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.

Shifting Trends in Obstetrics: An 18-year Analysis of Low-risk Births at a German University Hospital.

BACKGROUND/AIM: At the beginning of the 21st century, obstetric medicine took a turn from interventional to restrictive in low-risk birth. The present study examined the changes in peripartum management over the past 20 years at the Women's University Hospital Cologne. The attitudes of the becoming mother and physicians towards anesthesia, episiotomy, and vaginal-operative deliveries were compared and the factors influencing the duration of birth over the past 20 years were examined. PATIENTS AND METHODS: In this retrospective study, the low-risk singleton birth of 955 in 2000/2001 and 944 births in 2018 at the Women's University Hospital Cologne were analyzed. RESULTS: The age of women who tended to give birth has significantly increased at present compared to 20 years ago. In 2018, labor was induced significantly more often than in 2000/2001. The rate of vaginal operative deliveries has fluctuated between 15% and 20% in the last 20 years. Forceps are no longer used. The use of episiotomy has taken a fundamental turn in the last 20 years. Prophylactic episiotomy is not performed anymore, most vaginal operative deliveries take place without the episiotomy. The birth duration has been significantly shortened at present compared to 20 years ago. CONCLUSION: Pregnancy and childbirth over the last years are not considered as a disease, but as a natural course, and the trend of minimizing interventions in low-risk delivery has a positive effect on childbirth.

Maternal and Perinatal Outcome After Induction of Labor Versus Expectant Management in Low-risk Pregnancies Beyond Term.

BACKGROUND/AIM: Due to still controversial discussion regarding appropriate termination of low-risk singleton pregnancies beyond term, this retrospective study aimed to evaluate maternal and perinatal outcomes depending on gestational age and obstetric management. PATIENTS AND METHODS: This is a retrospective cohort analysis including 3.242 low-risk singleton deliveries at the Department of Obstetrics of the University Hospital of Cologne between 2017 and 2022. According to current national guidelines, the cohort was subdivided into three gestational groups, group 1: 40+0-40+6 weeks, group 2: 40+7-40+10 weeks and group 3>40+10 weeks. RESULTS: In our cohort, advanced gestational age was associated with higher rates of secondary caesarean sections, lower rates of spontaneous vaginal deliveries, higher rates of meconium-stained amniotic fluid and depressed neonates with APGAR < 7 after 5 min. Analyzing obstetric management, induction of labor significantly increased the rate of secondary sections and reduced the rate of spontaneous deliveries, while the percentage of assistant vaginal deliveries was independent from obstetric management and gestational age. Induction of labor also significantly enhanced the need for tocolytic subpartu and epidural anesthesia and caused higher rates of abnormalities in cardiotocography (CTG), which also resulted in more frequent fetal scalp blood testing; however, the rate of fetal acidosis was independent of both obstetric management and gestational age. CONCLUSION: Our study supports expectant management of low-risk pregnancies beyond term, as induction of labor increased the rate of secondary sections and did not improve perinatal outcome.

Extrauterine Placental Perfusion and Oxygenation in Infants With Very Low Birth Weight: A Randomized Clinical Trial.

Importance: An extrauterine placental perfusion (EPP) approach for physiological-based cord clamping (PBCC) may support infants with very low birth weight (VLBW) during transition without delaying measures of support. Objective: To test whether EPP in resuscitation of infants with VLBW results in higher hematocrit levels, better oxygenation, or improved infant outcomes compared with delayed cord clamping (DCC). Design, Setting, and Participants: This nonblinded, single-center randomized clinical trial was conducted at a tertiary care neonatal intensive care unit. Infants with a gestational age greater than 23 weeks and birth weight less than 1500 g born by cesarean delivery between May 2019 and June 2021 were included. Data were analyzed from October through December 2021. Intervention: Prior to cesarean delivery, participants were allocated to receive EPP or DCC. In the EPP group, infant and placenta, connected by an intact umbilical cord, were detached from the uterus and transferred to the resuscitation unit. Respiratory support was initiated while holding the placenta over the infant. The umbilical cord was clamped when infants showed regular spontaneous breathing, stable heart rates greater than 100 beats/min, and adequate oxygen saturations. In the DCC group, cords were clamped 30 to 60 seconds after birth before infants were transferred to the resuscitation unit, where respiratory support was started. Main Outcomes and Measure: The primary outcome was the mean hematocrit level in the first 24 hours after birth. Secondary prespecified outcome parameters comprised oxygenation during transition and short-term neonatal outcome. Results: Among 60 infants randomized and included, 1 infant was excluded after randomization; there were 29 infants in the EPP group (mean [SD] gestational age, 27 weeks 6 days [15.0 days]; 14 females [48.3%]) and 30 infants in the DCC group (mean [SD] gestational age, 28 weeks 1 day [17.1 days]; 17 females [56.7%]). The mean (SD) birth weight was 982.8 (276.6) g and 970.2 (323.0) g in the EPP and DCC group, respectively. Intention-to-treat analysis revealed no significant difference in mean hematocrit level (mean difference [MD], 2.1 percentage points; [95% CI, -2.2 to 6.4 percentage points]). During transition, infants in the EPP group had significantly higher peripheral oxygen saturation as measured by pulse oximetry (adjusted MD at 5 minutes, 15.3 percentage points [95% CI, 2.0 to 28.6 percentage points]) and regional cerebral oxygen saturation (adjusted MD at 5 minutes, 11.3 percentage points [95% CI, 2.0 to 20.6 percentage points]). Neonatal outcome parameters were similar in the 2 groups. Conclusions and Relevance: This study found that EPP resulted in similar hematocrit levels as DCC, with improved cerebral and peripheral oxygenation during transition. These findings suggest that EPP may be an alternative procedure for PBCC in infants with VLBW. Trial Registration: ClinicalTrials.gov Identifier: NCT03916159.

Impact of Advanced Maternal Age on Maternal and Neonatal Outcomes.

BACKGROUND/AIM: Due to better career opportunities for women and a shift in sex roles, as well as improved reproductive medicine, the age of women who conceive children is rising. A variety of maternal risks and complications that may occur during pregnancy or childbirth in women with advanced maternal age has been examined and reported controversial results. The present study focused on controversial and debatable conclusions regarding the impact of advanced maternal age on maternal and neonatal outcomes. PATIENTS AND METHODS: Data from 8,523 patients, who gave singleton birth at the Women's University Hospital Cologne between 2014 and 2018, were subdivided into two groups: those with maternal age ≥40 years and those <40, and analyzed. RESULTS: A significantly higher rate of C-section, more preterm births, more low birth weight, and higher incidence of retained placenta were observed in women older than or equal to 40. There were no significant differences regarding postpartum hemorrhage and fetal position. Younger patients tend to have more birth injuries and use more epidural administration. The evaluation of neonatal outcomes using fetal base-excess, birth pH, and Apgar score showed no significant clinical differences. CONCLUSION: More antenatal complications could be identified in patients with advanced maternal age. Nonetheless, the neonatal outcomes were comparable and no severe complications in women with advanced maternal age were observed. These findings are due to a well standardized management system for women with risk pregnancies. This encourages better monitoring and care of pregnant women with risk factors.

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.

Oral Misoprostol for the Induction of Labor: Comparison of Different Dosage Schemes With Respect to Maternal and Fetal Outcome in Patients Beyond 34 Weeks of Pregnancy.

BACKGROUND/AIM: Labor is induced in 1 out of 5 pregnancies. This is why we aimed to compare two different protocols of orally administered misoprostol for the induction of labor (IOL), with special regard to maternal and fetal outcome, delivery mode and duration. PATIENTS AND METHODS: One hundred and twenty four patients with a medical indication for IOL were divided into two groups: Group A (n=63), which initially received 50 µg misoprostol escalated to 100 and, subsequently, to 200 µg every 4 h with a daily maximum of 600µg, between 11/2007 and 01/2008; and Group B (n=61), which initially received 25 µg misoprostol followed by 100 µg every 4 h with a daily maximum of 300 µg, between 12/2009 and 04/2010. RESULTS: The mean administration-delivery interval was significantly lower in Group A (19.0 h) compared to Group B (27.1 h, p<0.05). Overall caesarean section rate, average birth weight, APGAR score, umbilical cord pH and meconium-stained fluid rates were similar between both groups. CONCLUSION: A higher dosage protocol of orally administered misoprostol significantly reduces the mean induction-delivery interval without increasing the risk for an adverse maternal or fetal outcome.

[Intrauterine fetal demise in extensive SARS-CoV-2-associated placental maternal vascular malperfusion in the setting of SARS-CoV-2 placentitis (severe acute respiratory syndrome coronavirus 2)]. / Intrauteriner Fruchttod bei massiver SARS-CoV-2-assoziierter ("severe acute respiratory syndrome coronavirus 2") plazentarer maternaler Malperfusion im Rahmen einer SARS-CoV-2-Plazentitis.

We report a case of a placenta with extensive maternal vascular malperfusion and chronic histiocytic intervillositis corresponding to SARS-CoV­2 placentitis in the context of fetal demise at 31 weeks of gestation. Placental swamp and PCR of the placental parenchyma, umbilical cord and amnion-chorion membrane showed SARS-CoV-2- and B­betacoronavirus-specific RNA. Maternal vascular malperfusion has been described in cases of SARS-CoV­2 infection; however, the manifested severity of this case in the setting of a severe SARS-CoV­2 placentitis is rare. It emphasizes the need of a maternal prophylactic anticoagulation.

CD34T+ Humanized Mouse Model to Study Mucosal HIV-1 Transmission and Prevention.

Humanized mice are critical for HIV-1 research, but humanized mice generated from cord blood are inefficient at mucosal HIV-1 transmission. Most mucosal HIV-1 transmission studies in mice require fetal tissue-engraftment, the use of which is highly restricted or prohibited. We present a fetal tissue-independent model called CD34T+ with enhanced human leukocyte levels in the blood and improved T cell homing to the gut-associated lymphoid tissue. CD34T+ mice are highly permissive to intra-rectal HIV-1 infection and also show normal env diversification in vivo despite high viral replication. Moreover, mucosal infection in CD34T+ mice can be prevented by infusion of broadly neutralizing antibodies. CD34T+ mice can be rapidly and easily generated using only cord blood cells and do not require any complicated surgical procedures for the humanization process. Therefore, CD34T+ mice provide a novel platform for mucosal HIV-1 transmission studies as well as rapid in vivo testing of novel prevention molecules against HIV-1.

Evaluating the Decision-to-Delivery Interval in Emergency Cesarean Sections and its Impact on Neonatal Outcome.

BACKGROUND/AIM: In Germany, performance of an emergency Cesarean section (ECS) is recommended within an interval of ≤20 min from decision to delivery (DDI). The aim of the study was to assess the duration of DDI in ECS as well as its impact on neonatal outcome. PATIENTS AND METHODS: Data from 437 patients at a single, tertiary care hospital were retrospectively analysed regarding influence on the duration of DDI. Subsequently the impact of DDI on neonatal outcome and incidence of adverse neonatal outcome was analysed. RESULTS: DDI of ECS performed outside core working hours was significantly prolonged (p<0.001). Shorter DDI showed a statistically worse arterial cord blood pH (p=0.001, r=0.162) and base excess (p=0.05; r=0.094). Duration of DDI had no significant impact on the incidence of adverse neonatal outcome (p=0.123). CONCLUSION: Awareness of influence on DDI might contribute to expediting DDI, but duration of DDI showed no impact on the incidence of adverse neonatal outcome. Data were not adequate to suggest a recommendation for DDI time standards.

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.

Doppler Indices and Notching Assessment of Uterine Artery Between the 19th and 22nd Week of Pregnancy in the Prediction of Pregnancy Outcome.

BACKGROUND/AIM: The aim of this study was to determine the value of Doppler indices and notching assessment of uterine artery between the 19th and 22nd week of gestation in the prediction of pregnancy outcome such as delivery mode, birth weight, Apgar score, afterbirth pH, fetal presentation, preeclampsia and fetal growth restriction in singleton pregnancy. PATIENTS AND METHODS: This is a retrospective cohort study of Doppler ultrasound of the uterine arteries at 19-22 week of gestation in 1,472 women with singleton pregnancies. RESULTS: Patients with bilateral high resistance-index (RI) and pulsatility-index (RI) or with the presence of a notch showed a significantly higher prevalence of small for gestational age (SGA) fetuses and intrauterine growth restriction (IUGR), low Apgar Scores at the 1st and the 5th min, high c-section rate, preterm birth, breech birth, placental insufficiency and placental abruption. The presence of a notch significantly increased the prevalence of severe preeclampsia, HELLP-syndrome and oligohydramnios. Also, patients with a bilateral uterine notching had a higher c-section rate along with higher prevalence of SGA and IUGR at screening time. CONCLUSION: Uterine artery Doppler waveform analysis as well as the assessment of the presence of a notch in the second trimester can be used as a screening method to identify women who will thereafter develop a severe adverse outcome.

Correlation of Cerebroplacental Ratio (CPR) With Adverse Perinatal Outcome in Singleton Pregnancies.

BACKGROUND/AIM: For many years clinical research has been concerned with doppler sonography as a non-invasive tool for intrauterine fetal status assessment. A new focus is now placed on the measurement of cerebroplacental index (CPR) as a predictor of fetal outcome. Our aim was to investigate the relationship between the cerebroplacental ratio (CPR), the delivery mode and the fetal outcome in singleton pregnancies. PATIENTS AND METHODS: A retrospective cohort study of pregnancies in which doppler sonography of middle cerebral artery (MCA) and umbilical artery (UA) was conducted up to 9 weeks before delivery took place. Patients with pathological (CPR≤1.0) and normal CPR (>1.0) were compared by umbilical cord pH, APGAR scores, birth weight, delivery week and delivery mode. RESULTS: A total of 2,270 singleton pregnancies were included. The APGAR score for 1, 5 and 10 minutes and the gestational age at delivery were significantly lower in the group of patients with pathological CPR (p<0.001). Overall, 50% of the cohort had a cesarean section, the difference between the groups was statistically significant (p<0.001), with a higher amount of cesareans in the group of patients with pathological CPR. The multiple regression analysis showed a significantly improved pH of delivery when cesarean section (p<0.001), female sex of fetus (p=0.013) and higher CPR (p=0.035) were present. CONCLUSION: The measurement of CPR is an important, non-invasive predictive parameter and leads to the identification of a risk collective even in the non-selected patient population and thus probably to a reduction of perinatal morbidity.

Comparison of Minimally Invasive Surgery and Abdominal Surgery Among Patients With Cervical Cancer.

BACKGROUND/AIM: The aim of this study was to evaluate the difference in clinical outcomes in patients with histologically confirmed cervical cancer of the uterus treated with either laparoscopy or laparotomy with curative intent between 2011 and 2017 at the Department of Gynecology and Obstetrics of University Hospital Cologne. MATERIALS AND METHODS: This retrospective analysis included all patients who received surgical treatment with curative intent between January 2011 and December 2017 for stages IA1 to IIB cervical carcinoma. Patients receiving primary or secondary surgery after neoadjuvant chemotherapy were also included. RESULTS: In total, 75 patients were included, of whom 34 patients underwent minimally invasive surgery and 41 underwent open surgery. Neoadjuvant chemotherapy was performed in 10 patients in the minimally-invasive group and in 14 patients in the laparotomy group. Statistically, no significant difference in overall survival (OS) was observed in both groups. Disease-free survival showed a significant difference in favor of the minimally invasive group. CONCLUSION: Minimally invasive surgical therapy for cervical cancer improves disease-free-survival. Prospective trials are needed to further confirm these results.

A multi-centre phase IIa clinical study of predictive testing for preeclampsia: improved pregnancy outcomes via early detection (IMPROvED).

BACKGROUND: 5% of first time pregnancies are complicated by pre-eclampsia, the leading cause of maternal death in Europe. No clinically useful screening test exists; consequentially clinicians are unable to offer targeted surveillance or preventative strategies. IMPROvED Consortium members have pioneered a personalised medicine approach to identifying blood-borne biomarkers through recent technological advancements, involving mapping of the blood metabolome and proteome. The key objective is to develop a sensitive, specific, high-throughput and economically viable early pregnancy screening test for pre-eclampsia. METHODS/DESIGN: We report the design of a multicentre, phase IIa clinical study aiming to recruit 5000 low risk primiparous women to assess and refine innovative prototype tests based on emerging metabolomic and proteomic technologies. Participation involves maternal phlebotomy at 15 and 20 weeks' gestation, with optional testing and biobanking at 11 and 34 weeks. Blood samples will be analysed using two innovative, proprietary prototype platforms; one metabolomic based and one proteomic based, both of which outperform current biomarker based screening tests at comparable gestations. Analytical and clinical data will be collated and analysed via the Copenhagen Trials Unit. DISCUSSION: The IMPROvED study is expected to refine proteomic and metabolomic panels, combined with clinical parameters, and evaluate clinical applicability as an early pregnancy predictive test for pre-eclampsia. If 'at risk' patients can be identified, this will allow stratified care with personalised fetal and maternal surveillance, early diagnosis, timely intervention, and significant health economic savings. The IMPROvED biobank will be accessible to the European scientific community for high quality research into the cause and prevention of adverse pregnancy outcome. TRIAL REGISTRATION: Trial registration number NCT01891240The IMPROvED project is funded by the seventh framework programme for Research and Technological development of the EU. http://www.fp7-improved.eu/