Age-related Disparities in Pan-Cancer Mortality and Causes of Death: Analysis of Surveillance, Epidemiology, and End Results (SEER) Data.

Comprehensive analysis of mortality and causes of death (COD) in cancers was of importance to conduct intervention strategies. The current study aimed to investigate the mortality rate and COD among cancers, and to explore the disparities between age. Initially, cancer patients diagnosed between 2010 and 2019 from the surveillance, epidemiology, and end results (SEER) database were extracted. Then, frequencies and percentage of deaths, and mortality rate in different age groups were calculated. Meanwhile, age distribution of different COD across tumor types was illustrated while the standardized mortality ratios (SMR) stratified by age were calculated and visualized. A total of 2,670,403 death records were included and digestive system cancer (688,953 death cases) was the most common primary cancer type. The mortality rate increased by 5.6% annually in total death, 4.0% in cancer-specific death and 10.9% in non-cancer cause. As for cancer-specific death, the age distribution varied among different primary tumor types due to prone age and prognosis of cancer. The top five non-cancer causes in patients older than 50 were cardiovascular and cerebrovascular disease, other causes, COPD and associated conditions, diabetes as well as Alzheimer. The SMRs of these causes were higher among younger patients and gradually dropped in older age groups. Mortality and COD of cancer patients were heterogeneous in age group due to primary tumor types, prone age and prognosis of cancer. Our study conducted that non-cancer COD was a critical part in clinical practice as well as cancer-specific death. Individualized treatment and clinical intervention should be made after fully considering of the risk factor for death in different diagnosis ages and tumor types.

Catastrophic Antiphospholipid Syndrome.

Unlike classic APS, CAPS causes multiple microthrombosis due to an increased inflammatory response, known as a "thrombotic storm". CAPS typically develops after infection, trauma, or surgery and begins with the following symptoms: fever, thrombocytopenia, muscle weakness, visual and cognitive disturbances, abdominal pain, renal failure, and disseminated intravascular coagulation. Although the presence of antiphospholipid antibodies in the blood is one of the diagnostic criteria, the level of these antibodies can fluctuate significantly, which complicates the diagnostic process and can lead to erroneous interpretation of rapidly developing symptoms. Triple therapy is often used to treat CAPS, which includes the use of anticoagulants, plasmapheresis, and high doses of glucocorticosteroids and, in some cases, additional intravenous immunoglobulins. The use of LMWH is recommended as the drug of choice due to its anti-inflammatory and anticoagulant properties. CAPS is a multifactorial disease that requires not only an interdisciplinary approach but also highly qualified medical care, adequate and timely diagnosis, and appropriate prevention in the context of relapse or occurrence of the disease. Improved new clinical protocols and education of medical personnel regarding CAPS can significantly improve the therapeutic approach and reduce mortality rates.

Intimate partner violence as a risk factor for venous thromboembolism in women on combined oral contraceptives: An international matched case-control study.

BACKGROUND: Intimate partner violence (IPV) targeting women is probably underestimated during a woman's lifetime. Venous thromboembolism (VTE) is a multifactorial disease associated with haemostasis-activating conditions. Minor injuries can trigger VTE. OBJECTIVES: We aimed to look for an association between VTE and IPV in women taking combined oral contraceptives (COCs) METHODS: We performed a multicentric, international, matched case-control study. Patients were women with a first VTE associated with COC intake. Controls were women taking COCs undergoing regular gynaecological check-ups. Patients and Controls were matched for country, age, length of COC intake and type (997 pairs). IPV was evaluated using the WAST self-administrated questionnaire. RESULTS: IPV, defined as a WAST score value at least 5, was diagnosed in 33 Controls (3.3 %) and 109 patients (10.9 %), conditional odds ratio (OR): 3.586, 95 % confidence interval (2.404-5.549), p < 0.0001. After multivariate analysis, the adjusted OR was 3.720 (2.438-5.677), p < 0.0001. Sensitivity analysis using increasing WAST score thresholds confirmed the association. CONCLUSIONS: A first VTE in women taking COCs is associated with IPV. This association can have strong human consequences but also raises significant medical issues, for instance on the haemorrhagic risk of anticoagulant treatments in abused women. Pathophysiological studies are warranted.

The Hemostatic System in Newborns and the Risk of Neonatal Thrombosis.

Newborns are the most vulnerable patients for thrombosis development among all children, with critically ill and premature infants being in the highest risk group. The upward trend in the rate of neonatal thrombosis could be attributed to progress in the treatment of severe neonatal conditions and the increased survival in premature babies. There are physiological differences in the hemostatic system between neonates and adults. Neonates differ in concentrations and rate of synthesis of most coagulation factors, turnover rates, the ability to regulate thrombin and plasmin, and in greater variability compared to adults. Natural inhibitors of coagulation (protein C, protein S, antithrombin, heparin cofactor II) and vitamin K-dependent coagulation factors (factors II, VII, IX, X) are low, but factor VIII and von Willebrand factor are elevated. Newborns have decreased fibrinolytic activity. In the healthy neonate, the balance is maintained but appears more easily converted into thrombosis. Neonatal hemostasis has less buffer capacity, and almost 95% of thrombosis is provoked. Different triggering risk factors are responsible for thrombosis in neonates, but the most important risk factors for thrombosis are central catheters, fluid fluctuations, liver dysfunction, and septic and inflammatory conditions. Low-molecular-weight heparins are the agents of choice for anticoagulation.

Is intimate partner abuse underestimated as a precipitating factor for venous thromboembolism in women?

Major and minor trauma increase the risk of venous thromboembolism (VTE), but violence against young women is not reported as a precipitating factor for thrombosis. Here, we report 20 cases of first VTE events in women of childbearing age after evidence of intimate partner violence. Other risk factors for VTE were often associated. In most cases, women did not report this state of violence at the first consultation and their doctors did not suspect it. We imagine that it is an underdiagnosed situation and should call for a systematic evaluation. Screening for intimate partner abuse could have significant consequences, both on protecting women who are affected by it and better evaluating the risk of bleeding with anticoagulant treatment in this situation.

Inflammation and Immune Reactions in the Fetus as a Response to COVID-19 in the Mother.

Background: Contracting COVID-19 during pregnancy can harm both the mother and the unborn child. Pregnant women are highly likely to develop respiratory viral infection complications with critical conditions caused by physiological changes in the immune and cardiopulmonary systems. Asymptomatic COVID-19 in pregnant women may be accompanied by fetal inflammatory response syndrome, which has adverse consequences for the newborn's life and health. Purpose: To conduct an inflammatory response assessment of the fetus due to the effects of COVID-19 on the mother during pregnancy by determining pro-inflammatory cytokines, cell markers, T regulatory cells, T cell response, evaluation of cardiac function, and thymus size. Materials and methods: A prospective study included pregnant women (n = 92). The main group consisted of 62 pregnant women with COVID-19 infection: subgroup 1-SARS-CoV-2 PCR-positive pregnant women 4-6 weeks before delivery (n = 30); subgroup 2-SARS-CoV-2 PCR-positive earlier during pregnancy (n = 32). The control group consisted of 30 healthy pregnant women. In all pregnant women, the levels of circulating cytokines and chemokines (IL-1α, IL-6, IL-8, IL-10, GM-CSF, TNF-α, IFN-γ, MIP-1ß, and CXCL-10) were determined in the peripheral blood and after delivery in the umbilical cord blood, and an analysis was performed of the cell markers on dendritic cells, quantitative and functional characteristics of T regulatory cells, and specific T cell responses. The levels of thyroxine and thyroid-stimulating hormone were determined in the newborns of the studied groups, and ultrasound examinations of the thymus and echocardiography of the heart were also performed. Results: The cord blood dendritic cells of newborns born to mothers who suffered from COVID-19 4-6 weeks before delivery (subgroup 1) showed a significant increase in CD80 and CD86 expression compared to the control group (p = 0.023). In the umbilical cord blood samples of children whose mothers tested positive for COVID-19 4-6 weeks before delivery (subgroup 1), the CD4+CCR7+ T cells increased with a concomitant decrease in the proportion of naive CD4+ T cells compared with the control group (p = 0.016). Significantly higher levels of pro-inflammatory cytokines and chemokines were detected in the newborns of subgroup 1 compared to the control group. In the newborns of subgroup 1, the functional activity of T regulatory cells was suppressed, compared with the newborns of the control group (p < 0.001). In all pregnant women with a severe coronavirus infection, a weak T cell response was detected in them as well as in their newborns. In newborns whose mothers suffered a coronavirus infection, a decrease in thymus size, transient hypothyroxinemia, and changes in functional parameters according to echocardiography were revealed compared with the newborns of the control group. Conclusions: Fetal inflammatory response syndrome can occur in infants whose mothers suffered from a COVID-19 infection during pregnancy and is characterized by the activation of the fetal immune system and increased production of pro-inflammatory cytokines. The disease severity in a pregnant woman does not correlate with SIRS severity in the neonatal period. It can vary from minimal laboratory parameter changes to the development of complications in the organs and systems of the fetus and newborn.

Combined oral contraceptive-associated venous thromboembolism revealing an antiphospholipid syndrome: International retrospective study of outcomes.

INTRODUCTION: Limitations in the data used to define thromboprophylaxis for patients with antiphospholipid antibodies (aPLAbs) and thrombosis include uncertainties after an initial provoked venous thromboembolic event (VTE). We aimed to study such cases associated with combined oral contraceptive (COC) intake. METHODS: We retrospectively analysed thrombotic outcomes after a first COC-associated VTE and positive aPLAbs, with a low risk HERDOO2 score, on low-dose aspirin (LDA) secondary thromboprophylaxis, seen from 2010 to 2021 in 3 tertiary referral centres, one in France and 2 in Russia. Data from 264 patients (distal deep vein thrombosis DVT: 62.9 %), cumulating in 1327.7 patient-years of observation, were collected. RESULTS: There were 22 cases of thrombosis: 16 distal DVTs, 3 proximal, 1 pulmonary embolism (PE) and 2 transient ischemic attacks. Recurrence rate was 1.66 per 100 patient-years (p-y; 95 % CI: 0.96-2.33). No major bleeding occurred. Risk factors affecting recurrence-free survival were the time between first COC intake and VTE (p < 0.0001; the shortest, the lower), proximal DVT (p = 0.021), active smoking (p = 0.039), an associated systemic disease (p = 0.043) and circulating monocyte counts (p = 0.001). CONCLUSIONS: We observed a low risk of recurrence which was modulated by classical risk factors for VTE. These observational data may provide clues for future randomized controlled trials.

Pregnancy after Combined Oral Contraceptive-Associated Venous Thromboembolism: An International Retrospective Study of Outcomes.

BACKGROUND: Few data are available on thrombotic outcomes during pregnancy and puerperium occurring after an initial provoked venous thromboembolic (VTE) event. OBJECTIVES: To describe thrombotic outcomes during pregnancy after a first combined oral contraceptive (COC)-associated VTE and the factors associated with recurrence. METHODS: This was an international multicentric retrospective study on patients referred for thrombophilia screening from January 1, 2010 to January 1, 2021 following a first COC-associated VTE, including women with neither inherited thrombophilia nor antiphospholipid antibodies and focusing on those who had a subsequent pregnancy under the same thromboprophylaxis treatment. Thrombotic recurrences during pregnancy and puerperium as well as risk factors for recurrence were analyzed. RESULTS: We included 2,145 pregnant women. A total of 88 thrombotic events, 58 antenatal and 29 postnatal, occurred, mostly during the first trimester of pregnancy and the first 2 weeks of puerperium. Incidence rates were 49.6 (37-62) per 1,000 patient-years during pregnancy and 118.7 (78-159) per 1,000 patient-years during puerperium. Focusing on pulmonary embolism, incidence rates were 1.68 (1-4) per 1,000 patient-years during pregnancy and 65.5 (35-97) per 1,000 patient-years during puerperium.Risk factors for antenatal recurrences were maternal hypercholesterolemia and birth of a very small-for-gestational-age neonate. A risk factor for postnatal recurrence was the incidence of preeclampsia. CONCLUSION: Our multicentric retrospective data show significant rates of VTE recurrence during pregnancy and puerperium in women with a previous VTE event associated with COC, despite a unique low-molecular-weight heparin-based thromboprophylaxis. These results may provide benchmarks and valuable information for designing future randomized controlled trials.

Managing puerperium in patients with systemic autoimmune diseases: an update.

INTRODUCTION: Puerperium is a critical period for patients affected by autoimmune rheumatic diseases for the risk of disease's flares and difficulties in treating lactating mothers. We want to summarize the literature data about psychological and pharmacological management of these patients and possible risk factors of disease's flares. AREAS COVERED: We made a narrative review on recent studies about puerperium in rheumatic autoimmune diseases patients. EXPERT OPINION: The physicians involved in management of patients during puerperium and in the follow-up of babies need to agree on maternal treatment because they need to reassure mothers about the safety of the prescribed medications. Furthermore, women with rheumatic diseases could present some musculoskeletal limitations and psychological problems, such as postpartum depression, which can lead to a sense of inadequacy to the mother's task. Families and physicians should be aware of these possible complications and support the new mothers providing correct counseling and practical help.

Modeling Pulsatility Index nomograms from different maternal and fetal vessels by quantile regression at 24-40 weeks of gestation: a prospective cross-sectional study.

OBJECTIVE: Recent evidences highlight a considerable heterogeneity in the methodology of previously published studies reporting reference ranges for maternal and fetal Dopplers, which may have relevant implications in clinical practice. In view of these limitations, a standardized methodology to construct Doppler charts has been proposed. The aim of this study was to develop charts for pulsatility index (PI) of maternal and fetal Dopplers based upon the recently proposed standardized methodology and using quantile regression. METHODS: Prospective cross-sectional study including 2516 low-risk singleton pregnancies between 24 and 40 weeks of gestation. The mean uterine, umbilical (UA), middle cerebral (MCA) and their ratio (cerebroplacental ratio, CPR) centile values were established by quantile regression in the considered gestational interval. Interclass correlation coefficient (ICC) of each maternal and fetal vessel was also computed to assess the intra- and inter-observer agreement of the results. RESULTS: There was a good intra- and inter-observer agreement for each of the explored vessels (ICC >0.92 and >0.91 for a single and two observers, respectively). The 5th, 10th, 50th, 90th and 95th centiles of the reference range for gestation were constructed by quantile regression and compared to previously established reference charts. All the Doppler indices significantly changed with gestation. Second-degree polynomial regression models better described the changes with gestation in PCR and MCA PI values while a linear model better predicted the changes of other Doppler indices with advancing gestation. When compared to other studies reporting reference ranges for maternal and fetal Dopplers, the present charts showed similar median values but different distribution from the median. CONCLUSIONS: We provided prospective charts of maternal and fetal Dopplers based upon a previously proposed standardized methodology and using quantile regression. When compared to previously published studies, these new charts showed similar median values but different deviations from the median which may help in better differentiating cases at higher risk of placental insufficiency and adverse perinatal outcome.

Neonatal thrombosis.

Neonatal thromboembolism in pediatric patients is a rare but life-threatening condition mainly caused by combinations of at least 2 prothrombotic triggering risk factors such as the central venous lines, septic condition, and prematurity. Other risk factors include asphyxia, dehydration, liver dysfunction, inflammation, and maternal condition. Neonatal hemostatic system is different from one of the older children and adults. Coagulation proteins do not cross the placenta but are synthesized in the fetus from an early stage. In the term neonate, concentrations of several procoagulant proteins, particularly the vitamin K dependent and contact factors are reduced when compared with adults. Conversely, levels of antithrombin, heparin cofactor II and protein C and S are low at birth and fibrinolysis system is characterized by the decreased level of plasminogen and alpha-1-antiplasmin, increased tissue plasminogen activator. These features all tend to be gestational dependent and are more present in the preterm infant. Primarily in this context neonates appear to be at a higher risk of thrombosis than older children. Thrombotic complications reach their peak in the group of children born at 22-27 weeks. The role of inherited thrombophilic risk factors in neonatal VTE development is poorly defined. The presence of inherited and acquired thrombophilia in mother and newborn is also responsible for the development of thrombosis in neonates and should be considered. Thrombophilia in the mother can lead to increased coagulation potential and prethrombotic conditions during pregnancy, causing thrombotic vasculopathy at the placental level. The benefit of identifying thrombophilia in the sick preterm newborns who are in the group of risk for development of thrombotic complications may facilitate the thromboprophylaxis. Further research regarding assessment of risk factors, diagnostics and treatment strategy is required.

Administration of antenatal corticosteroid is associated with reduced fetal growth velocity: a longitudinal study.

OBJECTIVE: To elucidate whether antenatal administration of corticosteroids in pregnancies with threatened preterm labor affects growth velocity. METHODS: A cohort of 262 pregnancies exposed to antenatal corticosteroids longitudinally studied and delivered from 36 weeks (cases) were compared to an unexposed group of 270 women (controls). METHODS: Fetal growth was assessed analyzing the growth velocity of head circumference (HC), abdominal circumference (AC), femur length (FL) and estimated fetal weight (EFW). Growth velocity (GV) was calculated as the difference in the Z-score between the biometric measurements recorded at the time of steroids administration and at 36 week of gestation, divided by the time interval (expressed in days) between the two scans and multiplied by 100. Similarly, changes in the Pulsatility Index (PI) of uterine, umbilical (UA), middle cerebral (MCA) arteries and cerebroplacental ratio (CPR) during the same time interval were also computed. RESULTS: Median gestational age at steroid administration (30.2 weeks vs 30.4) and follow-up ultrasound (36.4 weeks vs 36.4) were similar between cases and controls. In pregnancies exposed to antenatal corticosteroids, growth velocity in the HC (-0.61 vs. 0.12; p ≤ 0.001), AC (-0.55 vs. -0.04; p ≤ 0.001) and EFW (-0.89 vs. 0.06; p ≤ 0.001) were lower when compared to pregnancies not exposed to steroid therapy, while there was no difference in the growth velocity of FL (-0.05 vs 0.19; p = .06) or in any of the Doppler parameters explored. CONCLUSION: In pregnancies exposed to antenatal steroid therapy, there is a significant reduction in fetal growth velocity not otherwise associated with changes in cerebroplacental Dopplers.

Correlation between estimated fetal weight and weight at birth in infants with gastroschisis and omphalocele.

BACKGROUND: An accurate estimated fetal weight (EFW) calculated with traditional formulae in cases of abdominal wall defects (AWDs) can be challenging. As a result of reduced abdominal circumference, fetal weight may be underestimated, which could affect prenatal management. Siemer et al. proposed a formula without the use of abdominal circumference, but it is not used in our protocols yet. OBJECTIVES: Our aim was to evaluate the correlation of EFW and birth weight in fetuses with AWD by using Hadlock 1, Hadlock 2, and Siemer et al.'s formulae. Our secondary goal was to evaluate how often fetuses classified as small for gestational age (SGA) were in fact SGA at birth. STUDY DESIGN: This was a retrospective cohort study of gestations complicated by gastroschisis and omphalocele at two tertiary-care centers in Brazil and Italy during an 8-year period. Of a total of 114 cases, 85 (44 cases of gastroschisis and 41 cases of omphalocele) met our criteria. RESULTS: The last prenatal scan was performed 5.2 (±4.1) days before birth. The mean gestational age at birth was 37.2 (±1.8) weeks. Correlation of EFW with birth weight was calculated with the three formulae with and without adjustment for weight gain between scan and birth, with the use of the Spearman coefficient. The correlation between EFW and weight at birth was positive according to all three formulae for the infants with gastroschisis. This finding was not confirmed in the infants with omphalocele. All formulae overestimated the number of SGA cases: although only 17.6% of fetuses were actually SGA at birth, the Hadlock formulae had classified nearly 35% of them as SGA, and Siemer et al.'s formula, 15.3%. CONCLUSION: All three formulae yielded a good correlation between EFW in the last scan and birth weight in the infants with gastroschisis but not for those with omphalocele. Cases of SGA were overestimated.

Prenatal risk factors for urgent atrial septostomy at birth in fetuses with transposition of the great arteries: a systematic review and meta-analysis.

MATERIAL AND METHODS: Medline, Embase, and Cochrane databases were searched. The primary aim was to explore the differences in prenatal echocardiographic parameters among fetuses diagnosed with TGA that required urgent BAS within 24 h of birth due to life-threatening cyanosis compared to those who did not require such procedure. Random-effect meta-analyses were used to compute the data. RESULTS: Six studies (292 fetuses) were included. Restrictive appearance of the FO was present in 64.5% (95% CI = 39.8-85.7) of fetuses with TGA requiring BAS at birth compared to 7.9% (95% CI = 2.1-16.8) not requiring such procedure (OR = 71.1; 95% CI = 8.3-608.5, p < .0001). Hypermobile appearance of the atrial septum was present in 39.1% (95% CI = 26.4-56.5) of fetuses requiring BAS at birth compared to 9.8% (95% CI = 1.4-24.3) of those which did (OR 3.6; 95% CI = 1.4-9.0, p = .05). There was no difference in the prevalence of redundant (p = .374) or fixed (p = .051) atrial septum, bidirectional flow in the DA (p = .26) or an abnormal size of the DA (p = .06) in fetuses requiring urgent BAS at birth compared to those which did not. Mean (±SD) size of the right atrium was smaller in the fetuses with TGA undergoing urgent BAS at birth (23.4 ± 6.7) compared to those which did not (29.2 ± 6.2, p = .01). The mean (±SD) ratio between the FO and the aortic valve diameters (1.01 ± 0.41 versus 1.41 ± 0.43, p = .009) and the mean (±SD) ratio between the FO diameter and the septal length (0.36 ± 0.13 versus 0.51 ± 0.14, p = .001) were significantly smaller in fetuses requiring compared to those not undergoing urgent BAS at birth. The diagnostic accuracy of each independent ultrasound marker of the need for urgent BAS showed an overall good specificity but a low sensitivity. CONCLUSION: Fetal echocardiography prior to birth can stratify the risk of BAS in fetuses with TGA. Further studies are needed to validate these findings and build individualized multiparametric predictive models in order to more accurately identify those fetuses with TGA at a higher risk of urgent BAS after birth.

Maternal cardiovascular function in the prediction of fetal distress in labor: a prospective cohort study.

OBJECTIVE: To explore the strength of association and the diagnostic accuracy of maternal hemodynamic parameters detected noninvasively in predicting an adverse perinatal outcome in labor. METHODS: Prospective cohort study of singleton women undergoing antepartum care at 37-39 weeks of gestation. A noninvasive ultrasonic cardiac output monitor (USCOM®) was used for cardiovascular assessment. The study outcome was a composite score of adverse perinatal outcome, which included at least one of the following variables: Cesarean or instrumental delivery for abnormal fetal heart monitoring, umbilical artery pH <7.10 or admission to neonatal special care unit. Attending clinicians were blinded to maternal cardiovascular indices. Multivariate logistic regression and area under the curve (AUC) analyses were used to test the diagnostic accuracy of different maternal and ultrasound characteristics in predicting adverse perinatal outcome. RESULTS: A total of 133 women were recruited. The rate of adverse perinatal outcome was 25.6% (34/133). Women who delivered without abnormal perinatal outcome (controls) were more likely to be parous, compared to those who had an adverse perinatal outcome (44.4 vs. 73.5%; p = .005). Control women had significantly lower systemic vascular resistance (SVR) (median, 1166 vs. 1352 dynes × s/cm5, p = .023) and SVR index (SVRI) (median, 2168 vs. 2627 dynes × s/cm5/m2, p = .039) compared to women who had an adverse perinatal outcome. In this latter group the prevalence of SV <50 ml was significantly higher than in the control group (38.2% (13/34) vs. 11.1%, (11/99) p = .0012). At multivariable logistic regression analysis, SVR (aOR 1.307; 95% CI 1.112-2.23), SV <50 ml (aOR 4.70; 95% CI 1.336-12.006) and parity (3.90: 95% CI 1.545-10.334) were the only variables independently associated with adverse perinatal outcome. A model considering only SVR showed an AUC of 0.631. Integration of SVR with SV <50 ml and parity significantly improves the diagnostic performance of SVR alone to predict adverse outcome (AUC 0.732; p = .016). CONCLUSION: Pre-labor modifications of maternal cardiovascular variables are associated with adverse perinatal outcome. However, their predictive accuracy for perinatal compromise is low, and thus their use as standalone screening test for adverse perinatal outcome in singleton pregnancies at term is not supported.

Hydroxychloroquine in obstetric antiphospholipid syndrome: rationale and results of an observational study of refractory cases.

BACKGROUND: The current recommended therapy of obstetric antiphospholipid syndrome (APS) is a long-term anticoagulant therapy that affects the final event, namely, when the thrombosis has already occurred. Unfortunately, this schedule is not always effective and fails despite the correct risk stratification and an adequate adjusted dose. MATERIALS AND METHODS: From 2013 to 2020 we observed 217 women with antiphospholipid antibodies and obstetric morbidities who were treated with conventional treatment protocol (aspirin low doses ± LMWH). Among them 150 (69.1%) successfully completed pregnancy with delivery and live birth on the background of LMWH and aspirin therapy and in 67 (30.9%) women despite a traditional therapy regimen, obstetric complications were noted. Later, 56 of these 67 women became pregnant again and were offered traditional therapy plus hydroxychloroquine. Fifteen women refused HCQ treatment due to possible potential side effects. The final cohort consisted of 41 women with positive antiphospholipid antibodies and obstetric and thrombotic complications who received LMWH, aspirin low doses and HCQ at a dose of 200-400mg per day from the beginning of pregnancy. RESULTS: Forty-one aPL women treated with HCQ after failed previous anticoagulant therapy had live births in 32 cases (78%). Adding of HCQ to the combination of LMWH and LDA showed good overall obstetric results and increased the number of live births in another 32 women. So, a total of 182 (83.8%) of initial 217 aPL-women ended their pregnancies with live birth after adding the HCQ to the traditional therapy with LMWH and low doses of aspirin. CONCLUSION: In 20-30% of cases the live birth despite anticoagulation cannot be achieved. Perhaps APS is not just anticoagulation. The study of pathophysiological mechanisms suggests that some patients will benefit from other therapy (in addition to anticoagulant). Therapy that affects the early effects of aPL on target cells (monocytes, endothelial cells, etc.) or before binding to receptors-this therapy will be preferable and potentially less harmful than the officially accepted one to date. From this point of view, HCQ looks promising and can be used as an alternative candidate for women with refractory obstetric antiphospholipid syndrome. Adding HCQ should be considered in some selected patients with failed pregnancy after treatment with anticoagulants.

Prediction of delivery after 40 weeks by antepartum ultrasound in singleton multiparous women: a prospective cohort study.

OBJECTIVE: Universal elective induction of labor (IOL) in singleton parous pregnancies has been advocated to reduce the rate of cesarean section (CD), without impacting on maternal outcome. However, about 50% of women deliver after 40 weeks; therefore, an accurate estimation of the time of delivery might avoid unnecessary early IOL. The aim of this study was to test the diagnostic accuracy of ultrasound in predicting delivery ≥40 weeks of gestation in singleton parous women. METHODS: Prospective cohort study of singleton parous women undergoing a dedicated ultrasound assessment at 36-38 weeks of gestation. The primary outcome was spontaneous vaginal delivery ≥40 weeks of gestation. Cervical length (CL), posterior cervical angle (PCA), sonoelastographic hardness ratio (HR), angle of progression (AoP) and head perineal distance (HPD) were measured. Multivariate logistic regression and area under the curve (AUC) analyses were used to test the diagnostic accuracy of different maternal and ultrasound characteristics in predicting delivery ≥40 weeks. RESULTS: 518 singleton pregnancies were included in the analysis and 235 (45.4%) delivered ≥40 weeks. CL (29 vs 19 mm; p ≤ .0001) and HPD (50 vs 47 mm; p = .001) were longer, HR higher (38.9 vs 35.5; p = .04), while PCA (98° vs 104°; p ≤ .0001) and AOP narrower (93° vs 98°; p = .029) in pregnancies delivered compared to those not delivered after 40 weeks of gestation. At multivariable logistic regression analysis, CL (aOR 1.206; 95% CI 1.164-1.250), HPD (aOR 1.127; 95% CI 1.066-1.191) and HR (aOR 1.022; 95% CI 1.003-1.041 were the only variables independently associated with delivery ≥40 weeks. CL showed had an AUC of 0.863 in predicting delivery ≥40 weeks of gestation, with an optimal cutoff of 23.5 mm. Integration of HPD and HR did not significantly improve the diagnostic performance of CL alone to predict delivery ≥40 weeks (AUC 0.870; p = .472). CONCLUSION: Cervical length at 36-38 weeks has a good diagnostic accuracy to predict spontaneous vaginal delivery at ≥40 weeks. Universal assessment of CL in the third trimester of pregnancy may help in identifying those women who may benefit of elective IOL at 39 weeks.

Approach to the Evaluation and Treatment of Venous Thromboembolism in Pregnancy.

Thrombosis in pregnancy is a major cause of maternal and fetal morbidity and mortality. Risk stratification of venous thromboembolism (VTE) during pregnancy is complex. The hypercoagulability observed in pregnant women can reduce bleeding during childbirth, but may cause thrombosis especially in the presence of additional prothrombotic risk factors such as antiphospholipid antibodies or genetic thrombophilic defects. The availability of large datasets allows for the identification of additional independent risk factors, including assisted reproductive technologies (ARTs), endometriosis, and recurrent pregnancy loss. Data on the risk of VTE linked to COVID-19 in pregnant women are very limited, but suggest that infected pregnant women have an increased risk of VTE. Current guidelines on the prevention and treatment of VTE in pregnancy are based on available, albeit limited, data and mainly present expert opinion. Low-molecular-weight heparins (LMWHs) are the mainstay of anticoagulation to be employed during pregnancy. Administration of LMWH for VTE treatment in pregnancy should be based on the personalized approach, taking into account a weight-based adjusted scheme. During gestation, due to physiological changes, in women at high risk of VTE, monitoring of anti-Xa activity is performed to ensure adequate LMWH dosing. As for the treatment duration for pregnant women with acute VTE, guidelines suggest that anticoagulation should be continued for at least 6 weeks postpartum for a minimum total duration of therapy of 3 months.

Molecular mimicry between SARS-CoV-2 and the female reproductive system.

INTRODUCTION: Oogenesis, the process of egg production by the ovary, involves a complex differentiation program leading to the production of functional oocytes. This process comprises a sequential pathway of steps that are finely regulated. The question related to SARS-CoV-2 infection and fertility has been evoked for several reasons, including the mechanism of molecular mimicry, which may contribute to female infertility by leading to the generation of deleterious autoantibodies, possibly contributing to the onset of an autoimmune disease in infected patients. OBJECTIVE: The immunological potential of the peptides shared between SARS-CoV-2 spike glycoprotein and oogenesis-related proteins; Thus we planned a systematic study to improve our understanding of the possible effects of SARS-CoV-2 infection on female fertility using the angle of molecular mimicry as a starting point. METHODS: A library of 82 human proteins linked to oogenesis was assembled at random from UniProtKB database using oogenesis, uterine receptivity, decidualization, and placentation as a key words. For the analyses, an artificial polyprotein was built by joining the 82 a sequences of the oogenesis-associated proteins. These were analyzed by searching the Immune Epitope DataBase for immunoreactive SARS-CoV-2 spike glycoprotein epitopes hosting the shared pentapeptides. RESULTS: SARS-CoV-2 spike glycoprotein was found to share 41 minimal immune determinants, that is, pentapeptides, with 27 human proteins that relate to oogenesis, uterine receptivity, decidualization, and placentation. All the shared pentapeptides that we identified, with the exception of four, are also present in SARS-CoV-2 spike glycoprotein-derived epitopes that have been experimentally validated as immunoreactive.

Low Preconception Complement Levels Are Associated with Adverse Pregnancy Outcomes in a Multicenter Study of 260 Pregnancies in 197 Women with Antiphospholipid Syndrome or Carriers of Antiphospholipid Antibodies.

Antiphospholipid antibodies (aPL) can induce fetal loss in experimental animal models. Human studies did find hypocomplementemia associated with pregnancy complications in patients with antiphospholipid syndrome (APS), but these results are not unanimously confirmed. To investigate if the detection of low C3/C4 could be considered a risk factor for adverse pregnancy outcomes (APO) in APS and aPL carriers' pregnancies we performed a multicenter study including 503 pregnancies from 11 Italian and 1 Russian centers. Data in women with APS and asymptomatic carriers with persistently positive aPL and preconception complement levels were available for 260 pregnancies. In pregnancies with low preconception C3/C4, a significantly higher prevalence of pregnancy losses was observed (p = 0.008). A subgroup analysis focusing on triple aPL-positive patients found that preconception low C3 and/or C4 levels were associated with an increased rate of pregnancy loss (p = 0.05). Our findings confirm that decreased complement levels before pregnancy are associated with increased risk of APO. This has been seen only in women with triple aPL positivity, indeed single or double positivity does not show this trend. Complement levels are cheap and easy to be measured therefore they could represent a useful aid to identify patients at increased risk of pregnancy loss.