Use and Impact of Pessary, Cerclage, and Progesterone for the Secondary Prevention of Preterm Birth: Data from the German Neonatal Network.

BACKGROUND: To evaluate the use and effect of cervical stitch cerclage, pessary, and progesterone on pregnancy outcome in mothers of very low birth weight infants (VLBWI) born<32 weeks of gestation in the German Neonatal Network (GNN). METHODS: The GNN is a population-based cohort study enrolling VLBWI since 2009. We included 575 neonates from 424 mothers into our analysis, who were born between 2015 and 2019, after prenatal intervention with cerclage, pessary, progesterone or a combination between 20/0 to 25/0 weeks of gestation to prevent preterm birth. Median intervention-to-birth interval was the primary endpoint. RESULTS: 231 of 424 pregnant women had a cerclage only (54.5%), 76 women a pessary only (17.9%), and 27 were prescribed progesterone only (15.3%). The most common combination treatment (>1 intervention group) was cerclage plus progesterone (n=27), followed by cerclage plus pessary (n=13). The median intervention-to-birth interval for the whole cohort was 24 days (IQR 19.0 days). The earlier the intervention was started, the longer the intervention-to-birth interval lasted: When started at 20 weeks, the interval was 34 days in contrast to 11.5 days, when started at 25 weeks. The >1 group was born at a significantly higher median GA with 27.0 weeks (IQR 2.9 weeks) and a higher median birth weight of 980 g (IQR 394 g) accordingly. CONCLUSION: We propose that the earliest possible start of intervention leads to the most efficient pregnancy prolongation.

Changes in Heart Rate, Heart Rate Variability, Breathing Rate, and Skin Temperature throughout Pregnancy and the Impact of Emotions-A Longitudinal Evaluation Using a Sensor Bracelet.

(1) Background: Basic vital signs change during normal pregnancy as they reflect the adaptation of maternal physiology. Electronic wearables like fitness bracelets have the potential to provide vital signs continuously in the home environment of pregnant women. (2) Methods: We performed a prospective observational study from November 2019 to November 2020 including healthy pregnant women, who recorded their wrist skin temperature, heart rate, heart rate variability, and breathing rate using an electronic wearable. In addition, eight emotions were assessed weekly using five-point Likert scales. Descriptive statistics and a multivariate model were applied to correlate the physiological parameters with maternal emotions. (3) Results: We analyzed data from 23 women using the electronic wearable during pregnancy. We calculated standard curves for each physiological parameter, which partially differed from the literature. We showed a significant association of several emotions like feeling stressed, tired, or happy with the course of physiological parameters. (4) Conclusions: Our data indicate that electronic wearables are helpful for closely observing vital signs in pregnancy and to establish modern curves for the physiological course of these parameters. In addition to physiological adaptation mechanisms and pregnancy disorders, emotions have the potential to influence the course of physiological parameters in pregnancy.

Antibiotic Use During Pregnancy and Childbirth: Prospective Observational Study on Prevalence, Indications, and Prescribing Patterns in a German Tertiary Center.

Introduction Antibiotics are powerful drugs to prevent and treat perinatal infections. Overuse of antibiotics leads to antibiotic resistance, has potential side effects and influences the maternal and neonatal microbiome. Patients and Methods We performed a prospective observational study on the prevalence, indications, and prescribing patterns of antibiotics during pregnancy and childbirth. We included women who had given birth after 23+0 weeks of gestation at a single tertiary center in Germany from January 2020 to March 2021. Descriptive statistics and binomial regression were performed to analyze the factors influencing the prescription of antibiotics. Results We included 522 postpartum women into our study. 337 (64.6%) were exposed to antibiotics during pregnancy and/or childbirth. 115 women received antibiotics during pregnancy, 291 during birth. Most antibiotics during pregnancy were prescribed for urinary tract infections (UTIs) (56.0%). Most prescriptions were issued by obstetrics and gynecology physicians (65.8%), followed by hospitals (16.7%) and family medicine physicians (8.8%). Most antibiotics during childbirth were given for a cesarean section (64.3%), followed by preterm rupture of membranes (41.2%). 95.3% of women who had a preterm birth were exposed to antibiotics. In logistic regression models, lower gestational age at birth, higher maternal body-mass-index and smoking were independently associated with antibiotic use during pregnancy and childbirth. Conclusion We found a high rate of antibiotic exposure during pregnancy and childbirth. Our results imply an urgent need for antibiotic stewardship programs in perinatal medicine as well as further research on the effects of perinatal antibiotic exposure on microbiome development and childhood health.

Timing of antenatal steroid administration for imminent preterm birth: results of a prospective observational study in Germany.

PURPOSE: To evaluate the timing of antenatal steroid administration and associated medical interventions in women with imminent preterm birth. METHODS: We performed a prospective observational study at a single tertiary center in Germany from September 2018 to August 2019. We included pregnant women who received antenatal steroids for imminent preterm birth and evaluated the interval from administration to birth. 120 women with antenatal steroid application were included into our analysis. Descriptive statistics were performed to analyze factors influencing the timing of antenatal steroids and to evaluate additional medical interventions which women with imminent preterm birth experience. RESULTS: Of the 120 women included into our study, 35.8% gave birth before 34/0 weeks and 64.2% before 37/0 weeks of gestation. Only 25/120 women (20.8%) delivered within the optimal time window of 1-7 days after antenatal steroid application. 5/120 women (4.2%) only received one dose of antenatal steroids before birth and 3/120 (2.5%) gave birth within 8 to 14 days after antenatal steroids. Most women gave birth more than 14 days after steroid application (72.5%, 87/120). Women with preeclampsia (60%), PPROM (31%), and FGR (30%) had the highest rates of delivery within the optimal time window. Women of all timing groups received additional interventions and medications like antibiotics, tocolytics, or anticoagulation. CONCLUSION: Our observational data indicate that most pregnant women do not give birth within 7 days after the administration of antenatal steroids. The timing was best for preterm birth due to preeclampsia, PPROM, and FGR. Especially for women with symptoms of preterm labor and bleeding placenta previa, antenatal steroids should be indicated more restrictively to improve neonatal outcome and reduce untimely and unnecessary interventions.

A Timely Administration of Antenatal Steroids Is Highly Protective Against Intraventricular Hemorrhage: An Observational Multicenter Cohort Study of Very Low Birth Weight Infants.

Aim: The aim of the study is to evaluate the influence of the timing of antenatal steroids (ANSs) on neonatal outcome of very low birth weight infants (VLBWI) born before 30 weeks of gestation in the German Neonatal Network. Methods: The German Neonatal Network is a large population-based cohort study enrolling VLBWIs since 2009. We included 672 neonates, who were born between January 1, 2009 and December 31, 2019 in our analysis in 10 selected centers. Infants were divided into four subgroups based on the interval between the first steroid administration and preterm birth: (I) two doses of betamethasone, ANS-birth interval: >24 h to 7 days, n = 187, (II) only one dose of betamethasone, ANS-birth interval 0-24 h, n = 70, (III) two doses of betamethasone, ANS-birth interval >7 days, n = 177, and (IV) no antenatal steroids, n = 238. Descriptive statistics and logistic regression analyses were performed for the main neonatal outcome parameters. Group IV (no ANS) was used as a reference. Results: An ANS-birth interval of 24 h to 7 days after the first dose was associated with a reduced risk for intraventricular hemorrhage (OR 0.17; 95% CI 0.09-0.31, p < 0.001) and mechanical ventilation (OR 0.37; 95% CI 0.23-0.61, p < 0.001), whereas the group of infants that only received a single dose of steroids reflected a subgroup at high risk for adverse neonatal outcomes; an ANS-birth interval of >7 days was still associated with a lower risk for intraventricular hemorrhage (OR 0.43; 95% CI 0.25-0.72, p = 0.002) and the need for mechanical ventilation (OR 0.43; 95% CI 0.27-0.71, p = 0.001). Conclusion: Our observational data indicate that an ANS-birth interval of 24 h to 7 days is strongly associated with a reduced risk of intraventricular hemorrhage in VLBWIs. Further research is needed to improve the prediction of preterm birth in order to achieve a timely administration of antenatal steroids that may improve neonatal outcomes such as intraventricular hemorrhage.

Timing of antimicrobial prophylaxis for cesarean section is critical for gut microbiome development in term born infants.

Animal models imply that the perinatal exposure to antibiotics has a substantial impact on microbiome establishment of the offspring. We aimed to evaluate the effect of timing of antimicrobial prophylaxis for cesarean section before versus after cord clamping on gut microbiome composition of term born infants. We performed an exploratory, single center randomized controlled clinical trial. We included forty pregnant women with elective cesarean section at term. The intervention group received single dose intravenous cefuroxime after cord clamping (n = 19), the control group single dose intravenous cefuroxime 30 minutes before skin incision (n = 21). The primary endpoint was microbiome signature of infants and metabolic prediction in the first days of life as determined in meconium samples by 16S rRNA gene sequencing. Secondary endpoints were microbiome composition at one month and 1 year of life. In meconium samples of the intervention group, the genus Staphylococcus pre-dominated. In the control group, the placental cross-over of cefuroxime was confirmed in cord blood. A higher amino acid and nitrogen metabolism as well as increased abundance of the genera Cutibacterium, Corynebacterium and Streptophyta were noted (indicator families: Cytophagaceae, Lactobacilaceae, Oxalobacteraceae). Predictive models of metabolic function revealed higher 2'fucosyllactose utilization in control group samples. In the follow-up visits, a higher abundance of the genus Clostridium was evident in the intervention group. Our exploratory randomized controlled trial suggests that timing of antimicrobial prophylaxis is critical for early microbiome engraftment but not antimicrobial resistance emergence in term born infants.

[Smart sensors in pregnancy: Narrative review on the use of smart home technology in routine prenatal care]. / Smart Sensorik in der Schwangerschaft: Narratives Review über die Verlagerung der Schwangerschaftsvorsorge in den Smart Home Bereich.

INTRODUCTION: Today's routine prenatal care in Germany includes regular in-person appointments of pregnant women with doctors or midwives. Considering an increasing digitalization of the health care sector and in view of the global COVID-19 pandemic, the frequency of in-person visits could be reduced by remote monitoring using smart sensor technology. We aim to give an overview of the current international research on the use of smart sensors in prenatal care and its benefits, costs and resource consumption. METHODS: For this narrative review, PubMed and Science Direct were searched for clinical trials using smart sensors in prenatal care published in English or German language from 1/2016 to 12/2020. We included studies which addressed the benefits, costs and resource consumption of this innovative technology. RESULTS: We identified 13 projects using smart sensors in the fields of basic prenatal care, prenatal care for patients with hypertensive disease in pregnancy and prenatal care for women with gestational diabetes. The projects detected positive effects of smart sensors on health care costs and resource consumption and at least equal benefits for the pregnant women. DISCUSSION AND CONCLUSIONS: The current COVID-19 pandemic underlines the need for the introduction of smart sensor technology into German prenatal care routine. Remote monitoring could easily reduce the frequency of in-person visits by half. Smart sensor concepts could be approved as digital health applications in Germany. In order to increase user acceptance, there should not be any additional costs for pregnant women and health care professionals using modern health care apps. However, health insurance providers need to invest in smart sensor technology in order to eventually benefit from it.

Heterogenous use of misoprostol for induction of labour: results of an online survey among midwives in German-speaking countries.

PURPOSE: This online survey looked at the experiences and general perceptions of midwives concerning induction of labour and the specific use of misoprostol. METHODS: We published an online questionnaire with 24 questions in German on midwives' experiences and perceptions of different methods of induction of labour. RESULTS: The online survey was answered by 412 midwives between February 2016 and February 2017. At least 20% of the 24 questions were answered in 333 questionnaires, which were included in this analysis. Oral misoprostol was the most common induction method for primipara and for women with a previous vaginal birth and an unfavourable cervix. Apart from alternative methods for induction of labour like castor oil and complementary/alternative methods, oral misoprostol was the preferred method of induction of labour by midwives. Midwives described a wide range of dosage schedules concerning application intervals, starting doses, and the maximum daily dose of misoprostol. Approximately 50% of the participants of this study described prescriptions of more than 200 µg misoprostol daily for induction of labour. CONCLUSION: Misoprostol is widely used in Germany and was one of the three preferred methods of induction of labour among midwives in our study next to castor oil and complementary/alternative methods. The preparation and dosage of misoprostol vary significantly among hospitals and do not adhere to international guidelines. Midwives voiced their concerns about inconsistent indications and heterogenous use of different methods and dosages of induction. They wished for more patience with late-term pregnancies and individualized shared decision-making between pregnant women and obstetricians.

A Question of Timing: 10-year Retrospective Analysis on the Use of Antenatal Steroids for Imminent Preterm Birth.

OBJECTIVE: Antenatal steroids improve the neonatal outcome if they are administered within a therapeutic window of seven days before preterm birth. The aim of this study was to evaluate the timing of antenatal steroids for imminent preterm birth at a single center in Germany. MATERIAL AND METHODS: A 10-year retrospective analysis of 843 preterm births between 24/0 and 33/6 weeks was performed from January 2008 to December 2017 at a German university hospital. We evaluated the timing of antenatal steroids according to the indication for their application. Descriptive statistics and binomial regression were performed to analyze factors influencing the timing of antenatal steroid administration. RESULTS: Of 843 preterm births below 34 weeks included in our study, 752 pregnant women received antenatal steroids (89.2%). Only 301/843 women (35.7%) gave birth within the optimal window of 7 days after antenatal steroids. 91/843 women (10.8%) did not receive steroids. 130/843 women (15.4%) only received one dose, 76/843 (9.0%) gave birth within 8 to 14 days, and 245/843 (29.1%) more than 14 days later. In a binomial regression model, preterm premature rupture of membranes (OR 3.40, 95% CI 1.81 to 6.39, p<0.001), fetal growth restriction (OR 3.27, 95% CI 1.63 to 6.58, p=0.001), and preeclampsia (OR 2.83, 95% CI 1.37 to 5.83, p=0.005) were positively associated with optimal timing. CONCLUSION: Two thirds of women with preterm birth before 34 weeks received antenatal steroids outside the optimal therapeutic window. Further research is needed to achieve an optimal effect of antenatal steroids on neonatal outcome and to reduce untimely as well as unnecessary interventions.

Neonatal Outcome After Preeclampsia and HELLP Syndrome: A Population-Based Cohort Study in Germany.

Aim: To analyze short term outcomes of very low birth weight infants (VLBWI) born preterm after maternal preeclampsia and HELLP syndrome within the German Neonatal Network. Methods: The German Neonatal Network is a large population-based cohort study enrolling VLBWI since 2009. Two thousand six hundred and fifty two infants below 32 weeks of gestation born after maternal preeclampsia or HELLP syndrome and 13,383 infants born prematurely for other causes between 2009 and 2018 were included in our analysis. Descriptive statistics and multinomial regression models including preeclampsia and HELLP syndrome were performed for short-term outcome measures such as intracerebral hemorrhage, necrotizing enterocolitis requiring surgery, bronchopulmonary dysplasia, retinopathy of prematurity, periventricular leukomalacia, persistent ductus arteriosus requiring surgery, blood culture positive sepsis and death. Results: After adjustment for confounding variables, preterm birth due to preeclampsia or HELLP syndrome was associated with a reduced risk for intracerebral hemorrhage (OR 0.73, 95% CI 0.60-0.89), necrotizing enterocolitis requiring surgery (OR 0.35 95% CI 0.15-0.82), periventricular leukomalacia (OR 0.61 95% CI 0.40-0.92), and death (OR 0.72 95% CI 0.55-0.96) as compared to other causes of preterm birth. Conclusions: The indication for preterm birth has an impact on neonatal outcome in preterm infants born below 32 weeks. This notion should be included when counseling the families.

The circadian phase of antenatal glucocorticoid treatment affects the risk of behavioral disorders.

During pregnancy, maternal endocrine signals drive fetal development and program the offspring's physiology. A disruption of maternal glucocorticoid (GC) homeostasis increases the child's risk of developing psychiatric disorders later in life. We here show in mice, that the time of day of antenatal GC exposure predicts the behavioral phenotype of the adult offspring. Offspring of mothers receiving GCs out-of-phase compared to their endogenous circadian GC rhythm show elevated anxiety, impaired stress coping, and dysfunctional stress-axis regulation. The fetal circadian clock determines the vulnerability of the stress axis to GC treatment by controlling GC receptor (GR) availability in the hypothalamus. Similarly, a retrospective observational study indicates poorer stress compensatory capacity in 5-year old preterm infants whose mothers received antenatal GCs towards the evening. Our findings offer insights into the circadian physiology of feto-maternal crosstalk and assign a role to the fetal clock as a temporal gatekeeper of GC sensitivity.

Delivery mode and intraventricular hemorrhage risk in very-low-birth-weight infants: Observational data of the German Neonatal Network.

BACKGROUND: Very-low-birth-weight infants (VLBWI) are frequently delivered by cesarean section (CS). However, it is unclear at what gestational age the benefits of spontaneous delivery outweigh the perinatal risks, i.e. intraventricular hemorrhage (IVH) or death. OBJECTIVES: To assess the short-term outcome of VLBWI on IVH according to mode of delivery in a population-based cohort of the German Neonatal Network (GNN). STUDY DESIGN: A total cohort of 2203 singleton VLBWI with a birth weight <1500g and gestational age between 22 0/7 and 36 6/7 weeks born and discharged between 1st of January 2009 and 31st of December 2015 was available for analysis. VLBWI were stratified into three categories according to mode of delivery: (1) planned cesarean section (n=1381), (2) vaginal delivery (n=632) and (3) emergency cesarean section (n=190). Outcome was assessed in univariate and logistic regression analyses. RESULTS: Prevalence of IVH was significantly higher in the vaginal delivery (VD) (26.6%) and emergency CS group (31.1%) as compared to planned CS (17.2%), respectively. In a logistic regression analysis including known risk factors for IVH, vaginal delivery (OR 1.725 [1.325-2.202], p≤0.001) and emergency cesarean section (OR 1.916 [1.338-2.746], p≤0.001) were independently associated with IVH risk. In the subgroup of infants >30 weeks of gestation prevalence for IVH was not significantly different in VD and planned CS (5.3% vs. 4.4%). CONCLUSIONS: Our observational data demonstrate that elective cesarean section is associated with a reduced risk of IVH in preterm infants <30 weeks gestational age when presenting with preterm labor.

Low-molecular weight heparin increases circulating sFlt-1 levels and enhances urinary elimination.

RATIONALE: Preeclampsia is a devastating medical complication of pregnancy which leads to maternal and fetal morbidity and mortality. While the etiology of preeclampsia is unclear, human and animal studies suggest that excessive circulating levels of soluble fms-like tyrosine-kinase-1 (sFlt-1), an alternatively spliced variant of VEGF-receptor1, contribute to the signs and symptoms of preeclampsia. Since sFlt-1 binds to heparin and heparan sulfate proteoglycans, we hypothesized that the anticoagulant heparin, which is often used in pregnancy, may interfere with the levels, distribution and elimination of sFlt-1 in vivo. OBJECTIVE: We systematically determined serum and urine levels of angiogenic factors in preeclamptic women before and after administration of low molecular weight heparin and further characterized the interaction with heparin in biochemical studies. METHODS AND RESULTS: Serum and urine samples were used to measure sFlt-1 levels before and after heparin administration. Serum levels of sFlt-1 increased by 25% after heparin administration in pregnant women. The magnitude of the increase in circulating sFlt-1 correlated with initial sFlt-1 serum levels. Urinary sFlt-1 levels were also elevated following heparin administration and levels of elimination were dependent on the underlying integrity of the glomerular filtration barrier. Biochemical binding studies employing cation exchange chromatography revealed that heparin bound sFlt-1 had decreased affinity to negatively charged surfaces when compared to sFlt-1 alone. CONCLUSION: Low molecular weight heparin administration increased circulating sFlt1 levels and enhanced renal elimination. We provide evidence that both effects may be due to heparin binding to sFlt1 and masking the positive charges on sFlt1 protein.

Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia.

BACKGROUND: Targeted therapies to stabilize the clinical manifestations and prolong pregnancy in preeclampsia do not exist. Soluble fms-like tyrosine kinase 1 (sFlt-1), an alternatively spliced variant of the vascular endothelial growth factor receptor 1, induces a preeclampsia-like phenotype in experimental models and circulates at elevated levels in human preeclampsia. Removing sFlt-1 may benefit women with very preterm (<32 weeks) preeclampsia. METHODS AND RESULTS: We first show that negatively charged dextran sulfate cellulose columns adsorb sFlt-1 in vitro. In 5 women with very preterm preeclampsia and elevated circulating sFlt-1 levels, we next demonstrate that a single dextran sulfate cellulose apheresis treatment reduces circulating sFlt-1 levels in a dose-dependent fashion. Finally, we performed multiple apheresis treatments in 3 additional women with very preterm (gestational age at admission 28, 30, and 27+4 weeks) preeclampsia and elevated circulating sFlt-1 levels. Dextran sulfate apheresis lowered circulating sFlt-1, reduced proteinuria, and stabilized blood pressure without apparent adverse events to mother and fetus. Pregnancy lasted for 15 and 19 days in women treated twice and 23 days in a woman treated 4 times. In each, there was evidence of fetal growth. CONCLUSIONS: This pilot study supports the hypothesis that extracorporeal apheresis can lower circulating sFlt-1 in very preterm preeclampsia. Further studies are warranted to determine whether this intervention safely and effectively prolongs pregnancy and improves maternal and fetal outcomes in this setting.

Angiogenesis inhibitors in the management of breast cancer.

PURPOSE OF REVIEW: An improved understanding of the important role of angiogenesis in tumor biology has led to development of different antiangiogenic therapies. This review highlights therapeutic agents from recent breast cancer trials showing the greatest potential for further clinical use in the near future. RECENT FINDINGS: Numerous clinical studies for several antiangiogenic agents have recently been conducted in breast cancer patients and different antiangiogenic approaches have demonstrated their antitumor activity. Bevacizumab is the most advanced agent, being the first approved angiogenesis inhibitor in metastatic breast cancer. The multikinase inhibitors sorafenib, sunitinib, and pazopanib have also shown promising early results and are further evaluated. To maximize efficacy and safety of antiangiogenic agents and help selecting patients suitable for this therapy, identification of predictive biomarkers is essential. SUMMARY: Novel antiangiogenic agents have produced positive data in clinical trials for breast cancer leading to the approval of bevacizumab for the first-line therapy of metastatic breast cancer. Other interesting substances such as multikinase inhibitors are currently being investigated. So far, angiogenesis inhibitors provide an additional therapeutic option for metastatic breast cancer; their role in early breast cancer as well as optimal patient selection will need further research.