Evolution of Fetal Growth in Symptomatic Sars-Cov-2 Pregnancies.

INTRODUCTION: SARS-CoV-2 is a viral disease with potentially devastating effects. Observational studies of pregnant women infected with SARS-CoV-2 report an increased risk for FGR. This study utilizes data from a prospective SARS-CoV-2 registry in pregnancy, investigating the progression of fetuses to fetal growth restriction (FGR) at birth following maternal SARS-CoV-2 and evaluating the hypothesis of whether the percentage of SGA at birth is increased after maternal SARS-CoV-2 taking into account the time interval between infection and birth. MATERIALS & METHODS: CRONOS is a prospective German registry enrolling pregnant women with confirmed SARS-CoV-2 infection during their pregnancy. SARS-CoV-2 symptoms, pregnancy- and delivery-specific information were recorded. The data evaluated in this study range from March 2020 until August 2021. Women with SARS-CoV-2 were divided into three groups according to the time of infection/symptoms to delivery: Group I<2 weeks, Group II 2-4 weeks, and Group III>4 weeks. FGR was defined as estimated and/or birth weight<10% ile, appropriate for gestational age (AGA) was within 10 and 90%ile, and large for gestational age (LGA) was defined as fetal or neonatal weight>90%ile. RESULTS: Data for a total of 2,650 SARS-CoV-2-positive pregnant women were available. The analysis was restricted to symptomatic cases that delivered after 24+0 weeks of gestation. Excluding those cases with missing values for estimated fetal weight at time of infection and/or birth weight centile, 900 datasets remained for analyses. Group I consisted of 551 women, Group II of 112 women, and Group III of 237 women. The percentage of changes from AGA to FGR did not differ between groups. However, there was a significantly higher rate of large for gestational age (LGA) newborns at the time of birth compared to the time of SARS-CoV-2 infection in Group III (p=0.0024), respectively. CONCLUSION: FGR rates did not differ between symptomatic COVID infections occurring within 2 weeks and>4 weeks before birth. On the contrary, it presented a significant increase in LGA pregnancies in Group III. However, in this study population, an increase in the percentage of LGA may be attributed to pandemic measures and a reduction in daily activity.

[Evaluation of Psychological Distress in Obstetric Patients during the Visit Ban in Hospitals in the SARS-CoV-2 Pandemic: A Prospective, Multicentre, Controlled Study]. / Evaluation der psychischen Belastung geburtshilflicher Patientinnen während des Besuchsverbots der Kliniken im Rahmen der SARS-CoV-2-Pandemie: Eine prospektive, multizentrische, kontrollierte Studie.

INTRODUCTION: Risk factors for postpartum depression include a lack of social support and perceived social isolation. We would like to determine whether the isolation of inpatients on the maternity wards during Covid-19 leads to increased psychological stress. METHODS: This is a multicentre, controlled study of obstetric patients who gave birth during an inpatient stay. Patients were included during the visitation ban (study group) and after the visitation ban (control group). Psychological stress was evaluated with the Edinburgh Postnatal Depression Scale (EPDS) during the inpatient stay and six to eight weeks postpartum. RESULTS: A total of 194 women were included, 107 in the study group and 87 in the control group. The overall result of the first EPDS shows a higher score in the study group compared to the control group (7.0 vs. 4.9 points). Primipara show a higher score in the first EPDS compared to multipara (7.28 vs. 4.82). Caesarean section, regardless of isolation, shows a higher score in the first EPDS than vaginal birth (8.42 vs. 5.11). Comparison of vaginal birth shows a higher score only in the study group (5.97 vs. 4.07). CONCLUSION: In the context of Covid-19, women giving birth and new mothers, especially primipara, are exposed to increased psychological stress in the clinics. Caesarean section leads to increased psychological stress.

[Pregnant in the Intensive Care Unit]. / Schwanger auf der Intensivstation.

Although admission to an intensive care unit during pregnancy is rare, pregnant women may become critically ill due to either obstetric or non-obstetric illness. Whilst critical illness due to obstetric reasons during the peripartum period (e.g. peripartum haemorrhage, HELLP-syndrome) is more common, it is also important to know how to care for critically ill pregnant women with non-obstetric illness (e.g. infection, cardiovascular diseases, neurological diseases, trauma). Physiological changes during pregnancy may affect critical care treatment, variation in standard and target values for blood pressure management or artificial ventilation. Pregnancy specific reference values in interpretation of blood chemistry are important issues to consider. The use of different drugs is inevitable in critical care, knowing which drugs are safe to use during the different stages of pregnancy is essential. Caring for mother and unborn child in the ICU is a challenge, open communication, ethical considerations and interdisciplinary as well as multiprofessional collaborations should be key points when caring for critically ill pregnant patients.

Breastfeeding Behavior Within the Covid-19 Related Obstetric and Neonatal Outcome Study (CRONOS).

BACKGROUND: The SARS-CoV-2 pandemic and its influence on peripartum processes worldwide led to issues in breastfeeding support. RESEARCH AIM: The aim of this study was to describe breastfeeding behavior and peripartum in-hospital management during the pandemic in Germany and Austria. METHODS: This study was a descriptive study using a combination of secondary longitudinal data and a cross-sectional online survey. Registry data from the prospective multicenter COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS) cohort study (longitudinal, medical records of 1,815 parent-neonate pairs with confirmed SARS-CoV-2 infection during pregnancy) and a cross-sectional online survey of CRONOS hospitals' physicians (N = 67) were used for a descriptive comparison of feeding outcomes and postpartum management. RESULTS: In 93.7% (n = 1700) of the cases in which information on the neonate's diet was provided, feeding was with the mother's own milk. Among neonates not receiving their mother's own milk, 24.3% (n = 26) reported SARS-CoV-2 infection as the reason. Peripartum maternal SARS-CoV-2 infection, severe maternal COVID-19 including the need for intensive care unit (ICU) treatment or invasive ventilation, preterm birth, mandatory delivery due to COVID-19, and neonatal ICU admission were associated with lower rates of breastfeeding. Rooming-in positively influenced breastfeeding without affecting neonatal SARS-CoV-2 frequency (4.2% vs. 5.6%). CRONOS hospitals reported that feeding an infant their mother's own milk continued to be supported during the pandemic. In cases of severe COVID-19, four of five hospitals encouraged breastfeeding. CONCLUSION: Maintaining rooming-in and breastfeeding support services in the CRONOS hospitals during the pandemic resulted in high breastfeeding rates.

HER-2-Positive Tumors: A Continuously Evolving Field in Cancer Research.

Almost 25 years ago, trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER2), was licensed for the treatment of patients with metastatic HER2-positive breast cancer in the United States of America (USA) [...].

Global cervical cancer research: A scientometric density equalizing mapping and socioeconomic analysis.

Cervical cancer has caused substantial morbidity and mortality for millions of women over the past decades. While enormous progress has been made in diagnosis, prevention and therapy, the disease is still fatal for many women-especially in low-income countries. Since no detailed studies are available on the worldwide research landscape, we here investigated the global scientific output related to this cancer type by an established protocol. The "New Quality and Quantity Indices in Science" platform assessed all relevant cervical cancer research published in the Web of Science since 1900. A detailed analysis was conducted including country-specific research productivity, indicators for scientific quality, and relation of research activity to socioeconomic and epidemiologic figures. Visualization of data was generated by the use of density equalizing map projections. Our approach identified 22,185 articles specifically related to cervical cancer. From a global viewpoint, the United States of America was the dominating country in absolute numbers, being followed by China and Japan. By contrast, the European countries Sweden, Austria, and Norway were positioned first when the research activity was related to the population number. When the scientific productivity was related to annual cervical cancer cases, Scandinavian countries (Finland #1, Sweden #4, Norway #5, Denmark #7), the Alpine countries Austria (#2) and Switzerland (#6), and the Netherlands (#3) were leading the field. Density equalizing mapping visualized that large parts of Africa and South America were almost invisible regarding the global participation in cervical cancer research. Our data documented that worldwide cervical cancer research activity is continuously increasing but is imbalanced from a global viewpoint. Also, the study indicated that global and public health aspects should be strengthened in cervical carcinoma research in order to empower more countries to take part in international research activities.

[COVID-19 and pregnancy]. / COVID-19 und Schwangerschaft: Fallserie mit der Komorbidität Diabetes aus der Registerstudie "Covid-19 Related Obstetric and Neonatal Outcome Study" (CRONOS).

From March 3 to October 13, 2020, 27 cases with diabetes comorbidity have been recorded in the CRONOS registry (Covid-19 Related Obstetric and Neonatal Outcome Study in Germany) among 262 registered women with SARS-CoV­2 infection during their pregnancy. Of those, 21 presented with gestational diabetes, 5 with type 2 diabetes and 1 with type 1 diabetes. About half of the women were asymptomatic and were diagnosed via general screening at hospital admission. The most common symptoms were nasal congestion, cough, tiredness, malaise and changes in smell and taste. The majority of pregnant women showed a mild to moderate course, three women were admitted to the intensive care unit and none required invasive ventilation. In the type 2 diabetes group, there were two cases with late fetal death (37 and 40 weeks of gestation) and one with a malformation, an association with diabetes being most likely. Pregnant women with diabetes mellitus represent a special subgroup; 1 in 10 women in this small cohort required intensive care monitoring due to COVID-19. In addition, this case series underscores the need for unrestricted access to pregnancy care, especially in times of pandemic, for optimal perinatal outcome.

Endometrial cancer: mapping the global landscape of research.

BACKGROUND: From a global viewpoint, endometrial cancer belongs to the most common female cancers. Despite the heavy burden of diseases and numerous unanswered questions, no detailed pictures of the global structure of endometrial cancer research are available so far. Therefore, this malignancy was reviewed using the New Quality and Quantity Indices in Science (NewQIS) protocol. METHODS: Using NewQIS, we identified endometrial carcinoma related research published in the Web of Science from 1900-2015 (P1) and from 2016-2020 (P2). Item analysis was performed with regard to research activity. Also, semi-qualitative aspects and socio-economic benchmarks were visualized using density equalizing mapping. RESULTS: In total, 9,141 from 1900-2015 and 4,593 from 2016-2020 endometrial cancer related studies were identified with the USA having the largest numbers of publications, citations, institutions, as well as the highest country-specific h-Index concerning endometrial cancer research in both periods. In contrast to other fields of cancer research, the two East Asian countries Japan and China followed concerning total research activities until 2015. From 2016 until 2020, China was found in short distance to the USA and was ranked second. In the socio-economic analysis, European countries were in prominent positions. Greece published 579.83 endometrial carcinoma-related articles per billion US-$ GDP, Finland (527.29), Sweden (494.65), Israel (493.75), and Norway (367.85) followed in the ranking. Density equalizing mapping visualized that large parts of Africa, Asia and South America with a high burden of disease played almost no visible role in the endometrial cancer research activities. CONCLUSIONS: Endometrial cancer research activity is continuously increasing from a global viewpoint. However, the majority of original articles is published by authors based in high-income countries. Together with the finding that the research field of public health does only play a minimal role, our study points to the necessity that global health aspects should be introduced to endometrial cancer research.

Molecular Subtype Conversion between Primary and Metastatic Breast Cancer Corresponding to the Dynamics of Apoptotic and Intact Circulating Tumor Cells.

The presence of circulating tumor cells (CTCs), detected as a form of liquid biopsy is associated with poor survival in both early and metastatic breast cancer. Monitoring tumor biology based on intrinsic subtypes delivers treatment-relevant information on the heterogeneity or biomarker conversion between primary and metastatic tumors. This study aimed to correlate the change of the apoptotic and intact CTC counts with mRNA-assessed intrinsic subtype change. Thirty-four breast cancer patients with available triplets of primary tumors, distant metastasis biopsies and data on intact and apoptotic CTC dynamics were included in the analysis. The intrinsic subtype was determined per RT-qPCR quantification of the gene expression ESR1, PGR, ERBB2 and MKI67. Both luminal (p = 0.038) and triple negative (p = 0.035) patients showed a significant downregulation of apoptotic CTCs. Repeated biopsies of distant metastatic sites, as well as determining a potential shift of the intrinsic subtype, combined with data on intact and apoptotic CTC dynamics from liquid biopsies might help personalize systemic therapy and generate additional surrogate markers for successful systemic therapy.

Microbiota-based analysis reveals specific bacterial traits and a novel strategy for the diagnosis of infectious infertility.

Tubal factor infertility (TFI) accounts for more than 30% of the cases of female infertility and mostly resides from an inflammatory process triggered by an infection. Clinical appearances largely differ, and very often infections are not recognized or remain completely asymptomatic over time. Here, we characterized the microbial pattern in females diagnosed with infectious infertility (ININF) in comparison to females with non-infectious infertility (nININF), female sex workers (FSW) and healthy controls (fertile). Females diagnosed with infectious infertility differed significantly in the seroprevalence of IgG antibodies against the C. trachomatis proteins MOMP, OMP2, CPAF and HSP60 when compared to fertile females. Microbiota analysis using 16S amplicon sequencing of cervical swabs revealed significant differences between ININF and fertile controls in the relative read count of Gardnerella (10.08% vs. 5.43%). Alpha diversity varies among groups, which are characterized by community state types including Lactobacillus-dominated communities in fertile females, an increase in diversity in all the other groups and Gardnerella-dominated communities occurring more often in ININF. While all single parameters did not allow predicting infections as the cause of infertility, including C. trachomatis IgG/IgA status together with 16S rRNA gene analysis of the ten most frequent taxa a total of 93.8% of the females were correctly classified. Further studies are needed to unravel the impact of the cervical microbiota in the pathogenesis of infectious infertility and its potential for identifying females at risk earlier in life.

Heparins that block VEGF-A-mediated von Willebrand factor fiber generation are potent inhibitors of hematogenous but not lymphatic metastasis.

Von Willebrand factor (VWF) serves as a nidus for platelet aggregation and thrombosis. We hypothesize that VWF fibers contribute to the development of venous thromboembolism (VTE) and to metastasis formation. Here, we show that vascular and lymphatic endothelial cells (ECs) express VWF in vitro and release VWF fibers after activation by tumor cell supernatants. In contrast, an ex vivo analysis of primary mouse tumors revealed the presence of VWF fibers in the blood microvasculature but not in lymphatic vessels. Unlike the anticoagulant Fondaparinux, an inhibitor of thrombin generation, the low-molecular-weight heparin (LMWH) Tinzaparin inhibited VWF fiber formation and vessel occlusion in tumor vessels by blocking thrombin-induced EC activation and vascular endothelial growth factor-A (VEGF-A)-mediated VWF release. Intradermal tumor cell inoculation in VWF- and ADAMTS13-deficient mice did not alter lymph node metastases compared with wild type animals. Interestingly, multiple tumor-free distal organs exhibited hallmarks of malignancy-related VTE, including luminal VWF fibers, platelet-rich thrombi and vessel occlusions. Furthermore, ADAMTS13 deficiency, characterized by prolonged intraluminal VWF network lifetimes, resulted in a severely increased number of metastatic foci in an experimental model of hematogenous lung seeding. Treatment with Tinzaparin inhibited tumor-induced release of VWF multimers, impeded platelet aggregation and decreased lung metastasis. Thus, our data strongly suggest a critical role of luminal VWF fibers in determining the occurrence of thrombosis and cancer metastasis. Moreover, the findings highlight LMWHs as therapeutic strategy to treat thrombotic complications while executing anti-metastatic activities.

Management of Very Early-onset Fetal Growth Restriction: Results from 92 Consecutive Cases.

AIM: To evaluate management of early-onset intrauterine growth restriction (IUGR) and to define outcome according to obstetric setting. PATIENTS AND METHODS: During an 11-year period (2000-2011), data of patients presenting with IUGR and preterm delivery of less than 30 weeks of gestation at a tertiary perinatal center were retrospectively reviewed. RESULTS: A total of 92 pregnancies were investigated. Delivery was indicated for fetal reasons in 38 out of 92 patients. Sixteen children of our cohort died within one year post partum, out of which eight had suffered from severe early-onset IUGR causing iatrogenic preterm delivery. Concerning the fetal outcome, gestational age at delivery and antenatal exposure to corticosteroids were found to be crucial. CONCLUSION: In some cases, respiratory distress syndrome prophylaxis and a "wait and see" approach to management in favor of a prolongation of the pregnancy might be favorable. Randomized prospective trials in early-onset IUGR with threatened preterm deliveries are needed in order to define guidelines for an individually tailored management of early-onset preterm infants.

Low-molecular-weight heparin for women with unexplained recurrent pregnancy loss: a multicenter trial with a minimization randomization scheme.

BACKGROUND: A daily injection of low-molecular-weight heparin (LMWH) is often prescribed to women with unexplained recurrent pregnancy loss (RPL), although evidence suggesting a benefit is questionable. OBJECTIVE: To determine whether LMWH increases ongoing pregnancy and live-birth rates in women with unexplained RPL. DESIGN: Controlled, multicenter trial with randomization using minimization conducted from 2006 to 2013. (ClinicalTrials.gov: NCT00400387). SETTING: 14 university hospitals and perinatal care centers in Germany and Austria. PATIENTS: 449 women with at least 2 consecutive early miscarriages or 1 late miscarriage were included during 5 to 8 weeks' gestation after a viable pregnancy was confirmed by ultrasonography. INTERVENTION: Women in the control group received multivitamin pills, and the intervention group received vitamins and 5000 IU of dalteparin-sodium for up to 24 weeks' gestation. MEASUREMENTS: Primary outcome was ongoing pregnancy at 24 weeks' gestation. Secondary outcomes included the live-birth rate and late pregnancy complications. RESULTS: At 24 weeks' gestation, 191 of 220 pregnancies (86.8%) and 188 of 214 pregnancies (87.9%) were intact in the intervention and control groups, respectively (absolute difference, -1.1 percentage points [95% CI, -7.4 to 5.3 percentage points]). The live-birth rates were 86.0% (185 of 215 women) and 86.7% (183 of 211 women) in the intervention and control groups, respectively (absolute difference, -0.7 percentage point [CI, -7.3 to 5.9 percentage points]). There were 3 intrauterine fetal deaths (1 woman had used LMWH); 9 cases of preeclampsia or the hemolysis, elevated liver enzyme level, and low platelet count (HELLP) syndrome (3 women had used LMWH); and 11 cases of intrauterine growth restriction or placental insufficiency (5 women had used LMWH). LIMITATION: Placebo injections were not used, and neither trial staff nor patients were blinded. CONCLUSION: Daily LMWH injections do not increase ongoing pregnancy or live-birth rates in women with unexplained RPL. Given the burden of the injections, they are not recommended for preventing miscarriage. PRIMARY FUNDING SOURCE: Pfizer Pharma.

Lack of difference in acute nephrotoxicity of intravenous bisphosphonates zoledronic acid and ibandronate in women with breast cancer and bone metastases.

BACKGROUND: More than 50% of patients with advanced breast cancer develop bone metastases that may lead to multiple complications such as pathological fractures, bone pain or hypercalcaemia. The standard treatment, besides endocrine, targeted-therapy or chemotherapy, is the use of bisphosphonates. However, one of their main adverse side-effects is bisphosphonate-induced nephrotoxicity. The mechanism by which the latter occurs is not well-understood, although emerging evidence suggests that the effect of bisphosphonates on the kidney may differ between agents. PATIENTS AND METHODS: The aim of this evaluation was to compare the renal toxicity of 6 mg ibandronate i.v. versus 4 mg zoledronic acid i.v. over a period of six months in women with breast cancer and bone metastases. A prospective randomized trial was carried out to examine specific kidney and other parameters (α1- and ß2-microglobulin, albumin, α2-macroglobulin, IgG and C-reactive protein (CRP) generated from spontaneous urine samples from 17 patients of each group. RESULTS: We were unable to find any significant difference between the two treatment groups with regard to renal toxicity. All patients, independently of the applied bisphosphonate, experienced only temporary renal dysfunction without any evidence of irreversible damage in terms of acute nephrotoxicity during the study period. α1-Microglobulin, a marker for proximal tubular damage, in particular, was not differently elevated in either group. CONCLUSION: Both applied bisphosphonates were found to be well-tolerated and safe with regard to renal toxicity during a six-month treatment period in patients with otherwise healthy kidneys having advanced breast cancer and bone metastases.

Growth-modulatory effects of heparin and VEGF165 on the choriocarcinoma cell-line JEG-3 and its expression of heparanase.

BACKGROUND: Expression of heparanase (HPSE) in tumor cells is strongly associated with invasion, metastasis and angiogenesis. It also plays a key role during pregnancy, in processes of implantation as well as placentation. Vascular endothelial growth factor (VEGF) and heparin are known to alter HPSE expression, with heparin given prophylactically to women with a history of placenta-mediated complications in subsequent pregnancies. MATERIALS AND METHODS: We examined the growth-modulatory effects of different concentrations of heparin and VEGF on the choriocarcinoma cell-line JEG-3 and the expression of heparanase under VEGF and heparin by proliferation assays, PCR, and western blot. RESULTS: Proliferation of JEG-3 cells was induced by heparin in a dose-dependent manner, whereas highly concentrated VEGF led to a decreased cell proliferation. Both agents did not influence the HPSE-expression. CONCLUSION: The presumed pregnancy-protecting effects of heparin may partially be due to an increase of trophoblast proliferation and not via regulation of HPSE expression.

Does maternal underweight prior to conception influence pregnancy risks and outcome?

AIM: Data analyzing risks during pregnancy and neonatal outcome in Caucasian women with pre-conceptional underweight are scarce. PATIENTS AND METHODS: We conducted a retrospective cohort study in Northern Germany comparing pregnancy risks and neonatal outcomes in nulliparous women with either pre-conceptional underweight or normal weight. RESULTS: The data of 3,854 nulliparous women with either underweight (n = 243; BMI ≤ 18.5 kg/m(2)) or normal weight (n = 3611; BMI 18.5-24.9 kg/m(2)) were screened. The risks for preterm birth (23.3 vs. 18.6%; p = 0.004) and neonatal underweight were significantly higher in women with underweight prior to conception (p < 0.0001). The risk for secondary caesarean sections was significantly lower in underweight patients. CONCLUSION: To our knowledge, the present retrospective cohort study constitutes the largest sub-group analysis on delivery and maternal and neonatal outcome in pre-conceptionally underweight mothers. There are significantly more preterm deliveries in underweight mothers, while maternal outcome and birth-associated trauma (lacerations, caesarean section) is not disadvantageously influenced by maternal underweight. Further investigations are required in order to specify nutritional deficits in underweight pregnant women and to optimize medication in cases where nutritional balance cannot be achieved in order to improve the neonatal status at birth.

Prevention, management and extent of adverse pregnancy outcomes in women with hereditary antithrombin deficiency.

Antithrombin (AT) deficiency is a rare hereditary thrombophilia with a mean prevalence of 0.02 % in the general population, associated with a more than ten-fold increased risk of venous thromboembolism (VTE). Within this multicenter retrospective clinical analysis, female patients with inherited AT deficiency were evaluated concerning the type of inheritance and extent of AT deficiency, medical treatment during pregnancy and postpartally, VTE risk as well as maternal and neonatal outcome. Statistical analysis was performed with SPPS for Windows (19.0). A total of 18 pregnancies in 7 patients were evaluated, including 11 healthy newborns ≥37th gestational weeks (gw), one small for gestational age premature infant (25th gw), two late-pregnancy losses (21st and 28th gw) and four early miscarriages. Despite low molecular weight heparin (LMWH) administration, three VTE occurred during pregnancy and one postpartally. Several adverse pregnancy outcomes occurred including fetal and neonatal death, as well as severe maternal neurologic disorders occurred. Patients with substitution of AT during pregnancy in addition to LMWH showed the best maternal and neonatal outcome. Close monitoring with appropriate anticoagulant treatment including surveillance of AT levels might help to optimize maternal and fetal outcome in patients with hereditary AT deficiency.

Hybrid approach of retractor-based and conventional laparoscopy enabling minimally invasive hysterectomy in a morbidly obese patient: case report and review of the literature.

Minimally invasive hysterectomy in obese patients may be limited by laparoscopic sight on the one hand and by intraoperative complications related to reduced ventilation due to pneumoperitoneum on the other. Retractor-based laparoscopy offers an operative technique reducing anesthesia risks. We report the case of laparoscopic hysterectomy in an obese patient of short stature. Laparoscopic supracervical hysterectomy was performed by a hybrid approach of a retractor system exerting its effects on lifting the abdominal wall through gravity and conventional laparoscopy, thus bypassing the adverse effects of pneumoperitoneum on ventilation.