM (pRM), n=85 secondary RM (sRM), n=32 tertiary RM (tRM) and n=42 healthy controls. Finally, n=147 idiopathic RM (iRM) and n=121 non-iRM patients were identified. Peripheral blood levels of CD45+CD3-CD56+CD16+ NK cells were determined in non-pregnant patients and controls in the mid-luteal phase by FACS. In n=129 RM patients a uterine biopsy was taken to evaluate CD56+ NK cells by immunohistochemistry. PRM showed higher absolute pNK than sRM (median/μl (Q1;Q3): 234 (147;306) vs 176 (128;245), p=0.02). Further a trend towards higher pNK percentages in pRM was detected. UNK numbers did not differ between RM subgroups and did not correlate with pNK. However, the rate of highly elevated uNK was increased in iRM compared to non-iRM patients (p=0.04). Further, higher numbers of CD45+CD3-DR+ (p

Intrauterine growth restriction (IUGR) is present in fetuses that do not achieve their full in-utero growth potential. IUGR needs to be discriminated from small for gestational age (SGA) because IUGR newborns in particular experience long-term side effects from their small growth. IUGR fetuses have a significantly increased risk of prematurity and a distinct risk profile compared to adequate-for-gestational-age preterm newborns. Complications of prematurity are more frequent, including bronchopulmonary dysplasia, intraventricular hemorrhage, and meconium ileus. IUGR newborns are at risk of long-term health issues like cerebral palsy, impaired lung function, and delayed speech development. Interdisciplinary and interprofessional care of IUGR pregnancies in the context of a standardized health care research project is feasible: Pregnant women at risk are identified, early therapy with acetylsalicylic acid is started as indicated, risk-adapted care at level III centers is organized including psychosocial interventions and neonatal consultations. Postnatally, integrated neonatal care focusing on parent-child interaction and optimized nutrition is a hallmark. Afterwards, in-depth pediatric follow-up visits with local pediatricians help to identify growth and neurodevelopment problems early. The effects, acceptance. and cost efficiency of this approach are evaluated prospectively as part of an Innovationsfonds project.Eine intrauterine Wachstumsrestriktion (IUGR) betrifft Feten, die ihr intrauterines Wachstumspotenzial nicht nutzen können. Überschneidungen bestehen dabei zur Gruppe der small-for-gestational age (SGA) Kinder, doch sind speziell IUGR-Kinder von kurz- und langfristigen Folgen betroffen. IUGR-Feten haben ein deutlich erhöhtes Frühgeburtlichkeits-Risiko und ein spezielles Risikoprofil im Vergleich zu altersentsprechend gewachsenen Frühgeborenen. Dies umfasst das häufigere Auftreten typischer Komplikationen wie Bronchopulmonale Dysplasie, intraventrikuläre Hämorrhagie und Mekonium-Ileus. Neugeborene mit IUGR scheinen langfristig ein erhöhtes Risiko für Folgeprobleme, wie Zerebralparesen, eingeschränkte Lungenfunktion und Sprachentwicklungsverzögerungen zu haben. Eine transsektorale, interdisziplinäre und multiprofessionelle Betreuung der Schwangeren, Neugeborenen und Säuglinge im Rahmen eines Versorgungspfades ist eine aussichtsreiche neue Versorgungsform. Sie umfasst die frühe Identifizierung von Schwangeren mit einem erhöhten Risiko für eine fetale Wachstumsrestriktion, ggf. die Therapie mit Acetylsalicylsäure, die Risiko-adaptierte Anbindung an die Perinatalzentren mit psychologischen Interventionen und neonatologischen Gesprächen. Ziel des Pfades ist die Vermeidung von Verlegungen in die Perinatologie und Totgeburten. Postnatal steht eine umfassende Betreuung mit besonderem Augenmerk auf die Eltern-Kind-Bindung und Ernährungsoptimierung im Mittelpunkt. Vertiefende Vorsorgeuntersuchungen der ambulanten Kinderärzte dienen dem frühen Aufdecken von Entwicklungsproblemen. Die Wirkungen, Akzeptanz und Kosteneffizienz dieses Pfades werden im Rahmen eines Projektes des Innovationsfonds getestet.

This is an official guideline of the German Society for Gynecology and Obstetrics (DGGG), the Austrian Society for Gynecology and Obstetrics (ÖGGG) and the Swiss Society for Gynecology and Obstetrics (SGGG). The aim of this guideline is to improve the prediction, prevention and management of preterm birth based on evidence obtained from recent scientific literature, the experience of the members of the guideline commission and the views of self-help groups.Based on the international literature, the members of the participating medical societies and organizations developed Recommendations and Statements. These were adopted following a formal process (structured consensus conference with neutral moderation, voting was done in writing using the Delphi method to achieve consensus).Part I of this short version of the guideline lists Statements and Recommendations on the epidemiology, etiology, prediction and primary and secondary prevention of preterm birth.ZIEL: Offizielle Leitlinie der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG), der Österreichischen Gesellschaft für Gynäkologie und Geburtshilfe (ÖGGG) und der Schweizerischen Gesellschaft für Gynäkologie und Geburtshilfe (SGGG). Ziel der Leitlinie ist es, die Prädiktion, die Prävention und das Management der Frühgeburt anhand der aktuellen Literatur, der Erfahrung der Mitglieder der Leitlinienkommission einschließlich der Sicht der Selbsthilfe evidenzbasiert zu verbessern. METHODEN: Anhand der internationalen Literatur entwickelten die Mitglieder der beteiligten Fachgesellschaften und Organisationen Empfehlungen und Statements. Diese wurden in einem formalen Prozess (strukturierte Konsensuskonferenzen mit neutraler Moderation, schriftliche Delphi-Abstimmung) verabschiedet. EMPFEHLUNGEN: Der Teil I dieser Kurzversion der Leitlinie zeigt Statements und Empfehlungen zur Epidemiologie, Ätiologie, der Prädiktion sowie der primären und sekundären Prävention der Frühgeburt.

Background To determine the risk of cesarean delivery after labor induction among patients with prior placenta-mediated pregnancy complications (pre-eclampsia, late pregnancy loss, placental abruption or intrauterine growth restriction). Methods The AFFIRM database includes patient level data from 9 randomized controlled trials that evaluated the role of LMWH versus no LMWH during pregnancy to prevent recurrent placenta-mediated pregnancy complications. The primary outcome of this sub-study was the proportion of women who had an unplanned cesarean delivery after induction of labor compared to after spontaneous labor. Results There were 512 patients from 7 randomized trials included in our sub-study. There was no difference in the risk of cesarean delivery between women with labor induction (21/148, 14.2%) and spontaneous labor (79/364, 21.7%) (odds ratio (OR) 0.60, 95% CI, 0.35–1.01; p = 0.052). Among 274 women who used LMWH prophylaxis during pregnancy, the risk of cesarean delivery was lower among those that underwent labor induction (9.8%) compared to spontaneous labor (22.4%) (OR 0.38, 95% CI, 0.17–0.84; p = 0.01). Conclusions The risk of cesarean delivery is not increased after labor induction among a higher risk patient population with prior pregnancy complications. Our results suggest that women who receive LMWH during pregnancy might benefit from labor induction.

This is an official guideline of the German Society for Gynecology and Obstetrics (DGGG), the Austrian Society for Gynecology and Obstetrics (ÖGGG) and the Swiss Society for Gynecology and Obstetrics (SGGG). The aim of this guideline is to improve the prediction, prevention and management of preterm birth based on evidence obtained from recently published scientific literature, the experience of the members of the guideline commission and the views of self-help groups.The members of the participating medical societies and organizations developed Recommendations and Statements based on the international literature. The Recommendations and Statements were adopted following a formal consensus process (structured consensus conference with neutral moderation, voting done in writing using the Delphi method to achieve consensus).Part 2 of this short version of the guideline presents Statements and Recommendations on the tertiary prevention of preterm birth and the management of preterm premature rupture of membranes.ZIEL: Offizielle Leitlinie der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG), der Österreichischen Gesellschaft für Gynäkologie und Geburtshilfe (ÖGGG) und der Schweizerischen Gesellschaft für Gynäkologie und Geburtshilfe (SGGG). Ziel der Leitlinie ist es, die Prädiktion, die Prävention und das Management der Frühgeburt anhand der aktuellen Literatur, der Erfahrung der Mitglieder der Leitlinienkommission einschließlich der Sicht der Selbsthilfe evidenzbasiert zu verbessern. METHODEN: Anhand der internationalen Literatur entwickelten die Mitglieder der beteiligten Fachgesellschaften und Organisationen Empfehlungen und Statements. Diese wurden in einem formalen Prozess (strukturierte Konsensuskonferenzen mit neutraler Moderation, schriftliche Delphi-Abstimmung) verabschiedet. EMPFEHLUNGEN: Der Teil 2 dieser Kurzversion der Leitlinie zeigt Statements und Empfehlungen zur tertiären Prävention der Frühgeburt sowie zum Management des frühen vorzeitigen Blasensprungs.

Knowledge of risks, adequate pre- and post-partum care, and counseling is essential to reduce short- and long-term consequences for women with gestational diabetes mellitus (GDM) and their offspring. Our study explored the current GDM guideline knowledge and practiced patient counseling of private gynecologists in Germany. A survey assessing the GDM guidelines and patient counseling was mailed to 775 practicing gynecologists. We evaluated the knowledge of maternal and offspring disease risks, counseling practice, and guideline awareness. Descriptive statistics were used to analyze the responses and Chi-Square or Fisher exact test to explore differences between groups. Of the 418 private gynecologists (54.1 % response rate) who responded, the majority was aware of obesity and GDM in the previous pregnancy as risk factors for GDM. To a lesser extent, risk factors like recurrent miscarriages and stillbirth were recalled. Eighty percent stated that GDM was associated with a higher risk for the development for hypertension and 96 % with type 2 diabetes in the mother. Respondents with knowledge of the current GDM guidelines were more often aware of the development of chronic diseases, counseled patients more frequently, and performed post-partum glucose screenings more regularly compared with private gynecologists with no knowledge of the guidelines. The majority of participants incorporated recent recommendations into their practice patterns for GDM. Providing private gynecologists with additional training may further improve care for women with GDM-affected pregnancies.

This study presents sample size considerations derived from the Efficacy of Thromboprophylaxis as an Intervention during Gravidity (EThIGII) trial (ClinicalTrials.gov: NCT00400387) to address the question of low-molecular-weight heparin (LMWH) treatment in women with recurrent pregnancy loss (RPL) depending on the M2/ANXA5 haplotype. To evaluate the possible influence of such treatment on miscarriage rates of trial participants, a post hoc analysis of ANXA5 promoter genotypes in the light of M2/ANXA5 ( RPRGL3) distribution was performed using logistic models. DNA for genotyping was available from 129 LMWH and 95 control patients, 44 (19.6%) of whom were M2/ANXA5 carriers. Miscarriages occurred in 1 (4.0%) of 25 M2/ANXA5 carriers from the LMWH group compared to 4 (21.1%) of 19 in the control group, resulting in an odds ratio (95% confidence interval) for miscarriage of 0.16 (0.016-1.5) for women treated with LMWH. In noncarriers, miscarriage rates were 6 (5.8%) of 104 versus 7 (9.2%) of 76 for the LMWH and the control groups, respectively, corresponding to an odds ratio for miscarriage of 0.60 (0.19-1.9). The apparent beneficial effects of miscarriage rate reduction in M2/ANXA5 carriers with RPL concur with biological considerations about improvement in reduced ANXA5 function through LMWH treatment in an adequate murine model. The data obtained were instrumental to design proper assessment of the existence and magnitude of this effect.

We performed a meta-analysis of randomized controlled trials comparing low-molecular-weight heparin (LMWH) vs no LMWH in women with inherited thrombophilia and prior late (≥10 weeks) or recurrent early (

Fetal maturation age assessment based on heart rate variability (HRV) is a predestinated tool in prenatal diagnosis. To date, almost linear maturation characteristic curves are used in univariate and multivariate models. Models using complex multivariate maturation characteristic curves are pending.To address this problem, we use Random Forest (RF) to assess fetal maturation age and compare RF with linear, multivariate age regression. We include previously developed HRV indices such as traditional time and frequency domain indices and complexity indices of multiple scales.We found that fetal maturation was best assessed by complexity indices of short scales and skewness in state-dependent datasets (quiet sleep, active sleep) as well as in state-independent recordings. Additionally, increasing fluctuation amplitude contributed to the model in the active sleep state. None of the traditional linear HRV parameters contributed to the RF models. Compared to linear, multivariate regression, the mean prediction of gestational age (GA) is more accurate with RF than in linear, multivariate regression (quiet state: R 2 = 0 , 617 vs. R 2 = 0 , 461 , active state: R 2 = 0 , 521 vs. R 2 = 0 , 436 , state independent: R 2 = 0 , 583 vs. R 2 = 0 , 548 ).We conclude that classification and regression tree models such as RF methodology are appropriate for the evaluation of fetal maturation age. The decisive role of adjustments between different time scales of complexity may essentially extend previous analysis concepts mainly based on rhythms and univariate complexity indices. Those system characteristics may have implication for better understanding and accessibility of the maturating complex autonomic control and its disturbance. HighlightsRandom Forest identifies maturation related hrv parameters without pre-selection.Complexity indices in short time scales and skewness mainly predicted fetal maturation.Traditional hrv parameters did not contribute considerably to the prediction.Prediction with Random Forest is comparable to multivariate linear regression.

IntroductionLeukemia Inhibitory Factor (LIF) regulates behavior of trophoblast cells and their interaction with immune and endothelial cells.In vitro, trophoblast cell response to LIF may vary depending on the cell model. Reported differences in the miRNA profile of trophoblastic cells may be responsible for these observations. Therefore, miRNA expression was investigated in four trophoblastic cell lines under LIF stimulation followed byin silicoanalysis of altered miRNAs and their associated pathways.MethodsLow density TaqMan miRNA assays were used to quantify levels of 762 mature miRNAs under LIF stimulation in three choriocarcinoma-derived (JEG-3, ACH-3P and AC1-M59) and a trophoblast immortalized (HTR-8/SVneo) cell lines. Expression of selected miRNAs was confirmed in primary trophoblast cells and cell lines by qPCR. Targets and associated pathways of the differentially expressed miRNAs were inferred from the miRTarBase followed by a KEGG Pathway Enrichment Analysis. HTR-8/SVneo and JEG-3 cells were transfected with miR-21-mimics and expression of miR-21 targets was assessed by qPCR.ResultsA similar number of miRNAs changed in each tested cell line upon LIF stimulation, however, low coincidence of individual miRNA species was observed and occurred more often among choriocarcinoma-derived cells (complete data set athttp://www.ncbi.nlm.nih.gov/geo/under GEO accession number GSE130489). Altered miRNAs were categorized into pathways involved in human diseases, cellular processes and signal transduction. Six cascades were identified as significantly enriched, including JAK/STAT and TGFB-SMAD. Upregulation of miR-21-3p was validated in all cell lines and primary cells and STAT3 was confirmed as its target.DiscussionDissimilar miRNA responses may be involved in differences of LIF effects on trophoblastic cell lines.

Background In search of potential early biomarkers for timely prediction of gestational diabetes mellitus (GDM), we focused on afamin, a vitamin E–binding protein in human plasma.. Afamin plays a role in anti-apoptotic cellular processes related to oxidative stress and is associated with insulin resistance and other features of metabolic syndrome. During uncomplicated pregnancy its serum concentrations increase linearly. The aim of this study was to investigate the suitability of afamin as early marker for predicting GDM. Methods In a first-trimester cohort from a prospective observational study of adverse pregnancy outcomes we secondarily analyzed afamin concentrations in 59 patients diagnosed with GDM and 51 controls. Additionally, afamin concentrations were cross-sectionally examined in a mid-trimester cohort of 105 women and compared with results from a simultaneously performed oral glucose tolerance test (OGTT). Subgroup analysis comparing patients treated with either insulin (iGDM) or dietary intervention (dGDM) was performed in both cohorts. Patients were recruited at the University Hospital Essen, Germany, between 2003 and 2016. Results Results were adjusted for body-mass-index (BMI) and gestational age. First and mid-trimester cohorts yielded significantly elevated afamin concentrations in patients with pathological OGTT compared to patients without GDM (first trimester cohort: mean, 113.4 mg/l; 95% CI, 106.4–120.5 mg/l and 87.2 mg/l; 95% CI, 79.7–94.7 mg/l; mid-trimester cohort: mean, 182.9 mg/l; 95% CI, 169.6–196.2 mg/l and 157.3 mg/l; 95% CI, 149.1–165.4 mg/l, respectively). In the first-trimester cohort, patients developing iGDM later in pregnancy presented with significantly higher afamin concentrations compared to patients developing dGDM and compared to patients without GDM. In the mid-trimester cohort, mean concentrations of afamin differed significantly between patients with dGDM compared to controls and between patients with iGDM and controls. Patients with iGDM showed only slightly higher afamin levels compared to patients with dGDM. Conclusion Afamin may serve as a new early biomarker for pathological glucose metabolism during pregnancy. Further research is needed to determine afamin’s concentrations during pregnancy, its predictive value for early detection of pregnancies at high risk to develop GDM and its diagnostic role during the second trimester.

Epidermal growth factor (EGF) is expressed by decidual and trophoblast cells and influences manifold cellular functions during embryo implantation. Thus far, signaling of EGF via Signal Transducer and Activator of Transcription 5 (STAT5) has been only partially investigated. STAT5 stimulates proliferation and cell cycle progression in several cell types. Its dysregulation is associated with pregnancy. The aim of this study was to investigate STAT5 activation and function mediated by EGF in 2 trophoblastic cell lines, namely, HTR8/SVneo and JAR. Additionally, expression of STAT5B messenger RNA (mRNA) in trophoblast models has been compared to that of primary cells isolated from term placentas. Our results demonstrate the highest STAT5B mRNA expression in isolated trophoblast cells, lower expression in HTR8/SVneo cells, and the significantly lowest in JAR cells. Moreover, EGF-mediated STAT5 activation increases cell proliferation and viability in both cell lines. The STAT5 knockdown results in significant decrease in cell viability induced by EGF. Only in HTR8/SVneo cells, invasion decreases after STAT5 silencing and this effect cannot be rescued by further addition of EGF. These results demonstrate that STAT5 activated by EGF constitutes an important cascade for the regulation of cell proliferation and invasion in trophoblast cells.

With the objective of evaluating the functional maturation age and developmental disturbances we have previously introduced the fetal autonomic brain age score (fABAS) using 30 min fetal magnetocardiographic recordings (fMCG, Jena). The score is based on heart rate pattern indices that are related to universal principles of developmental biology. The present work aims at the validation of the fABAS methodology on 5 min recordings from an independent database (fMCG, Bochum).We found high agreement of fABAS obtained from Jena normal fetuses (5 min subsets, n = 364) and Bochum recordings (n = 322, normal fetuses). fABAS of 48 recordings from fetuses with intra-uterine growth restriction (IUGR, Bochum) was reduced in most of the cases, a result consistent with IUGR fetuses from Jena previously reported. fABAS calculated from 5 min snapshots only partly covers the accuracy when compared to fABAS from 30 min recordings. More precise diagnosis requires longer recordings.fABAS obtained from fMCG recordings is a strong candidate for standardized assessment of functional maturation age and developmental disturbances. Even 5 min recordings seem to be valuable for screening for maturation problems.

To evaluate the efficacy of inducing labor using a double-balloon catheter and vaginal prostaglandin E2 (PGE2) sequentially, in comparison with vaginal PGE2 alone after previous cesarean section. A total of 264 pregnant women with previous cesarean section undergoing labor induction at term were included in this prospective multicentre cohort study. Induction of labor was performed either by vaginal PGE2 gel or double-balloon catheter followed by vaginal PGE2. The primary outcome measure was the cesarean section rate. The cesarean section rate was 37 % without any statistically significant difference between the two groups (PGE2: n = 41, 37 % vs. balloon catheter/PGE2: n = 41, 42 %; P = 0.438). The median (range) number of applications of PGE2 [2 (1–10) versus 1 (0–8), P

Adverse prenatal environmental influences to the developing fetus are associated with mental and cardiovascular disease in later life. Universal developmental characteristics such as self-organization, pattern formation, and adaptation in the growing information processing system have not yet been sufficiently analyzed with respect to description of normal fetal development and identification of developmental disturbances. Fetal heart rate patterns are the only non-invasive order parameter of the developing autonomic brain available with respect to the developing complex organ system. The objective of the present study was to investigate whether universal indices, known from evolution and phylogeny, describe the ontogenetic fetal development from 20 weeks of gestation onwards. By means of a 10-fold cross-validated data-driven multivariate regression modeling procedure, relevant indices of heart rate variability (HRV) were explored using 552 fetal heart rate recordings, each lasting over 30 min. We found that models which included HRV indices of increasing fluctuation amplitude, complexity and fractal long-range dependencies largely estimated the maturation age (coefficients of determination 0.61–0.66). Consideration of these characteristics in prenatal care may not only have implications for early identification of developmental disturbances, but also for the development of system-theory-based therapeutic strategies.

Aim: In pregnancies complicated by impaired utero-placental perfusion, pentaeritrithyltetranitrate (PETN) has been shown to reduce the risk of severe fetal growth restriction (FGR) and perinatal death by 39%. The effect is most likely related to the vasodilatative influence of PETN. To assess its impact on utero-placental and fetal perfusion, we analyzed the Doppler parameters measured during the PETN pilot-trial. Methods: One hundred and eleven pregnancies presenting impaired utero-placental resistance at mid-gestation were included in the trial. Fifty-four women received PETN, while 57 received a placebo. Doppler velocimetry measurements were monitored biweekly. Statistical analysis was performed using a mixed linear model. Results: Within the first week of treatment, the mean pulsatility index (PI) of the uterine artery (UtA) dropped more prominently in the PETN group [−0.20, 95% confidence interval (CI): −0.34 to −0.05, P=0.007). The adjusted relative risk (RR) for abnormal cerebro-placental ratio (CPR) was significantly reduced by PETN [RR 0.412 (95% CI: 0.181–0.941)]. Kaplan-Meier analysis demonstrates the postponement of absent end-diastolic flow (AED), absent or reverse end-diastolic flow (ARED), brain sparing and abnormal cerebroplacental ratio (CPR) in the PETN group. Conclusion: The demonstrated effect of PETN on utero-placental and feto-placental perfusion strengthens the evidence for a positive impact in pregnancies complicated by impaired placental perfusion and might explain the effect on neonatal outcome, as shown in the PETN-pilot trial.

We investigated the effects of maternal age, body weight, body height, weight gain during pregnancy, smoking during pregnancy, previous live births and being a single mother on somatic development at birth. We analysed data from the German Perinatal Survey for the years 1998–2000 from eight German federal states. We had available data on 508,926 singleton pregnancies and neonates in total; for 508,893 of which we could classify the neonates as small, appropriate or large for gestational age (SGA, AGA or LGA) based on the 10th and 90th birth weight percentiles. Multivariable regression analyses found statistically significant effects of a clinically relevant magnitude for smoking during pregnancy [odds ratio (OR) 2.9 for SGA births for women smoking >10 cigarettes per day], maternal height (OR 1.4 for SGA births for women 172 cm), maternal weight (OR 1.5 for SGA births for women 69 kg), weight gain during pregnancy (OR 1.9 for SGA births for women with a weight gain 18 kg) and previous live births (OR 2.1 for LGA births for women with one or more previous live births). Maternal age and being a single mother also had significant effects but their magnitude was small. Our analysis confirms the clinically relevant effects of smoking, maternal anthropometric measures and weight gain during pregnancy on neonatal somatic development.

Trophoblast proliferation and invasion are controlled by cytokines and growth factors present at the implantation site. Members of the Interleukin-6 (IL-6) family of cytokines trigger their effects through activation of intracellular cascades including the Janus Kinase/Signal Transducer and Activator of Transcription (JAK-STAT) pathway. Functions of several STAT molecules in trophoblast cells have been described, but the role of STAT1 remained unclear. Here, potential functions of STAT1 and its activation by Oncostatin M (OSM) have been investigated in an in vitro model. STAT1 expression and phosphorylation were analyzed in human term placenta tissue by immunohistochemistry. HTR-8/SVneo cells (immortalized human extravillous trophoblast cells) were stimulated with OSM, IL-6, IL-11, Leukemia Inhibitory Factor (LIF) and Granulocyte Macrophage Colony-Stimulating Factor. Expression and phosphorylation of STAT1 were analyzed by Western blotting and immunocytochemistry. Fludarabine and STAT1 siRNA were employed for STAT1 depletion. STAT1 transcriptional activity was evaluated by DNA-binding capacity assay. Cell viability and invasion were assessed by MTS and Matrigel assays, respectively. STAT1 was expressed in villous and extravillous trophoblast cells. Low phosphorylation was detectable exclusively in extravillous trophoblast cells. Only OSM and LIF induced phosphorylation of STAT1 in the in vitro model. Challenge with OSM increased cell invasion but not proliferation. Inhibition of STAT1 by fludarabine treatment or STAT1 siRNA transfection reduced cell viability and invasiveness in presence and absence of OSM. These results indicate the potential involvement of STAT1 in the regulation of trophoblast behavior. Furthermore, STAT 1 functions are more efficiently inhibited by blocking its expression than its phosphorylation.

Monitoring the fetal behavior does not only have implications for acute care but also for identifying developmental disturbances that burden the entire later life. The concept, of 'fetal programming', also known as 'developmental origins of adult disease hypothesis', e.g. applies for cardiovascular, metabolic, hyperkinetic, cognitive disorders. Since the autonomic nervous system is involved in all of those systems, cardiac autonomic control may provide relevant functional diagnostic and prognostic information. The fetal heart rate patterns (HRP) are one of the few functional signals in the prenatal period that relate to autonomic control and, therefore, is predestinated for its evaluation. The development of sensitive markers of fetal maturation and its disturbances requires the consideration of physiological fundamentals, recording technology and HRP parameters of autonomic control. Based on the ESGCO2016 special session on monitoring the fetal maturation we herein report the most recent results on: (i) functional fetal autonomic brain age score (fABAS), Recurrence Quantitative Analysis and Binary Symbolic Dynamics of complex HRP resolve specific maturation periods, (ii) magnetocardiography (MCG) based fABAS was validated for cardiotocography (CTG), (iii) 30 min recordings are sufficient for obtaining episodes of high variability, important for intrauterine growth restriction (IUGR) detection in handheld Doppler, (iv) novel parameters from PRSA to identify Intra IUGR fetuses, (v) evaluation of fetal electrocardiographic (ECG) recordings, (vi) correlation between maternal and fetal HRV is disturbed in pre-eclampsia. The reported novel developments significantly extend the possibilities for the established CTG methodology. Novel HRP indices improve the accuracy of assessment due to their more appropriate consideration of complex autonomic processes across the recording technologies (CTG, handheld Doppler, MCG, ECG). The ultimate objective is their dissemination into routine practice and studies of fetal developmental disturbances with implications for programming of adult diseases.

International audience; BACKGROUND:Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and birth of a small-for-gestational-age (SGA) neonate. These complications are leading causes of maternal, fetal, and neonatal morbidity and mortality in high-income countries. Affected women are at high risk of recurrence in subsequent pregnancies; however, effective strategies to prevent recurrence are absent. Findings from our previous study-level meta-analysis suggested that low-molecular-weight heparin reduced the risk of recurrent placenta-mediated pregnancy complications. However, we identified significant heterogeneity in the results, possibly due to trial design or inclusion criteria. To identify which patients benefit from, and which outcomes are prevented by, low-molecular-weight heparin, we did an individual patient data meta-analysis.METHODS:We did a systematic review in May, 2013, which identified eight eligible randomised trials done between 2000 and 2013 of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. We excluded studies on the basis of the wrong population, the study being ongoing, inability to confirm eligibility of participants, intervention stopped too early, and no response from the principal investigator. We requested individual patient data from the study authors for eligible women (women pregnant at the time of the study with a history of previous pregnancy that had been complicated by one or more of the following: pre-eclampsia, placental abruption, birth of an SGA neonate [

The immunological milieu in the placenta may be crucial for priming the developing foetal immune system. Early imbalances may promote the establishment of immune-mediated diseases in later life, including allergies. The initial exposure to allergens seems to occur in utero, but little is known about allergen-induced placental cytokine and chemokine release. The release of several cytokines and chemokines from placenta tissue after exposure to mast cell degranulator compound 48/80 or apple allergen in placentas from allergic and healthy mothers was to be analysed. Four placentas from women with apple allergy and three controls were applied in a placental perfusion model with two separate cotyledons simultaneously perfused with and without apple allergen (Mal d 1). Two control placentas were perfused with compound 48/80. In outflow, histamine was quantified spectrophotofluorometrically, IL-2, IL-4, IL-6, IL-10, TNF and IFN-gamma by a cytometric multiplex bead array and IL-13 and CXCL10, CXCL11, CCL17 and CCL22 with an in-house multiplex Luminex assay. Compound 48/80 induced a rapid release of histamine, CXCL10, CXCL11, CCL17 and CCL22, but not of the other factors. Apple allergen induced a time-dependent release of IL-6 and TNF, but not of histamine, in placentas of women with apple allergy compared with the unstimulated cotyledon. CCL17 levels were slightly increased after allergen stimulation in control placentas. Allergens can induce placental cytokines and chemokines distinctly in allergic and healthy mothers. These mediators may affect the prenatal development of the immune system and modify the risk of diseases related to immune disorders in childhood such as allergies. Funding Agencies|Institut Danone (Haar, Germany); European Network of Excellence within the 6th Framework Programme of the European Union [512040]; Swedish Research Council [K2011-56X-21854-01-06]; Cancer and Allergy Association; Olle Engkvist Foundation