The Phenomenon of Thrombotic Microangiopathy in Cancer Patients.

Thrombotic microangiopathy (TMA) encompasses a range of disorders characterized by blood clotting in small blood vessels, leading to organ damage. It can manifest as various syndromes, including thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), and others, each with distinct causes and pathophysiology. Thrombo-inflammation plays a significant role in TMA pathogenesis: inflammatory mediators induce endothelial injury and activation of platelet and coagulation cascade, contributing to microvascular thrombosis. Primary TMA, such as TTP, is primarily caused by deficient ADAMTS13 metalloproteinase activity, either due to antibody-mediated inhibition or intrinsic enzyme synthesis defects. In cancer patients, a significant reduction in ADAMTS13 levels and a corresponding increase in VWF levels is observed. Chemotherapy further decreased ADAMTS13 levels and increased VWF levels, leading to an elevated VWF/ADAMTS13 ratio and increased thrombotic risk. Drug-induced TMA (DITMA) can result from immune-mediated or non-immune-mediated mechanisms. Severe cases of COVID-19 may lead to a convergence of syndromes, including disseminated intravascular coagulation (DIC), systemic inflammatory response syndrome (SIRS), and TMA. Treatment of TMA involves identifying the underlying cause, implementing therapies to inhibit complement activation, and providing supportive care to manage complications. Plasmapheresis may be beneficial in conditions like TTP. Prompt diagnosis and treatment are crucial to prevent serious complications and improve outcomes.

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.

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.

Venous thrombosis risk factors in pregnant women.

Venous thromboembolism (VTE) is the third most common cause of death on Earth after myocardial infarctions and strokes, according to the World Health Organization (WHO). Pregnancy is a unique condition of woman, when enormous changes occur in functioning of the most important systems of homeostasis in a relatively short time. These are physiological hypercoagulation, slowing of blood flow, increase in circulating blood volume, etc. However, while being physiological, these changes increase the risks of venous thromboembolism by almost 6 times. In some cases, there appears an imbalance or dissociation between the functioning of natural antithrombotic systems and the activation of coagulation as a consequence of genetically or acquired determined causes (genetic thrombophilia, antiphospholipid syndrome, comorbidities, obstetric complications and other exogenous and endogenous factors). Accordingly, identification of risk factors, their systematization, and determination of VTE risks in pregnancy and puerperium is one of the most important tasks of clinical medicine. Various recommendations have appeared for practitioners during the last 10-15 years on the basis of the risk factors analysis in order to prevent VTE in pregnant women more effectively. Nevertheless, none of these recommendations can yet take into account all risk factors, although convenient scoring systems have emerged for risk assessment and clear recommendations on anti-thrombotic prophylaxis regimens in risk groups in recent years. This article will review historical understanding of thrombosis in pregnant women, progress in understanding VTE risk factors in pregnant women, and available reserves in identifying new risk factors during pregnancy and puerperium in order to stratify risks more efficiently.

Findings from a multicentre, observational study on reproductive outcomes in women with unexplained recurrent pregnancy loss: the OTTILIA registry.

STUDY QUESTION: What evaluation and care is offered to women after unexplained recurrent pregnancy loss (RPL) or intra-uterine foetal death (IUFD) and what are the reproductive outcomes? SUMMARY ANSWER: Women are assessed for thrombophilia and often treated with low-molecular weight heparin (LMWH) and/or low-dose aspirin (ASA). WHAT IS KNOWN ALREADY: Randomized controlled trials (RCTs) on possible efficacy of heparins and/or aspirin have been inconclusive due to limited power to detect a difference and patient heterogeneity. STUDY DESIGN, SIZE, DURATION: Prospective multicentre cohort study performed in 12 hospitals in three countries between 2012 and 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: All consecutive pregnant women with recurrent PL (≥3 losses or 2 losses in the presence of at least one euploid foetal karyotype) or at least one IUFD. Eligible women may have undergone thrombophilia testing before conception, at the discretion of local providers. The possible assignment of women to treatments (such as LMWH) was not decided a priori but was determined based on the responsible provider's current practice. Aims of the study were: (i) to evaluate factors associated with pregnancy outcome; (ii) to compare clinical management strategies in women with and without a subsequent successful pregnancy; and (iii) to evaluate characteristics of women who may benefit from antithrombotic therapy. A propensity score matching method was used to balance the differences in baseline characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: A matched sample of 265 pregnant women was analysed, with all undergoing thrombophilia screening; 103 out of 119 (86.6%) with and 98/146 (67.1%) without thrombophilia were prescribed with LMWH and/or ASA. Overall, live-births were recorded in 204 cases (77%), PL or IUFD in 61 (23%) pregnancies. Logistic regression showed a significant interaction between thrombophilia and treatment with LMWH (P = 0.03). Findings from sensitivity analysis showed odds ratio (OR) for pregnancy loss in women with inherited or acquired thrombophilia in absence of any treatment was 2.9 (95% CI, 1.4-6.1); the administration of LMWH (with or without ASA) was associated with higher odds of live-birth (OR, 10.6; 95% CI, 5.0-22.3). Furthermore, in women without thrombophilia, the odds of live-birth was significantly and independently associated with LMWH prophylaxis (alone or in association with ASA) (OR, 3.6; 95% CI, 1.7-7.9). LIMITATIONS, REASONS FOR CAUTION: While the propensity score matching allows us to balance the differences in baseline characteristics, it does not eliminate all confounding. WIDER IMPLICATIONS OF THE FINDINGS: Antithrombotic prophylaxis during pregnancy may be effective in women with otherwise unexplained PL or IUFD, and even more useful in those with thrombophilia. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by Italian Ministry of Health (Ricerca Corrente 2018-2020). Dr G.P. has received research grant support from Bristol Myers Squibb/Pfizer Alliance, Janssen, Boston Scientific Corporation, Bayer, and Portola and consultant fees from Amgen and Agile Therapeutics. Dr E.G. has received consultant fees from Italfarmaco and Sanofi. All other authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: NCT02385461.

Effect of SARS-CoV-2 infection during the second half of pregnancy on fetal growth and hemodynamics: A prospective study.

INTRODUCTION: Our objective was to compare the fetal growth velocity and fetal hemodynamics in pregnancies complicated and in those not complicated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. MATERIAL AND METHODS: Prospective case-control study of consecutive pregnancies complicated by SARS-CoV-2 infection during the second half of pregnancy matched with unaffected women. The z scores of head circumference, abdominal circumference, femur length, and estimated fetal weight were compared between the two groups. Fetal growth was assessed by analyzing the growth velocity of head circumference, abdominal circumference, femur length, and estimated fetal weight between the second- and third-trimester scans. Similarly, changes in the pulsatility index of uterine, umbilical, and middle cerebral arteries, and their ratios were compared between the two study groups. RESULTS: Forty-nine consecutive pregnancies complicated, and 98 not complicated, by SARS-CoV-2 infection were included. General baseline and pregnancy characteristics were similar between pregnant women with and those without SARS-CoV-2 infection. There was no difference in head circumference, abdominal circumference, femur length, and estimated fetal weight z scores between pregnancies complicated and those not complicated by SARS-CoV-2 infection at both the second- and third-trimester scans. Likewise, there was no difference in the growth velocity of all these body parameters between the two study groups. Finally, there was no difference in the pulsatility index of both maternal and fetal Doppler scans throughout gestation between the two groups. CONCLUSIONS: Pregnancies complicated by SARS-CoV-2 infection are not at higher risk of developing fetal growth restriction through impaired placental function. The findings from this study do not support a policy of increased fetal surveillance in these women.

The added value of umbilical vein flow in predicting fetal macrosomia at 36 weeks of gestation: A prospective cohort study.

INTRODUCTION: Current models based on fetal biometry and maternal characteristics have a poor performance in predicting macrosomia. The primary aim of this study was to elucidate the diagnostic performance of fetal venous and arterial Dopplers in predicting macrosomia in the third trimester of pregnancy; the secondary aim was to build a multiparametric prediction model including pregnancy, ultrasound and Doppler characteristics able to predict macrosomia accurately. MATERIAL AND METHODS: Prospective cohort study including 2156 singleton pregnancies scheduled for routine ultrasound assessment at 36 weeks of gestation. Fetal biometry, estimated fetal weight (EFW), pulsatility index of the uterine, umbilical, and middle cerebral arteries, cerebroplacental ratio and umbilical vein blood flow (UVBF) normalized for fetal abdominal circumference (UVBF/AC) were recorded. Primary outcome was the prediction of fetal macrosomia, defined as a birthweight >90th percentile; secondary outcome was the prediction of newborns >4000 g. Logistic regression and area under the curve (AUC) analyses were used to analyze the data. RESULTS: Fetal macrosomia complicated 9.8% of pregnancies, and 7.7% of newborns had a birthweight >4000 g. At multivariate logistic regression analysis, maternal body mass index (adjusted odds ratio [aOR] 1.23), pregestational diabetes (aOR 1.83), a prior newborn with a birthweight >95th centile (aOR 1.49), EFW (aOR 2.23) and UVBF (aOR1.84) were independently associated with macrosomia, whereas gestational diabetes mellitus (P = .07) or any of the other Doppler parameters were not. EFW had an AUC of 0.750 and of 0.801 alone and in association with maternal characteristics for the prediction of macrosomia, respectively. The addition of UVBF to this model significantly improved the prediction of fetal macrosomia provided by maternal and ultrasound parameters with an AUC of 0.892 (De Long P = .044 and P = .0078, respectively). The predictive performance for birthweight >4000 g was similar and significantly improved when UVBF was included in the diagnostic algorithm. CONCLUSIONS: Umbilical vein blood flow evaluation in the third trimester improves the diagnosis of fetal macrosomia. The optimal diagnostic performance for macrosomia is achieved by a multiparametric model including umbilical vein flow, maternal characteristics and EFW.

Sonoelastographic Assessment of the Uterine Cervix in the Prediction of Imminent Delivery in Singleton Nulliparous Women Near Term: A Prospective Cohort Study.

OBJECTIVES: To explore the role of newly developed software to assess cervical sonoelastography in predicting the onset of spontaneous delivery in singleton pregnancies at term and to compare its diagnostic performance with that provided by the cervical length (CL) and posterior cervical angle (PCA). METHODS: This work was a prospective study including nulliparous singleton pregnancies at gestational ages of 37 weeks to 38 weeks 6 days. The CL, PCA, hardness ratio (HR), and mean strain from the internal os and external os were obtained by a transvaginal ultrasound approach using semiautomatic software (E-Cervix; Samsung Medison Co, Ltd, Seoul, Korea). Multivariate logistic regression and area under the curve analyses were used to test the strength of the association and the diagnostic performance of the variables considered in predicting delivery within 7 days. RESULTS: A total of 398 women were included, and 24.6% delivered within 7 days. The CL was shorter (19.5 versus 2 7 mm; P = .0001), PCA narrower (99° versus 102°; P = .02) HR lower (35.3 versus 40.7; P = .0001), mean strain from the external os higher (0.41 versus 0.35; P = .0001), and mean strain from the internal os higher (0.38 versus 0.33; P = .0001) higher in women who delivered within 7 days from the assessment. At the multivariable logistic regression analysis, the CL (adjusted odds ratio, 1.307) and HR (adjusted odds ratio, 1.227) were the only variables independently associated with delivery within 1 week. A model combining the CL and HR showed an area under the curve of 0.873 in predicting delivery within 7 days, higher than that obtained by using the CL and HR singularly (P ≤ .0001). CONCLUSIONS: The HR assessed by sonoelastography improves the efficacy of the CL in predicting imminent delivery in nulliparous women close to term.

Venous thrombosis risk factors in pregnant women.

OBJECTIVES: Assess all risk factors of venous thromboembolism (VTE) in pregnancy and puerperium. METHODS: Different guidelines for VTE prevention have been analyzed. RESULTS: Various recommendations have appeared for practitioners during the last 10-15 years on the basis of the risk factors analysis in order to prevent VTE in pregnant women more effectively. Nevertheless, none of these recommendations can yet take into account all risk factors, although convenient scoring systems have emerged for risk assessment and clear recommendations on anti-thrombotic prophylaxis regimens in risk groups in recent years. CONCLUSIONS: VTE is the third most common cause of death on Earth after myocardial infarctions and strokes, according to the World Health Organization. Pregnancy is a unique condition of woman, when enormous changes occur in functioning of the most important systems of homeostasis in a relatively short time. These are physiological hypercoagulation, slowing of blood flow, increase in circulating blood volume, etc. However, while being physiological, these changes increase the risks of venous thromboembolism by almost six times. In some cases, there appears an imbalance or dissociation between the functioning of natural antithrombotic systems and the activation of coagulation as a consequence of genetically or acquired determined causes (genetic thrombophilia, antiphospholipid syndrome, comorbidities, obstetric complications and other exogenous and endogenous factors). Accordingly, identification of risk factors, their systematization, and determination of VTE risks in pregnancy and puerperium is one of the most important tasks of clinical medicine. This article will review historical understanding of thrombosis in pregnant women, progress in understanding VTE risk factors in pregnant women, and available reserves in identifying new risk factors during pregnancy and puerperium in order to stratify risks more efficiently.

Fetal Cardiac Remodeling Is Affected by the Type of Embryo Transfer in Pregnancies Conceived by in vitro Fertilization: A Prospective Cohort Study.

OBJECTIVE: Pregnancies conceived via intracytoplasmic sperm injection (ICSI) are associated with a higher risk of fetal cardiac remodeling. The aim of this study was to evaluate whether the type of embryo transfer may affect the magnitude of fetal cardiac remodeling in pregnancies conceived via ICSI. METHODS: Prospective cross-sectional study including 212 pregnancies conceived by ICSI (111 with frozen and 101 with fresh embryos) and 120 spontaneously conceived gestations. All women underwent ultrasound biometric evaluation, Doppler, and echocardiographic assessment, including evaluation of left and right atrial areas and sphericity index (SI), at 20-24 weeks of gestation. The χ2 and Kruskal-Wallis H tests were used to analyze the data. RESULTS: There was no difference in maternal characteristics, gestational age at ultrasound, Doppler, and fetal weight among the study groups. In pregnancies conceived by ICSI, left and right atrial areas were higher (p < 0.0001) and SI was lower (p < 0.0001) compared to spontaneously conceived pregnancies. Left (p = 0.004) and right (p = 0.023) atrial areas and left (p = 0.036) and right (p = 0.002) SIs were more affected in ICSI pregnancies conceived by fresh embryos. CONCLUSION: The risk of fetal cardiac remodeling is higher in pregnancies conceived by ICSI and independent from fetal size and Doppler. The magnitude of these changes is affected by the type of ICSI technique and is higher in pregnancies conceived by fresh embryos.

Hemodynamic factors associated with fetal cardiac remodeling in late fetal growth restriction: a prospective study.

Background Altered cardiac geometry affects a proportion of fetuses with growth restriction (FGR). The aim of this study was to explore the hemodynamic factors associated with cardiac remodeling in late FGR. Methods This was a prospective study of singleton pregnancies complicated by late-onset FGR undergoing assessment of left (LV) and right (RV) ventricular sphericity-index (SI). The study population was divided in two groups according to the presence of cardiac remodelling, defined as LVSI <5th centile. The following outcomes were explored: gestational age at birth, birthweight, caesarean section (CS) for fetal distress, umbilical artery (UA) pH and neonatal admission to special care unit. The differences between the 2 groups in UA pulsatility index (PI), middle cerebral artery (MCA) PI, uterine artery PI, cerebroplacental ratio (CPR) and umbilical vein (UV) flow corrected for fetal abdominal circumference (UVBF/AC) were tested. Results In total, 212 pregnancies with late FGR were enrolled in the study. An abnormal LV SI was detected in 119 fetuses (56.1%). Late FGR fetuses with cardiac remodeling had a lower birthweight (2390 g vs. 2490; P = 0.04) and umbilical artery pH (7.21 vs. 7.24; P = 0.04) and were more likely to have emergency CS (42.8% vs. 26.9%; P = 0.023) and admission to special care unit (13.4% vs. 4.3%; P = 0.03) compared to those with normal LVSI. No difference in either UA PI (p = 0.904), MCA PI (P = 0.575), CPR (P = 0.607) and mean uterine artery PI (P = 0.756) were present between fetuses with or without an abnormal LV SI. Conversely, UVBF/AC z-score was lower (-1.84 vs. -0.99; P ≤ 0.001) in fetuses with cardiac remodeling and correlated with LV (P ≤ 0.01) and RV SI (P ≤ 0.02). Conclusion Fetal cardiac remodelling occurs in a significant proportion of pregnancies complicated by late FGR and is affected by a high burden of short-term perinatal compromise. The occurrence of LV SI is independent from fetal arterial Dopplers while it is positively associated with umbilical vein blood flow.

Thromboprophylaxis in pregnant women with thrombophilia and a history of thrombosis.

Background Despite intensive research, thromboembolism still accounts for significant maternal morbidity and mortality. We examined thrombophilia in patients with thromboembolism during pregnancy and evaluated the efficiency of antithrombotic prophylaxis in patients with thrombophilia for the prevention of recurrent thromboembolism. Materials and methods Sixty-eight women with a history of thromboembolism were managed during pregnancy, in light of their thrombotic history and the result of thrombophilia assessment. Group I (n=50) received prophylaxis with low molecular weight heparin (LMWH)±aspirin (50-100 mg/day) in preconception period or from the 1st trimester, during pregnancy and at least 6 weeks postpartum. Group II (n=18) received LMWH±aspirin from the II to III trimester. Results Thromboses were associated with pregnancy in 27 patients (39.7%), with systemic diseases - in nine (13.2%), oral contraceptives use - 22 (32.3%), immobilization due to surgery and/or trauma, long flight - six (8.9%), septic complications - two (2.9%). Nevertheless, 24.5% of patients had no apparent provoking factor for the development of thrombotic complications. Thirty-seven (54%) patients with venous thromboembolism (VTE) had familial history of VTE, and 25 (36.7%) had personal history of pregnancy complications (fetal loss syndrome, preeclampsia and placental abruption) (P<0.05 vs. control). Thrombophilia was detected in 58 (85.3%). Usual thrombogenic polymorphisms [factor V (FV) Leiden and prothrombin G20210A, heterozygous forms] were revealed in 16 (23.5%) and eight (11.7%) patients, respectively. Antiphospholipid antibodies (aPL) circulation was found in 34 (50%) patients. Non-usual thrombogenic polymorphisms were identified in 44 (64.7%) of the women and hyperhomocysteinemia - in 30 (44.2%). In group I no one had severe obstetric complications. All the patients were delivered at term and all the babies were alive. In group II moderate-to-severe obstetric complications were noted: preeclampsia - in 11 (16.2%), severe preeclampsia - seven (10.3%), preterm delivery - in 18 (26.4%) patients from subgroup II (P<0.05). Conclusions Women with a personal or a family history of thromboembolism and obstetric complications should be screened for thrombophilia. Beginning anticoagulant therapy early in such patients is effective not only for preventing recurring thrombosis but also preventing obstetric complications. Late prophylaxis after the completion of the trophoblast invasion therapy is much less effective.

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.

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.

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.

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.

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.

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.