Is There a Cumulative Effect for Congenital Heart Defects in Monochorionic Twins after Assisted Reproduction? - A Retrospective Analysis at a Tertiary Referral Center.

Introduction: The aim of our study was to compare maternal, chorionicity and neonatal complications in monochorionic (MC) twins between spontaneously conceived (SC) and assisted reproductive technologies (ART) pregnancies. Material and Methods: This was a retrospective cohort study between January 2010 to December 2019 at a tertiary referral University center. All consecutive pregnancies with MC twins that delivered at our University hospital were included. Maternal, chorionicity and neonatal complications were recorded and compared between SC and ART pregnancies. Results: 393 MC pregnancies were included for final analysis, including 353 (89.8%) SC and 40 (10.2%) pregnancies conceived after ART. Hypothyroidism was the only maternal condition seen significantly more often in ART pregnancies (35.0% vs 12.5%, p = 0.001). There were no significant differences in chorionicity complications, such as twin-twin transfusion syndrome, selective fetal growth restriction and twin anemia-polycythemia sequence (40.0% in ART pregnancies vs 31.6% in SC pregnancies, p = 0.291). At least one congenital anomaly in one twin was seen significantly more often in ART pregnancies (18.8% vs 8.1%, p = 0.004), especially congenital heart defects (16.3% vs 6.2%, p = 0.005). There were no other significant differences in neonatal outcomes between both groups, however, there were non-significant trends in gestational age at delivery (34 weeks in ART pregnancies vs 35 weeks, p = 0.078) and birthweight (1951 g ± 747 in ART pregnancies vs 2143 g ± 579, p = 0.066). Conclusion: This is the largest cohort study to date comparing maternal, chorionicity and neonatal complications between MC twin pregnancies after ART and after SC. Hypothyroidism was the only maternal condition occurring more frequently in pregnancies conceived after ART. There were no significant differences in chorionicity complications, in contrast to previously reported studies. While MC twins and ART pregnancies per se are known to be at risk for congenital heart defects, there seems to be a cumulative effect in MC pregnancies conceived after ART.

Fetal lung growth predicts the risk for early-life respiratory infections and childhood asthma.

BACKGROUND: Early-life respiratory infections and asthma are major health burdens during childhood. Markers predicting an increased risk for early-life respiratory diseases are sparse. Here, we identified the predictive value of ultrasound-monitored fetal lung growth for the risk of early-life respiratory infections and asthma. METHODS: Fetal lung size was serially assessed at standardized time points by transabdominal ultrasound in pregnant women participating in a pregnancy cohort. Correlations between fetal lung growth and respiratory infections in infancy or early-onset asthma at five years were examined. Machine-learning models relying on extreme gradient boosting regressor or classifier algorithms were developed to predict respiratory infection or asthma risk based on fetal lung growth. For model development and validation, study participants were randomly divided into a training and a testing group, respectively, by the employed algorithm. RESULTS: Enhanced fetal lung growth throughout pregnancy predicted a lower early-life respiratory infection risk. Male sex was associated with a higher risk for respiratory infections in infancy. Fetal lung growth could also predict the risk of asthma at five years of age. We designed three machine-learning models to predict the risk and number of infections in infancy as well as the risk of early-onset asthma. The models' R2 values were 0.92, 0.90 and 0.93, respectively, underscoring a high accuracy and agreement between the actual and predicted values. Influential variables included known risk factors and novel predictors, such as ultrasound-monitored fetal lung growth. CONCLUSION: Sonographic monitoring of fetal lung growth allows to predict the risk for early-life respiratory infections and asthma.

High-Sensitivity Cardiac Troponin I Enhances Preeclampsia Prediction Beyond Maternal Factors and the sFlt-1/PlGF Ratio.

BACKGROUND: Preeclampsia shares numerous risk factors with cardiovascular diseases. Here, we aimed to assess the potential utility of high-sensitivity cardiac troponin I (hs-cTnI) values during pregnancy in predicting preeclampsia occurrence. METHODS: This study measured hs-cTnI levels in 3721 blood samples of 2245 pregnant women from 4 international, prospective cohorts. Three analytical approaches were used: (1) a cross-sectional analysis of all women using a single blood sample, (2) a longitudinal analysis of hs-cTnI trajectories in women with multiple samples, and (3) analyses of prediction models incorporating hs-cTnI, maternal factors, and the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio. RESULTS: Women with hs-cTnI levels in the upper quarter had higher odds ratios for preeclampsia occurrence compared with women with levels in the lower quarter. Associations were driven by preterm preeclampsia (odds ratio, 5.78 [95% CI, 2.73-12.26]) and remained significant when using hs-cTnI as a continuous variable adjusted for confounders. Between-trimester hs-cTnI trajectories were independent of subsequent preeclampsia occurrence. A prediction model incorporating a practical hs-cTnI level of detection cutoff (≥1.9 pg/mL) alongside maternal factors provided comparable performance with the sFlt-1/PlGF ratio. A comprehensive model including sFlt-1/PlGF, maternal factors, and hs-cTnI provided added value (cross-validated area under the receiver operator characteristic, 0.78 [95% CI, 0.73-0.82]) above the sFlt-1/PlGF ratio alone (cross-validated area under the receiver operator characteristic, 0.70 [95% CI, 0.65-0.76]; P=0.027). As assessed by likelihood ratio tests, the addition of hs-cTnI to each prediction model significantly improved the respective prediction model not incorporating hs-cTnI, particularly for preterm preeclampsia. Net reclassification improvement analyses indicated that incorporating hs-cTnI improved risk prediction predominantly by correctly reclassifying women with subsequent preeclampsia occurrence. CONCLUSIONS: These exploratory findings uncover a potential role for hs-cTnI as a complementary biomarker in the prediction of preeclampsia. After validation in prospective studies, hs-cTnI, alongside maternal factors, may either be considered as a substitute for angiogenic biomarkers in health care systems where they are sparce or unavailable, or as an enhancement to established prediction models using angiogenic markers.

The Arabin cervical pessary for the prevention of preterm birth in twin-to-twin transfusion syndrome treated by fetoscopic laser coagulation: a multicenter randomized controlled trial.

BACKGROUND: Miscarriage and preterm birth are leading causes of loss and disability in monochorionic twins after laser treatment of twin-twin transfusion syndrome. OBJECTIVE: This study aimed to investigate the use of cervical pessary to reduce preterm birth before 32 weeks of gestation in monochorionic diamniotic twin pregnancies after fetal surgery for twin-twin transfusion syndrome. STUDY DESIGN: In this open-label multicenter randomized trial, pregnant women carrying monochorionic diamniotic twins requiring fetoscopic laser coagulation for twin-twin transfusion syndrome were randomly assigned in a 1:1 ratio to pessary placement or conservative management. The primary outcome was birth before 32 weeks of gestation. The secondary outcomes were birth before 28, 30, 34, or 37 weeks of gestation; preterm premature rupture of membranes; fetal and neonatal survival; and a composite of maternal and neonatal complications. The estimated sample size was 364 patients, with 182 cases in each arm of the study. The analysis was performed according to the intention-to-treat principle. Moreover, 2 interim analyses were planned. RESULTS: The trial was stopped prematurely after the first planned interim analysis for futility. Overall, 137 women were included in the analysis, 67 in the pessary group and 70 in the conservative management group. Preterm birth before 32 weeks of gestation occurred in 27 of 67 women (40.3%) in the pessary group and in 25 of 70 women (35.7%) in the conservative management group (adjusted odds ratio, 1.19; 95% confidence interval, 0.58-2.47; P=.63). No differences between groups was observed in the rate of deliveries before 28, 30, 34, and 37 weeks of gestation. Overall survival to delivery was 91.2% (125/137) for at least 1 twin, and 70.8% (97/137) for both twins, with no difference between groups. Neonatal survival at 30 days was 76.5% (208/272). There was no difference between the groups in maternal or neonatal morbidity. CONCLUSION: In monochorionic diamniotic twin pregnancies requiring fetal therapy for twin-twin transfusion syndrome, routine use of cervical pessary did not reduce the rate of preterm birth before 32 weeks of gestation.

Maternal PlGF and umbilical Dopplers predict pregnancy outcomes at diagnosis of early-onset fetal growth restriction.

BACKGROUNDSevere, early-onset fetal growth restriction (FGR) causes significant fetal and neonatal mortality and morbidity. Predicting the outcome of affected pregnancies at the time of diagnosis is difficult, thus preventing accurate patient counseling. We investigated the use of maternal serum protein and ultrasound measurements at diagnosis to predict fetal or neonatal death and 3 secondary outcomes: fetal death or delivery at or before 28+0 weeks, development of abnormal umbilical artery (UmA) Doppler velocimetry, and slow fetal growth.METHODSWomen with singleton pregnancies (n = 142, estimated fetal weights [EFWs] below the third centile, less than 600 g, 20+0 to 26+6 weeks of gestation, no known chromosomal, genetic, or major structural abnormalities) were recruited from 4 European centers. Maternal serum from the discovery set (n = 63) was analyzed for 7 proteins linked to angiogenesis, 90 additional proteins associated with cardiovascular disease, and 5 proteins identified through pooled liquid chromatography and tandem mass spectrometry. Patient and clinician stakeholder priorities were used to select models tested in the validation set (n = 60), with final models calculated from combined data.RESULTSThe most discriminative model for fetal or neonatal death included the EFW z score (Hadlock 3 formula/Marsal chart), gestational age, and UmA Doppler category (AUC, 0.91; 95% CI, 0.86-0.97) but was less well calibrated than the model containing only the EFW z score (Hadlock 3/Marsal). The most discriminative model for fetal death or delivery at or before 28+0 weeks included maternal serum placental growth factor (PlGF) concentration and UmA Doppler category (AUC, 0.89; 95% CI, 0.83-0.94).CONCLUSIONUltrasound measurements and maternal serum PlGF concentration at diagnosis of severe, early-onset FGR predicted pregnancy outcomes of importance to patients and clinicians.TRIAL REGISTRATIONClinicalTrials.gov NCT02097667.FUNDINGThe European Union, Rosetrees Trust, Mitchell Charitable Trust.

Increased late preterm birth risk and altered uterine blood flow upon exposure to heat stress.

BACKGROUND: Climate change, in particular the exposure to heat, impacts on human health and can trigger diseases. Pregnant people are considered a vulnerable group given the physiological changes during pregnancy and the potentially long-lasting consequences for the offspring. Evidence published to date on higher risk of pregnancy complications upon heat stress exposure are from geographical areas with high ambient temperatures. Studies from geographic regions with temperate climates are sparse; however, these areas are critical since individuals may be less equipped to adapt to heat stress. This study addresses a significant gap in knowledge due to the temperature increase documented globally. METHODS: Birth data of singleton pregnancies (n = 42,905) from a tertiary care centre in Hamburg, Germany, between 1999 and 2021 were retrospectively obtained and matched with climate data from the warmer season (March to September) provided by the adjacent federal meteorological station of the German National Meteorological Service to calculate the relative risk of heat-associated preterm birth. Heat events were defined by ascending temperature percentiles in combination with humidity over exposure periods of up to 5 days. Further, ultrasound data documented in a longitudinal prospective pregnancy cohort study (n = 612) since 2012 were used to identify pathophysiological causes of heat-induced preterm birth. FINDINGS: Both extreme heat and prolonged periods of heat exposure increased the relative risk of preterm birth (RR: 1.59; 95% CI: 1.01-2.43; p = 0.045; RR: 1.20; 95% CI: 1.02-1.40; p = 0.025). We identified a critical period of heat exposure during gestational ages 34-37 weeks that resulted in increased risk of late preterm birth (RR: 1.67; 95% CI: 1.14-1.43; p = 0.009). Pregnancies with a female fetus were more prone to heat stress-associated preterm birth. We found heat exposure was associated with altered vascular resistance within the uterine artery. INTERPRETATION: Heat stress caused by high ambient temperatures increases the risk of preterm birth in a geographical region with temperate climate. Prenatal routine care should be revised in such regions to provide active surveillance for women at risk. FUNDING: Found in acknowledgements.

Anti-SARS-CoV-2 antibodies in breast milk during lactation after infection or vaccination: A cohort study.

Breast milk is a pivotal source to provide passive immunity in newborns over the first few months of life. Very little is known about the antibody transfer levels over the period of breastfeeding. We conducted a prospective study in which we evaluated concentrations of anti-SARS-CoV-2 Spike IgA and RBD IgG/M/A antibodies in maternal serum and breast milk over a duration of up to 6 months after delivery. We compared antibody levels in women with confirmed COVID-19 infection during pregnancy (n = 16) to women with prenatal SARS-CoV-2 vaccination (n = 5). Among the recovered women, n = 7 (44%) had been vaccinated during the lactation period as well. We observed intraindividual moderate positive correlations between antibody levels in maternal serum and breast milk (r = 0.73, p-value<0.0001), whereupon the median levels were generally higher in serum. Anti-RBD IgA/M/G transfer into breast milk was significantly higher in women recovered from COVID-19 and vaccinated during lactation (35.15 AU/ml; IQR 21.96-66.89 AU/ml) compared to the nonvaccinated recovered group (1.26 AU/ml; IQR 0.49-3.81 AU/ml), as well as in the vaccinated only group (4.52 AU/ml; IQR 3.19-6.23 AU/ml). Notably, the antibody level in breast milk post SARS-CoV-2 infection sharply increased following a single dose of vaccine. Breast milk antibodies in all groups showed neutralization capacities against an early pandemic SARS-CoV-2 isolate (HH-1) and moreover, also against the Omicron variant, although with lower antibody titer. Our findings highlight the importance of booster vaccinations especially after SARS-CoV-2 infection in pregnancy in order to optimize protection in mother and newborn.

Behavioral Inhibition in the Second Year of Life Is Predicted by Prenatal Maternal Anxiety, Overprotective Parenting and Infant Temperament in Early Infancy.

Background: Behavioral inhibition, characterized by shyness, fear and avoidance of novel stimuli, has been linked with internalizing personality traits in childhood, adolescence and early adulthood, and particularly later social anxiety disorder. Little is known about the relevance of potential prenatal precursors and early predictors for the development of inhibited behavior, such as infant vulnerability and family risk factors like parental anxiety and overprotection. Pregnancy-related anxiety has been associated with both infant temperament and maternal overprotective parenting. Thus, the aim of this study was investigating the predictive relevance of prenatal pregnancy-related anxiety for behavioral inhibition in toddlerhood, by considering the mediating role of maternal overprotection and infant distress to novelty. Materials and Methods: As part of a longitudinal pregnancy cohort, behavioral inhibition at 24 months postpartum was assessed in N = 170 mother-child pairs. Maternal pregnancy-related anxiety was examined in the third trimester of pregnancy, and maternal overprotection and infant distress to novelty at 12 months postpartum. Results: Mediation analysis with two parallel mediators showed that the significant direct effect of pregnancy-related anxiety on child behavioral inhibition was fully mediated by infant distress to novelty p < 0.001 and maternal overprotection (p < 0.05). The included variables explained 26% of variance in behavioral inhibition. A subsequent explorative mediation analysis with serial mediators further showed a significant positive association between distress to novelty and maternal overprotective parenting (p < 0.05). Conclusion: Results indicate a predictive relevance of both infant and maternal factors for the development of behavioral inhibition in toddlerhood. Mothers who perceived more pregnancy-related anxiety showed more overprotective parenting and had infants with more distress to novelty. Further, mothers being more overprotective reported their child to be more inhibited in toddlerhood. Our findings also indicate the stability of reported infant distress to novelty as one aspect of later behavioral inhibition. Addressing specific forms of parental anxiety from pregnancy on and in interaction with child-related variables seems to be a promising approach for future studies and clinical interventions.

Practice patterns amongst fetal centers performing intrauterine transfusions (PACT): An international survey study.

OBJECTIVES: Fetal anemia secondary to incompatibility between maternal-fetal blood types can result in hydrops and demise. Intrauterine transfusions have improved survival in experience centers. Our objective was to determine the practice patterns amongst fetal centers. STUDY DESIGN: Thirteen fetal centers across the world were surveyed. Results from all participating centers were recorded, analyzed, and presented as ratios. Questions on the survey were related to experience of the physician, preferred methods of transfusion, fetal surveillance, and timing of delivery. RESULTS: Differences amongst centers were as follows: 54% of the centers performed transfusions in operating room, the remaining did them in a clinic room or close to the operating room; 31% did not use maternal anesthesia, 31% used oral or intravenous sedation and 38% used a combination of local with oral or intravenous sedation. The similarities include: 84% performed intravenous transfusions, while 2 centers reported intraperitoneal and intracardiac transfusions were performed for very early cases; 85% of centers performed the last transfusion at 34-35 weeks and 77% electively delivered their patients at 37 weeks. CONCLUSION: Method of transfusion and delivery timing was similar in most centers; however, differences were seen in location of procedure, anesthetic coverage, and surveillance. Further assessment is needed to determine if these differences in practice have any potential neonatal effects.

Twin-to-twin transfusion syndrome: Controversies in the diagnosis and management.

In twin-to-twin transfusion syndrome (TTTS) communicating placental vessels on the chorionic plate between the donor and recipient twins are responsible for the chronic imbalance of blood flow. Evidence demonstrates that fetoscopic laser ablation is superior to serial amnioreductions in terms of survival and neurological outcome for stages II-IV TTTS. However, the optimal management of stage I TTTS remains poorly understood. It is well established that all chorionic plate anastomoses should be closed by laser ablation. Compared to the selective laser method, the Solomon technique yields a significant reduction of recurrent TTTS and post-laser twin anemia polycythemia sequence (TAPS). Over the past 25 years, survival rates after fetoscopic laser surgery have significantly increased. High volume centers report up to 70% double survival and at least one survivor in >90% cases. In this review, we discuss the controversies in the diagnosis and management of TTTS, especially, the optimal management in stage I cases, very early or late diagnosis, and the optimal laser technique. Furthermore, we will discuss a stage-related outcome after laser surgery and examine whether it is necessary at all to distinguish between stages I and II. Finally, the optimal timing as well as mode of delivery after TTTS laser treatment will be discussed.

Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise: the TRUFFLE 2 randomised trial protocol.

INTRODUCTION: Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years. METHODS AND ANALYSIS: Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is <10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire. ETHICS AND DISSEMINATION: The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy. TRIAL REGISTRATION NUMBER: Main sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical & Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200.

Estimation of Optimal Nasotracheal Tube Insertion Depth in Neonates Based on Fetal Biometric Measurements.

BACKGROUND: Current recommendations for neonatal endotracheal tube (ETT) insertion depths require the knowledge of anthropometric measurements, which are not immediately available in the delivery room setting. OBJECTIVE: This study aimed to develop recommendations based on prenatally available fetal biometric measurements. METHODS: In this retrospective study, the optimal ETT depths for nasotracheal insertion were correlated with fetal demographic and biometric data. Using linear regression analysis, diagrams with best-fit lines and tables for the recommendation of ETT insertion depth based on the prenatally available data were generated. RESULTS: We analyzed optimal nasotracheal ETT insertion depth in 98 neonates (gestational age range: 23.7-42.0 weeks). Linear regression analysis revealed high correlations between fetal measurements and the optimal ETT insertion depth (R2 = 0.712-0.837). CONCLUSION: We provide recommendations for neonatal nasotracheal ETT insertion depths based on prenatally available data with the potential to facilitate rapid and accurate intubation of neonates.

[Recommendations for SARS-CoV-2/COVID-19 during Pregnancy, Birth and Childbed - Update November 2021 (Short Version)]. / Empfehlungen zu SARS-CoV-2/COVID-19 in Schwangerschaft, Geburt und Wochenbett ­ Update November 2021 (Kurzfassung).

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).

Clinical Opinion: The diagnosis and management of suspected fetal growth restriction: an evidence-based approach.

This study reviewed the literature about the diagnosis, antepartum surveillance, and time of delivery of fetuses suspected to be small for gestational age or growth restricted. Several guidelines have been issued by major professional organizations, including the International Society of Ultrasound in Obstetrics and Gynecology and the Society for Maternal-Fetal Medicine. The differences in recommendations, in particular about Doppler velocimetry of the ductus venosus and middle cerebral artery, have created confusion among clinicians, and this review has intended to clarify and highlight the available evidence that is pertinent to clinical management. A fetus who is small for gestational age is frequently defined as one with an estimated fetal weight of <10th percentile. This condition has been considered syndromic and has been frequently attributed to fetal growth restriction, a constitutionally small fetus, congenital infections, chromosomal abnormalities, or genetic conditions. Small for gestational age is not synonymous with fetal growth restriction, which is defined by deceleration of fetal growth determined by a change in fetal growth velocity. An abnormal umbilical artery Doppler pulsatility index reflects an increased impedance to flow in the umbilical circulation and is considered to be an indicator of placental disease. The combined finding of an estimated fetal weight of <10th percentile and abnormal umbilical artery Doppler velocimetry has been widely accepted as indicative of fetal growth restriction. Clinical studies have shown that the gestational age at diagnosis can be used to subclassify suspected fetal growth restriction into early and late, depending on whether the condition is diagnosed before or after 32 weeks of gestation. The early type is associated with umbilical artery Doppler abnormalities, whereas the late type is often associated with a low pulsatility index in the middle cerebral artery. A large randomized clinical trial indicated that in the context of early suspected fetal growth restriction, the combination of computerized cardiotocography and fetal ductus venosus Doppler improves outcomes, such that 95% of surviving infants have a normal neurodevelopmental outcome at 2 years of age. A low middle cerebral artery pulsatility index is associated with an adverse perinatal outcome in late fetal growth restriction; however, there is no evidence supporting its use to determine the time of delivery. Nonetheless, an abnormality in middle cerebral artery Doppler could be valuable to increase the surveillance of the fetus at risk. We propose that fetal size, growth rate, uteroplacental Doppler indices, cardiotocography, and maternal conditions (ie, hypertension) according to gestational age are important factors in optimizing the outcome of suspected fetal growth restriction.

Infant immunity against viral infections is advanced by the placenta-dependent vertical transfer of maternal antibodies.

Neonatal passive immunity, derived from transplacental transfer of IgG antibodies from mother to fetus during pregnancy, can mitigate the risk for severe infections in the early postnatal period. Understanding the placenta as the gateway organ in this process, we aimed to evaluate the influence of specific factors modulating the transplacental IgG transfer rate (TPTR) in 141 mother/neonate pairs. We further evaluated the potential health advantage elicited by maternal IgG with regard to respiratory tract infections during infancy and early childhood. Data and biological samples collected within the prospective longitudinal pregnancy cohort study PRINCE (Prenatal Identification of Children's Health) were used for these analyses. We tested IgG antibody levels against seven pathogens (measles, mumps, rubella, tetanus, diphtheria, pertussis and influenza A) by ELISA and detected seropositivity in 72.6-100% of pregnant women and in 76.3-100% of their neonates, respectively. Cord blood IgG levels reached 137-160% of levels detected in maternal blood. Strikingly, assessment of TPTR for all seven antigens highlighted that TPTR strongly depends on individual placental function. Subsequent in-depth analysis of anti-influenza A IgG revealed a link between cord blood levels and uterine perfusion, measured by uterine artery pulsatility index. Moreover, higher cord blood anti-influenza A IgG levels were associated with a significantly reduced risk for respiratory tract infections during the first six months of life, indicating a high degree of cross-reactivity and possible pathogen-agnostic effects of anti-influenza A antibodies. Taken together, our data suggest that early life immunity is modulated by maternal IgG levels and individual placental features such as perfusion. Vaccination of pregnant women, i.e. against influenza, can increase neonatal antibody levels and hereby protect against early life respiratory infections. Consequently, specific guidelines should evolve in order to safeguard neonates born from pregnancies with poorer placental capacity for vertical transfer of protective antibodies.

[Recommendations for SARS-CoV-2/COVID-19 during Pregnancy, Birth and Childbed - Update November 2021 (Long Version)]. / Empfehlungen zu SARS-CoV-2/COVID-19 in Schwangerschaft, Geburt und Wochenbett ­ Update November 2021 (Langfassung).

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).

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

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

Inefficient Placental Virus Replication and Absence of Neonatal Cell-Specific Immunity Upon Sars-CoV-2 Infection During Pregnancy.

Pregnant women have been carefully observed during the COVID-19 pandemic, as the pregnancy-specific immune adaptation is known to increase the risk for infections. Recent evidence indicates that even though most pregnant have a mild or asymptomatic course, a severe course of COVID-19 and a higher risk of progression to diseases have also been described, along with a heightened risk for pregnancy complications. Yet, vertical transmission of the virus is rare and the possibility of placental SARS-CoV-2 infection as a prerequisite for vertical transmission requires further studies. We here assessed the severity of COVID-19 and onset of neonatal infections in an observational study of women infected with SARS-CoV-2 during pregnancy. Our placental analyses showed a paucity of SARS-CoV-2 viral expression ex vivo in term placentae under acute infection. No viral placental expression was detectable in convalescent pregnant women. Inoculation of placental explants generated from placentas of non-infected women at birth with SARS-CoV-2 in vitro revealed inefficient SARS-CoV-2 replication in different types of placental tissues, which provides a rationale for the low ex vivo viral expression. We further detected specific SARS-CoV-2 T cell responses in pregnant women within a few days upon infection, which was undetectable in cord blood. Our present findings confirm that vertical transmission of SARS-CoV-2 is rare, likely due to the inefficient virus replication in placental tissues. Despite the predominantly benign course of infection in most mothers and negligible risk of vertical transmission, continuous vigilance on the consequences of COVID-19 during pregnancy is required, since the maternal immune activation in response to the SARS-CoV2 infection may have long-term consequences for children's health.

[Effects of Obstetric Analgesia with Systemic Opioids on the Newborn - A Review]. / Auswirkungen geburtshilflicher Analgesie mit systemischen Opioiden auf das Neugeborene ­ eine Übersichtsarbeit.

INTRODUCTION: Three-quarters of all women receive analgesia during labor. There are regional and systemic analgesia procedures available. In this review, we investigate the impact of obstetric analgesia using systemic opioids on neonatal outcomes. METHODS: We searched the PubMed and Cochrane Library databases using the following search terms: "meptazinol", "meptide", "analgesia", "painkiller", "pain reliever", "obstetrics", "labor", "labour", "delivery", "neonate", "newborn", "child", "baby", "infant", "fetus", "fetal", "opioid" and "opiate" as well as performed an additional MeSH Terms search in PubMed. RESULTS: Of 355 potentially relevant studies, we included 23 studies in this review. The studies varied widely in quality, sample size, and outcome criteria. Neonatal outcome was often only a secondary endpoint. Rarely were significant differences related to neonatal outcome reported between the different systemic opioids or compared with control groups. Twelve studies compared neonatal APGAR scores between treatment groups, with ten (83%) of these studies showing no differences. DISCUSSION/OUTLOOK: In summary, we assess the evidence as limited and ambiguous as to whether systemic obstetric opioid therapy negatively affects the newborn. Studies regarding the long-term outcome of the newborns are lacking. A statement regarding the necessity of postnatal monitoring of newborns after maternal obstetric opioid therapy cannot be concluded. Further studies, ideally with a prospective study design and control group, should be considered.