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BackgroundPreterm birth and fetal growth restriction are the main determinants of perinatal mortality. In the absence of therapeutic interventions, management is restricted to the observation of fetal growth and fetoplacental perfusion to determine the timing of delivery. Fetal circulatory redistribution, known as “brain sparing,” represents a sign of fetal hypoxia and has been implemented in algorithms for when to deliver. In the absence of any other option, the nitric oxide donor pentaerythrityl tetranitrate (PETN), which has been shown to improve fetoplacental flow and reduce preterm birth in high-risk patients, is offered to patients as a personal therapy attempt. The aim of this study was to evaluate determinants related to pregnancy, including PETN intake during pregnancy, on immediate neonatal outcomes in a cohort of growth-restricted infants born before 32 completed weeks of gestation.MethodsWe performed a retrospective cohort study of 98 infants born with a birth weight below the 10th percentile before 32 completed weeks of gestation at our tertiary care center between 2010 and 2019. PETN was offered to all mothers with a history of severe adverse pregnancy outcomes who were at high risk of developing fetal growth restriction as an individual therapy attempt.ResultsThe mean gestational age at birth was 188.5 days, and the mean birth weight was 549 g, corresponding to a median percentile of three. In 73 (79.3%) cases, brain sparing occurred during pregnancy. A total of 22 (22.4%) neonates were stillborn, 20 died postnatally, and 37.3% developed a severe complication. Multivariable analysis revealed birth weight percentile, gestational age at birth, and gestational age when brain sparing first occurred to be robust predictors of mortality or severe neonatal morbidity. In 39 neonates of mothers taking PETN, this impact of brain sparing was not observed.ConclusionOur study is the first to demonstrate a significant association between the early occurrence of brain-sparing and severe neonatal outcomes in a cohort of very early preterm, growth-restricted newborns. The data suggest that PETN intake may ameliorate the effect of brain sparing in the affected neonates.

Introduction Pregnancy is a known independent risk factor for a severe course of COVID-19. The relationship of SARS-CoV-2 infection and gestational diabetes mellitus (GDM) on neonatal outcomes is unclear. Our aim was to determine if SARS-CoV-2 infection represents an independent risk factor for adverse perinatal outcomes in pregnancy with GDM.Research design and methods We compared data from two German registries including pregnant women with GDM, established during the SARS-CoV-2 pandemic (COVID-19-Related Obstetric and Neonatal Outcome Study (CRONOS), a multicenter prospective observational study) and already existing before the pandemic (German registry of pregnant women with GDM; GestDiab). In total, 409 participants with GDM and SARS-CoV-2 infection and 4598 participants with GDM, registered 2018–2019, were eligible for analyses. The primary fetal and neonatal outcomes were defined as: (1) combined: admission to neonatal intensive care unit, stillbirth, and/or neonatal death, and (2) preterm birth before 37+0 weeks of gestation. Large and small for gestational age, maternal insulin therapy, birth weight >4500 g and cesarean delivery were considered as secondary outcomes.Results Women with SARS-CoV-2 infection were younger (32 vs 33 years) and had a higher median body mass index (28 vs 27 kg/m²). In CRONOS, more neonates developed the primary outcome (adjusted OR (aOR) 1.48, 95% CI 1.11 to 1.97) and were born preterm (aOR 1.50, 95% CI 1.07 to 2.10). Fasting glucose was higher in women in CRONOS versus GestDiab (5.4 vs 5.3 mmol/L) considering each 0.1 mmol/L increase was independently associated with a 5% higher risk of preterm birth among women in CRONOS only (aOR 1.05, 95% CI 1.01 to 1.09).Conclusions GDM with SARS-CoV-2 infection in pregnancy is associated with an increased risk of adverse fetal and neonatal outcomes as compared with GDM without SARS-CoV-2 infection.

Placenta accreta spectrum (PAS) is one of the major causes of maternal morbidity and mortality worldwide with increasing incidence. PAS refers to a group of pathological conditions ranging from the abnormal attachment of the placenta to the uterus wall to its perforation and, in extreme cases, invasion into surrounding organs. Among them, placenta accreta is characterized by a direct adhesion of the villi to the myometrium without invasion and remains the most common diagnosis of PAS. Here, we identify the potential regulatory miRNA and target networks contributing to placenta accreta development. Using small RNA-Seq followed by RT-PCR confirmation, altered miRNA expression, including that of members of placenta-specific miRNA clusters (e.g., C19MC and C14MC), was identified in placenta accreta samples compared to normal placental tissues. In situ hybridization (ISH) revealed expression of altered miRNAs mostly in trophoblast but also in endothelial cells and this profile was similar among all evaluated degrees of PAS. Kyoto encyclopedia of genes and genomes (KEGG) analyses showed enriched pathways dysregulated in PAS associated with cell cycle regulation, inflammation, and invasion. mRNAs of genes associated with cell cycle and inflammation were downregulated in PAS. At the protein level, NF-κB was upregulated while PTEN was downregulated in placenta accreta tissue. The identified miRNAs and their targets are associated with signaling pathways relevant to controlling trophoblast function. Therefore, this study provides miRNA:mRNA associations that could be useful for understanding PAS onset and progression.

Abstract A mother’s postpartum ingestion of raw or processed placental tissue—referred to as human maternal placentophagy—is an emerging health trend observed in industrialized nations. Placenta is commonly consumed as small pieces of raw tissue, or as raw or steamed dehydrated pulverized and encapsulated tissue. To investigate the potential neonatal health risks of this behavior, the present study focused on microbial colonization of processed placenta preparations with potentially pathogenic bacteria Streptococcus agalactiae (Group-B-Streptococci; GBS) and Escherichia coli (E. coli). In the clinical approach placentas from 24 mothers were analyzed. Two placentas, from 13 mothers with confirmed positive maternal GBS status, showed GBS-growth on their surface (2/13; 15.4%) independent from delivery mode or antibiotic treatment. All processed samples (n = 24) were free from GBS. In the experimental approach, a standardized inoculation protocol was introduced to resemble ascending vaginal and hematogenous colonization. Six placentas from elective term C-sections of GBS negative mothers were collected and artificially inoculated with highly concentrated suspensions of GBS and E. coli. Heat processing significantly reduced the number of colony forming units (CFU) for GBS and E. coli. Our results suggest placentophagy of processed tissue is an unlikely source of clinical infection.

Abstract Background Euglycaemic diabetic ketoacidosis (DKA) during pregnancy is a life-threatening obstetric emergency. It requires early identification and prompt action. Obstetricians’ knowledge about symptoms, diagnostic pitfalls and management during pregnancy and delivery need to be improved. We report a case of a young diabetic woman developing severe euglycaemic DKA in two consecutive pregnancies; the first pregnancy resulted in the most deviating outcome (i.e., intrauterine death), while the second pregnancy resulted in the delivery of a healthy newborn. Thus, the novelty of the case presented here is the possibility to demonstrate how the management of DKA in pregnancy can dramatically change outcomes. Case presentation We report a case of a young diabetic woman in whom DKA was concealed by hyperemesis and oesophageal reflux. This woman presented to our delivery unit with severe euglycaemic DKA during her first pregnancy. While the mother’s condition could be successfully stabilized, the foetus died shortly after admission. Two years later, the same woman presented with similar problems. Repeated episodes of mild euglycaemic DKA could be successfully managed with consequent interdisciplinary treatment and close observation, leading to a good pregnancy outcome, i.e., the birth of a healthy child. Conclusion Awareness of euglycaemic DKA needs to be increased to reduce the risk of severe complications during pregnancies in diabetic women. This case report demonstrates that increased awareness of DKA with immediate recognition and a successful multidisciplinary approach are mandatory for an positive pregnancy outcomes.

(1) Background: The aim of this work is to investigate the extent to which pregnant women’s well-being is burdened by the diagnosis of gestational diabetes, as well as their sensitivities and illness perceptions. Since gestational diabetes is associated with mental disorders, we hypothesized that the burden of illness might be related to pre-existing mental distress. (2) Methods: Patients treated for gestational diabetes in our outpatient clinic were retrospectively asked to complete a survey, including the self-designed Psych-Diab-Questionnaire to assess treatment satisfaction, perceived limitations in daily life and the SCL-R-90 questionnaire to assess psychological distress. The association between mental distress and well-being during treatment was analyzed. (3) Results: Of 257 patients invited to participate in the postal survey, 77 (30%) responded. Mental distress was found in 13% (n = 10) without showing other relevant baseline characteristics. Patients with abnormal SCL-R-90 scores showed higher levels of disease burden, were concerned about glucose levels as well as their child’s health, and felt less comfortable during pregnancy. (4) Conclusions: Analogous to the postpartum depression screening, screening for mental health problems during pregnancy should be considered to target psychologically distressed patients. Our Psych-Diab-Questionnaire has been shown to be suitable to assess illness perception and well-being.

The NO-donor Pentaerytrithyltetranitrate (PETN) has vasodilatative properties and direct protective effects on endothelial cells. We formerly demonstrated that PETN, given to pregnant women during the second and third trimester, influences endothelial dysfunction related pregnancy complications like preeclampsia (PE) and fetal growth restriction (FGR). PETN treatment showed to delay PE to late pregnancy and achieved a profound risk reduction for FGR and/or perinatal death of 40%. The aim of this study was to confirm the effect of PETN on endothelial cell dysfunction at molecular level in an experimental approach. To induce endothelial dysfunction HUVEC were treated with 10 U/l of thrombin in the presence or absence of PETN. qRT-PCR analysis showed that PETN induced the expression of heme-oxygenase-1 and superoxide dismutase two but not endothelial NO-synthase under basal conditions. The induction of antioxidant proteins did not change basal reactive oxygen species (ROS) levels as measured by MitoSOX™ staining. PETN treatment significantly delayed the thrombin-induced disruption of the endothelial monolayer, determined using the xCELLigence® and attenuated the disrupting effect of thrombin on tubular junctions as seen in a tube-forming assay on Matrigel™. In western-blot-analysis we could show that PETN significantly reduced thrombin-induced extracellular signal-regulated kinase activation which correlates with reduction of thrombin-induced ROS. These experimental results establish the concept of how PETN treatment could stabilize endothelial resistance and angiogenic properties in pregnancy-induced stress. Thus, our results underscore the assumption, that the shown clinical effects of PETN are associated to its endothelial cell protection.

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

Abstract Background Migrant women may have an increased risk of adverse birth outcomes. This study analyses the occurrence of low birth weight, preterm birth and intrauterine growth restriction / fetal growth restriction (IUGR/FGR) in pregnant migrants. Method Cross-sectional study of 82 mother-child pairs of pregnant migrants attending medical care in Germany. Results The Median age was 27 years, 49% of patients were of oriental-asian ethnicity and median year of migration was 2015. At least one previous pregnancy was reported in 76% of patients, in 40% the delivery mode was caesarian section. Median gestational age was 39.7 weeks. Preterm birth occurred in 6.1% of pregnancies. Median gestational age for preterm birth was 32.3 weeks. Low birth weight (

(1) Background: Obesity is an increasing challenge in the care of pregnant women. The aim of our study was to investigate whether obesity is an independent risk factor for severe maternal and neonatal outcomes in pregnant women with COVID-19. (2) Methods: Data from the COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS), a prospective multicenter registry for SARS-CoV-2 positive pregnant women, was used to analyze the effect of obesity on selected individual and combined outcome parameters (3) Results: With 20.1%, the prevalence of obesity in the CRONOS registry exceeds the German background rate of 17.5%. Obese women showed significantly higher rates of GDM (20.4% vs. 7.6%; p < 0.001), hypertensive pregnancy disorders (6.2% vs. 2%; p = 0.004) and C-sections (50% vs. 34.5%; p < 0.001). BMI was revealed to be an individual risk factor for the severe combined pregnancy outcome (maternal death, stillbirth or preterm birth < 32 weeks) (OR 1.050, CI 1.005–1.097). (4) Conclusions: Maternal BMI is a predictor for the most severe outcome as maternal or neonatal death and preterm delivery

The evaluation of endothelial function is gaining interest and importance during pregnancy, since the impaired adaptation in early pregnancy has been associated with an increased risk in preeclampsia and fetal growth restriction. To standardize the risk assessment and to implement the evaluation of vascular function in routine pregnancy care, a suitable, accurate and easy to use method is needed. Flow-mediated dilatation (FMD) of the brachial artery assessed by ultrasound is considered to be the gold standard for measuring the vascular endothelial function. The challenges of the FMD measurement have so far prevented its introduction into clinical routine. The VICORDER® device allows an automated determination of the flow-mediated slowing (FMS). The equivalence of FMD and FMS has not yet been proven in pregnant women. We collected data of 20 pregnant women randomly and consecutively while they presented for a vascular function assessment in our hospital. The gestational age at investigation was between 22 and 32 weeks of gestation, three had preexisting hypertensive pregnancy disease and three were twin pregnancies. The results for FMD or FMS below 11.3% were considered to be abnormal. Comparing FMD to FMS results in our cohort revealed a convergence in 9/9 cases, indicating normal endothelial function (specificity of 100%) and a sensitivity of 72.7%. In conclusion, we verify that the FMS measurement is a convenient, automated and operator-independent test method of endothelial function in pregnant women.

Background: Infections, as well as adverse birth outcomes, may be more frequent in migrant women. Schistosomiasis, echinococcosis, and hepatitis E virus (HEV) seropositivity are associated with the adverse pregnancy outcomes of fetal growth restriction and premature delivery. Methods: A cohort study of 82 pregnant women with a history of migration and corresponding delivery of newborns in Germany was conducted. Results: Overall, 9% of sera tested positive for anti-HEV IgG. None of the patients tested positive for anti-HEV IgM, schistosomiasis, or echinococcus serology. Birth weights were below the 10th percentile for gestational age in 8.5% of the neonates. No association between HEV serology and fetal growth restriction (FGR) frequency was found. Conclusions: In comparison to German baseline data, no increased risk for HEV exposure or serological signs of exposure against schistosomiasis or echinococcosis could be observed in pregnant migrants. An influence of the anti-HEV serology status on fetal growth restriction could not be found.

ObjectivesQ fever is a zoonosis caused by the bacterium Coxiella burnetii. It is recognised as an occupational hazard for individuals who are in regular contact with animal birth products. Data from the literature are not comparable because different serological assays perform very differently in detecting past infections. It is therefore essential to choose the right assay for obtaining reliable data of seroprevalence. Obstetricians are another profession potentially at risk of Q fever. They can be infected from birth products of women with Q fever during pregnancy. There is little data, however, for Q fever in this occupational group. Our study therefore had two purposes. The first was to obtain reliable seroprevalence data for occupational groups in regular contact with animal birth products by using an assay with proven excellent sensitivity and specificity for detecting past infections. The second purpose was to obtain primary data for obstetricians.DesignWe carried out a cross-sectional study.SettingThe study included shepherds, cattle farmers, veterinarians and obstetricians from Thuringia.Participants77 shepherds, 74 veterinarians, 14 cattle farmers, 17 office employees and 68 obstetricians participated. The control group consisted of 92 blood donors.Primary outcome measureThe primary outcome measure was C. burnetii phase II specific IgG. The assay used was evaluated for this purpose in a previous study.ResultsOf the 250 blood samples we analysed, the very highest seroprevalences (64%–77%) occurred in individuals with frequent animal contact. There were no significant differences between shepherds, cattle farmers and veterinarians. The seroprevalence in people working in administration was lower but still significantly greater than the control. No obstetricians or midwives tested positive.ConclusionsShepherds, cattle farmers and veterinarians have a high risk of C. burnetii infection. However, our study clearly proves that there was no increased risk for people working in an obstetric department.

The diagnosis of gestational diabetes is usually very stressful for pregnant women, especially because they fear that insulin treatment may become necessary. Knowledge about personal risk factors predicting the probability of insulin treatment could therefore help to improve acceptance of the diagnosis and therapy adherence. The aim of this study was to find potential risk factors for insulin dependency and treatment requirements using information available at the time of diagnosis of gestational diabetes during pregnancy. We included 454 singleton pregnancies diagnosed ≥24 weeks of gestation. Multivariate regression analysis was used to evaluate independent associations of metabolic, anthropometric and fetal ultrasound parameters with the general need for insulin treatment and further stratified treatment options: diet (n = 275), bolus insulin only (n = 45), basal insulin only (n = 73) and multiple daily injections (n = 61). Receiver operator characteristics and cut-off values for independent variables were generated. Treatment groups differed significantly concerning pre-pregnancy weight and BMI as well as fasting glucose and 1 h glucose test values. Significant cut-offs for insulin dependency were HbA1c level of 5.4%, FPG of 5.5 mmol/L and 1 h glucose of 10.6 mmol/L. At time of diagnosis, certain patient characteristics and measurements can help to predict treatment necessities and therefore improve individualized counselling.

(1) Background: Maternal metabolic control in gestational diabetes is suggested to influence fetal autonomic control and movement activity, which may have fetal outcome implications. We aimed to analyze the relationship between maternal metabolic control, fetal autonomic heart rate regulation, activity and birth weight. (2) Methods: Prospective noninterventional longitudinal cohort monitoring study accompanying 19 patients with specialist clinical care for gestational diabetes. Monthly fetal magnetocardiography with electro-physiologically-based beat-to-beat heart rate recording for analysis of heart rate variability (HRV) and the ‘fetal movement index’ (FMI) was performed. Data were compared to 167 healthy pregnant women retrieved from our pre-existing study database. (3) Results: Fetal vagal tone was increased with gestational diabetes compared to controls, whereas sympathetic tone and FMI did not differ. Within the diabetic population, sympathetic activation was associated with higher maternal blood-glucose levels. Maternal blood-glucose levels correlated positively with birth weight z scores. FMI showed no correlation with birth weight but attenuated the positive correlation between maternal blood-glucose levels and birth weight. (4) Conclusion: Fetal autonomic control is altered by gestational diabetes and maternal blood-glucose level, even if metabolic adjustment and outcome is comparable to healthy controls.

The aim of diabetes care of pregnant women with gestational diabetes mellitus (GDM) is to attain pregnancy outcomes including rates of large-for-gestational-age (LGA) newborns, pre-eclampsia, C-sections (CS) and other neonatal outcomes similar to those of the non-GDM pregnant population. Obesity and excessive weight gain during pregnancy have been shown to also impact perinatal outcome. Since GDM is frequently associated with elevated body mass index (BMI), we evaluated the impact of maternal prepregnancy BMI, development of GDM and gestational weight gain (GWG) during pregnancy on perinatal outcome. We compared 614 GDM patients with 5175 non-diabetic term deliveries who gave birth between 2012 and 2016. Multivariate regression analysis was used to evaluate the independent contribution of each factor on selected perinatal outcome variables. Additionally, subgroup analysis for obese (BMI ≥ 30 kg/m2) and non-obese women (BMI < 30 kg/m2) was performed. LGA was significantly influenced by BMI, GWG and GDM, while Neonatal Intensive Care Unit (NICU) admission was solely impacted by GDM. Maternal outcomes were not dependent on GDM but on GWG and prepregnancy BMI. These results remained significant in the non-obese subgroup only. Thus, GDM still affects perinatal outcomes and requires further improvement in diabetic care and patient counseling.

IL-36 cytokines (the agonists IL-36α, IL-36β, IL-36γ, and the antagonist IL-36Ra) are expressed in the mouse uterus and associated with maternal immune response during pregnancy. Here, we characterize the expression of IL-36 members in human primary trophoblast cells (PTC) and trophoblastic cell lines (HTR-8/SVneo and JEG-3) and upon treatment with bacterial and viral components. Effects of recombinant IL-36 on the migration capacity of trophoblastic cells, their ability to interact with endothelial cells and the induction of angiogenic factors and miRNAs (angiomiRNAs) were examined. Constitutive protein expression of IL-36 (α, β, and γ) and their receptor (IL-36R) was found in all cell types. In PTC, transcripts for all IL-36 subtypes were found, whereas in trophoblastic cell lines only for IL36G and IL36RN. A synthetic analog of double-stranded RNA (poly I:C) and lipopolysaccharide (LPS) induced the expression of IL-36 members in a cell-specific and time-dependent manner. In HTR-8/SVneo cells, IL-36 cytokines increased cell migration and their capacity to interact with endothelial cells. VEGFA and PGF mRNA and protein, as well as the angiomiRNAs miR-146a-3p and miR-141-5p were upregulated as IL-36 response in PTC and HTR-8/SVneo cells. In conclusion, IL-36 cytokines are modulated by microbial components and regulate trophoblast migration and interaction with endothelial cells. Therefore, a fundamental role of these cytokines in the placentation process and in response to infections may be expected.

Guidelines on the management of gestational diabetes (GDM) instruct physicians to involve ultrasound-based monitoring of fetal growth in addition to blood glucose. So far, glucose control besides clinical parameters like maternal body mass index (BMI) and gestational weight gain have been shown to predict neonatal outcome. We aimed to evaluate the discriminative ability of fetal abdominal subcutaneous tissue (FAST) in addition to standard ultrasound parameters like abdominal circumference (AC) and estimated fetal weight (EFW) for perinatal complications like large for gestational age (LGA), hypoglycemia, hyperbilirubinemia, mode of delivery and admission to neonatal intensive care unit (NICU). Ultrasound data and neonatal outcome was collected of 805 GDM cases from 2012 to 2016: 3205 FAST, 3195 AC-measurements and 3190 EFW calculations were included. AC, EFW and FAST increased linear with gestational age. Combining ultrasound and clinical parameters improved predictive power for LGA. In the subgroup where fetuses grow with an AC > 75th additional adding of FAST to standard ultrasound parameters increased predictive power for hypoglycemia. Our results confirm inclusion of ultrasound parameters to be beneficial in monitoring GDM pregnancies. Additional FAST determination revealed to be of potential clinical relevance in the subgroup AC > 75th percentile.

Schistosomiasis in pregnancy may cause low birth weight, prematurity and stillbirth of the offspring. The placenta of pregnant women might be involved when schistosome ova are trapped in placental tissue. Standard histopathological methods only allow the examination of a limited amount of placental tissue and are therefore not sufficiently sensitive. Thus, placental schistosomiasis remains underdiagnosed and its role in contributing to schistosomiasis-associated pregnancy outcomes remains unclear. Here we investigated an advanced maceration method in order to recover a maximum number of schistosome ova from the placenta. We examined the effect of different potassium hydroxide (KOH) concentrations and different tissue fixatives with respect to maceration success and egg morphology. Placental tissue was kept either in 0.9% saline, 5% formalin or 70% ethanol and was macerated together with Schistosoma mansoni infested mouse livers and KOH 4% or 10%, respectively. We found that placenta maceration using 4% KOH at 37°C for 24 h was the most effective method: placental tissue was completely digested, egg morphology was well preserved and alkaline concentration was the lowest. Ethanol proved to be the best fixative for this method. Here we propose an improved maceration technique in terms of sensitivity, safety and required skills, which may enable its wider use also in endemic areas. This technique may contribute to clarifying the role of placental involvement in pregnant women with schistosomiasis.