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Fifty newborn Saanen kids were used to study the effects of inulin supplementation on faecal score, faecal pH, selected faecal bacterial population, BW, body temperature, haematological traits, selected health parameters and the incidence of diarrhoea. Kids were sorted by parity of their dams and multiple birth (twin or triplet) and assigned to one of the two groups (control: CG, and experimental: EG) at birth. Each group consisted of 25 kids. The groups were similar with regard to sex and birth weight. All kids were fed colostrum for the first 3 days after birth, and then the kids in EG were adapted to inulin supplementation by an increased dosage from day 4 to 7. Each kid in EG was supplemented with 0.2 g, 0.3 g, 0.4 g, 0.5 g and 0.6 g inulin on day 4, 5, 6, 7 and from day 8 to 28, respectively, whereas the kids in CG did not receive inulin. Faecal score and faecal bacterial population were not affected by inulin supplementation (P > 0.05). There were differences in faecal pH on day 14 (P = 0.01) and 28 (P 0.05) was detected between groups. No differences (P > 0.05) in BW and haematological traits were found between groups. Body temperature did not differ on day 14 and 21 (P > 0.05), whereas there was a difference in body temperature on day 28 (P = 0.01) between groups. The numbers of kids with pneumonia and kids treated for pneumonia and diarrhoea were similar for CG and EG. Kid losses during the study were the same for CG and EG. The incidence of diarrhoea was not affected by inulin supplementation (P > 0.05). Inulin supplemented to kids did not adversely affect faecal score. The effect of inulin on faecal pH was not consistent. The results of our study suggested that daily dose (0.6 g) of inulin might not be enough to observe effects of it. Our data will be useful to determine the dose and timing of inulin supplementation in future studies investigating the effects of inulin on the parameters associated with performance and health status in kids and other young ruminants.

Gravitational Field-Flow Fractionation (GrFFF) is an elution-based method designed for the separation of particles ranging from a few micrometers up to approximately 100 μm in diameter. Separation occurs over time, with particles being fractionated based on size and other physico-chemical properties. GrFFF takes advantage of gravitational forces acting perpendicularly to a laminar flow in a thin channel. The fluid exhibits a parabolic velocity profile, with the maximum velocity at the center of the channel and zero velocity at the walls. The exit time of particles depends on their equilibrium position relative to the bottom wall. In hyperlayer mode, larger particles elute faster than smaller ones due to their higher velocities within the channel. This study investigated the effect of adding methylcellulose (MC) to the carrier fluid on the elution behavior - specifically, peak time (t peak ) and resolution (R) - of polystyrene-based (PS) microparticles with sizes of 7, 8, and 10 μm. The results demonstrated that MC not only increases the viscosity of the carrier fluid but also exerts a secondary, predominant effect that improves resolution (R), thereby enhancing the separation of particle populations. This was confirmed by comparing the use of water as the carrier fluid at two different temperatures: 14 °C (high viscosity) and 28 °C (low viscosity). While increasing viscosity by lowering temperature only led to modest reduction in elution time of the fractograms, the addition of MC had a size-dependent effect on the microparticles, significantly improving R without changing other experimental parameters. This suggests the presence of additional phenomena contributing to the improved separation. In conclusion, the addition of MC to the carrier fluid increases the resolving power of GrFFF, enabling the separation of PS microbeads with a size difference of up to 2 μm. This advancement pushes the boundaries of GrFFF and opens up potential new applications. These studies, conducted on PS microbeads, provide a preliminary basis for future work on cells, which have similar density and size. This could pave the way for improved cell separation in diagnostic applications., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Irene Cetin reports financial support was provided by Italian Ministry of Health. Debora Lattuada has patent #WO2014173997A3 issued to Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: The study of the macroscopic appearance of the placenta may represent a useful tool to understand the pathophysiology of adverse pregnancy outcomes. The aim of this study was to evaluate biometry and morphology of placentas in relation to maternal, neonatal and pregnancy course characteristics., Methods: Clinical and placental data (biometry and macroscopic features of chorionic disk and adnexa) from unselected consecutive singleton pregnancies were recorded at the same Institution. Placental efficiency was approximated as ratio between fetal and placental weight (FPR). The total population was grouped according to the presence of any maternal comorbidity or pregnancy complication (group 1), neonatal complications diagnosed only at birth (2) and absence of any comorbidity (3). Multi-adjusted general linear and logistic regression models were performed to analyze associations between groups and placental biometry and morphology., Results: The study population counted 1008 pregnancies: 576 (57.2 %) classified as group 1, 76 (7.5 %) as group 2 and 356 (35.3 %) uncomplicated controls (group 3). In multivariate models adjusted for confounding factors, no significant differences in placental biometry and macroscopic features were observed among the three groups. Maternal BMI was significantly associated with higher placental and birth weight and lower FPR; moreover FPR was significantly higher in pregnancies carrying males compared to female neonates., Discussion: Maternal comorbidity or pregnancy disease was not associated with significant changes in placental macroscopic biometry and morphology. Conversely, maternal pregestational BMI and fetal sex impact on placental biometry and efficiency, suggesting different intrauterine adaptations in obese mothers and in male and female fetuses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2023 Università degli Studi di Milano. Published by Elsevier Ltd.. All rights reserved.)

Autoimmune rheumatic diseases (ARD) can affect women and men during fertile age, therefore reproductive health is a priority issue in rheumatology. Many topics need to be considered during preconception counselling: fertility, the impact of disease-related factors on pregnancy outcomes, the influence of pregnancy on disease activity, the compatibility of medications with pregnancy and breastfeeding. Risk stratification and individualized treatment approach elaborated by a multidisciplinary team minimize the risk of adverse pregnancy outcomes (APO). Research has been focused on identifying biomarkers that can be predictive of APO. Specifically, preeclampsia and hypertensive disorders of pregnancy tend to develop more frequently in women with ARD. Placental insufficiency can lead to intrauterine growth restriction and small-for-gestational age newborns. Such APO have been shown to be associated with maternal disease activity in different ARD. Therefore, a key message to be addressed to the woman wishing for a pregnancy and to her family is that treatment with compatible drugs is the best way to ensure maternal and fetal wellbeing. An increasing number of medications have entered the management of ARD, but data about their use in pregnancy and lactation are scarce. More information is needed for most biologic drugs and their biosimilars, and for the so-called small molecules, while there is sufficient evidence to recommend the use of TNF inhibitors if needed for keeping maternal disease under control. Other issues related to the reproductive journey have emerged as "unmet needs", such as sexual dysfunction, contraception, medically assisted reproduction techniques, long-term outcome of children, and they will be addressed in this review paper. Collaborative research has been instrumental to reach current knowledge and the future will bring novel insights thanks to pregnancy registries and prospective studies that have been established in several Countries and to their joint efforts in merging data., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aims: Although adequate clinical management of patients with hypercholesterolemia without a history of known cardiovascular disease is essential for prevention, these subjects are often disregarded. Furthermore, the scientific literature on primary cardiovascular prevention is not as rich as that on secondary prevention; finally, physicians often lack adequate tools for the effective management of subjects in primary prevention and have to face some unsolved relevant issues. This document aims to discuss and review the evidence available on this topic and provide practical guidance., Data Synthesis: Available algorithms and risk charts represent the main tool for the assessment of cardiovascular risk in patients in primary prevention. The accuracy of such an estimate can be substantially improved considering the potential contribution of some additional risk factors (C-reactive protein, lipoprotein(a), family history of cardiovascular disease) and conditions (environmental pollution, sleep quality, socioeconomic status, educational level) whose impact on the cardiovascular risk has been better understood in recent years. The availability of non-invasive procedures to evaluate subclinical atherosclerosis may help to identify subjects needing an earlier intervention. Unveiling the presence of these conditions will improve cardiovascular risk estimation, granting a more appropriate intervention., Conclusions: The accurate assessment of cardiovascular risk in subjects in primary prevention with the use of algorithms and risk charts together with the evaluation of additional factors will allow physicians to approach each patient with personalized strategies, which should translate into an increased adherence to therapy and, as a consequence, a reduced cardiovascular risk., Competing Interests: Declaration of competing interest ALC reports grant(s)/support from Akcea, Amarin, Amgen, Menarini, Mylan, Sanofi, and Sanofi/Regeneron; consultant for Akcea, Amgen, Amarin, Daiichi-Sankyo, Eli Lilly, Esperion, Kowa, Ionis Pharmaceuticals, Menarini, MSD, Mylan, Novartis, Recordati, Regeneron, and Sanofi, outside the submitted work. AFGC reports scientific advice and/or speaking fees from Servier Italia, Fidia Farmaceutici, and Sharper SpA; AC reports scientific advice and/or speaking fees from Servier, DOC, Fidia, Amgen, Sanofi, Daichi Sankyo, AstraZeneca, Novartis; DP reports scientific advice with Merck Serono and Boehringer; GS reports scientific advice and/or speaking fees from Novo Nordisk, Servier, MSD, Sanofi, Daiichi Sankyo, Eli Lilly, Sobi, Vifor Pharma, Amarin, Novartis, Sobi, Teva, and Amgen. Other authors report no conflict of interest related to the topic of this document., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Monochorionic twins (MC) develop under unique intrauterine conditions and show a high risk of compromise during fetal life. Here we describe umbilical vein blood flow (UVBF) and fetal oxygen and glucose utilization in uncomplicated MC twins and investigate possible differences within twin-pairs according to birth-order., Methods: Prospective single-center study on 48 uncomplicated MC twins enrolled at the time of elective cesarean delivery. Ultrasound measurements of UVBF for Twin 1 and Twin 2 labelled according to birth-order were performed before spinal anesthesia. Umbilical arterial and venous blood samples were collected for each twin after fetal delivery, and fetal oxygen and glucose deliveries and uptakes were computed., Results: All twins were delivered within 2 min from one-another under steady-state conditions at 36.4 weeks of median gestational age (IQR 36.0-37.0). Birthweight and umbilical cord gas analyses were within physiological ranges for all twins. Second-born twins showed significantly lower UVBF, measured before delivery, and lower median birthweight compared to first-borns. Moreover, median values of estimated fetal oxygen and glucose consumption were lower in second compared to first MC twins., Discussion: Uncomplicated MC twins show different birthweight, oxygenation and metabolic rates based on their position in utero, hinting at pre-existing conditions possibly deriving by uneven vascular and metabolic distribution of the two placental territories. The innovative findings of this study emphasize the biological uniqueness of these pregnancies and prompt further physiological studies on MC twins and placenta metabolism., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To estimate the incidence, and to investigate risk factors, management, and perinatal outcomes of eclampsia in Italy., Study Design: This is a prospective population-based cohort study enrolling all women admitted for eclampsia between November 2017 and March 2020. Incident cases were reported using electronic and anonymous data collection forms., Main Outcome Measures: Incidence, risk factors, maternal and perinatal morbidity, and mortality., Results: 109 cases were included for an estimated incidence rate of 1.5 (95 % CI 1.2-1.8) per 10.000 births. Risk of developing eclampsia was associated with multiple pregnancies (RR = 4.51; p < 0.001) and with pregnancies achieved with assisted reproductive technologies (RR = 3.03; p < 0.001). Magnesium sulfate was used as prophylaxis in almost 30 % of women with preeclampsia, and to treat an eclamptic fit in 89 % of women. The time interval between the first fit and delivery was 62 min for antepartum and 10 min for intrapartum cases. Around one third of women developed at least one other major complication and one mother died. Severe morbidity affected 13.3 % of the newborns. Two fetal and one neonatal death were reported., Conclusions: Our data revealed low incidence of eclampsia in Italy and prompt administration of antihypertensive drugs and magnesium sulfate to prevent eclampsia and to treat the recurrence of seizures. However, the rate of severe maternal complications is still high: increasing the time interval between fit and delivery seems to be crucial to achieve an effective stabilization of maternal conditions and reduce maternal major complications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objectives: It is now well established that in utero vertical SARS-CoV-2 transmission can occur during the late third trimester. However, little is known about other gestational ages. Recently, an increased risk of early miscarriage was reported in pregnant women who were SARS-CoV-2-positive. The objective of the current study was to evaluate the putative SARS-CoV-2 vertical transmission during the first trimester of pregnancy., Design: This is an observational study on pregnant women who were SARS-CoV-2-positive during the first trimester. Fetal and syncytiotrophoblastic specimens were collected by hysterosuction from 17 pregnant women who were SARS-CoV-2-positive and voluntarily terminated the pregnancy between week 8 and 12. We investigated the viral vertical transmission using SARS-CoV-2 RNA detection in the fetus and syncytiotrophoblast by two different techniques., Results: The results suggest that SARS-CoV-2 vertical transmission is indeed possible during the first trimester in asymptomatic women. Although maternal viremia was never detected, roughly 30% of the fetuses and 17% of the syncytiotrophoblasts were found to be SARS-CoV-2-positive., Conclusion: Indeed, SARS-CoV-2 can spread to the fetus through the syncytiotrophoblast. Concerningly, this happens in asymptomatic pregnant women as well. Possible long-term detrimental consequences on fetal development still need to be assessed. This should be taken into consideration in the management of pregnant women by implementing preventive strategies., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The effect of COVID-19 in pregnancy on maternal outcomes and its association with preeclampsia and gestational diabetes mellitus have been reported; however, a detailed understanding of the effects of maternal positivity, delivery mode, and perinatal practices on fetal and neonatal outcomes is urgently needed., Objective: To evaluate the impact of COVID-19 on fetal and neonatal outcomes and the role of mode of delivery, breastfeeding, and early neonatal care practices on the risk of mother-to-child transmission., Study Design: In this cohort study that took place from March 2020 to March 2021, involving 43 institutions in 18 countries, 2 unmatched, consecutive, unexposed women were concomitantly enrolled immediately after each infected woman was identified, at any stage of pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed up until hospital discharge. COVID-19 in pregnancy was determined by laboratory confirmation and/or radiological pulmonary findings or ≥2 predefined COVID-19 symptoms. The outcome measures were indices of neonatal and perinatal morbidity and mortality, neonatal positivity and its correlation with mode of delivery, breastfeeding, and hospital neonatal care practices., Results: A total of 586 neonates born to women with COVID-19 diagnosis and 1535 neonates born to women without COVID-19 diagnosis were enrolled. Women with COVID-19 diagnosis had a higher rate of cesarean delivery (52.8% vs 38.5% for those without COVID-19 diagnosis, P<.01) and pregnancy-related complications, such as hypertensive disorders of pregnancy and fetal distress (all with P<.001), than women without COVID-19 diagnosis. Maternal diagnosis of COVID-19 carried an increased rate of preterm birth (P≤.001) and lower neonatal weight (P≤.001), length, and head circumference at birth. In mothers with COVID-19 diagnosis, the length of in utero exposure was significantly correlated to the risk of the neonate testing positive (odds ratio, 4.5; 95% confidence interval, 2.2-9.4 for length of in utero exposure >14 days). Among neonates born to mothers with COVID-19 diagnosis, birth via cesarean delivery was a risk factor for testing positive for COVID-19 (odds ratio, 2.4; 95% confidence interval, 1.2-4.7), even when severity of maternal conditions was considered and after multivariable logistic analysis. In the subgroup of neonates born to women with COVID-19 diagnosis, the outcomes worsened when the neonate also tested positive, with higher rates of neonatal intensive care unit admission, fever, gastrointestinal and respiratory symptoms, and death, even after adjusting for prematurity. Breastfeeding by mothers with COVID-19 diagnosis and hospital neonatal care practices, including immediate skin-to-skin contact and rooming-in, were not associated with an increased risk of newborn positivity., Conclusion: In this multinational cohort study, COVID-19 in pregnancy was associated with increased maternal and neonatal complications. Cesarean delivery was significantly associated with newborn COVID-19 diagnosis. Vaginal delivery should be considered the safest mode of delivery if obstetrical and health conditions allow it. Mother-to-child skin-to-skin contact, rooming-in, and direct breastfeeding were not risk factors for newborn COVID-19 diagnosis, thus well-established best practices can be continued among women with COVID-19 diagnosis., (Copyright © 2022. Published by Elsevier Inc.)

Background: Among nonpregnant individuals, diabetes mellitus and high body mass index increase the risk of COVID-19 and its severity., Objective: This study aimed to determine whether diabetes mellitus and high body mass index are risk factors for COVID-19 in pregnancy and whether gestational diabetes mellitus is associated with COVID-19 diagnosis., Study Design: INTERCOVID was a multinational study conducted between March 2020 and February 2021 in 43 institutions from 18 countries, enrolling 2184 pregnant women aged ≥18 years; a total of 2071 women were included in the analyses. For each woman diagnosed with COVID-19, 2 nondiagnosed women delivering or initiating antenatal care at the same institution were also enrolled. The main exposures were preexisting diabetes mellitus, high body mass index (overweight or obesity was defined as a body mass index ≥25 kg/m 2 ), and gestational diabetes mellitus in pregnancy. The main outcome was a confirmed diagnosis of COVID-19 based on a real-time polymerase chain reaction test, antigen test, antibody test, radiological pulmonary findings, or ≥2 predefined COVID-19 symptoms at any time during pregnancy or delivery. Relationships of exposures and COVID-19 diagnosis were assessed using generalized linear models with a Poisson distribution and log link function, with robust standard errors to account for model misspecification. Furthermore, we conducted sensitivity analyses: (1) restricted to those with a real-time polymerase chain reaction test or an antigen test in the last week of pregnancy, (2) restricted to those with a real-time polymerase chain reaction test or an antigen test during the entire pregnancy, (3) generating values for missing data using multiple imputation, and (4) analyses controlling for month of enrollment. In addition, among women who were diagnosed with COVID-19, we examined whether having gestational diabetes mellitus, diabetes mellitus, or high body mass index increased the risk of having symptomatic vs asymptomatic COVID-19., Results: COVID-19 was associated with preexisting diabetes mellitus (risk ratio, 1.94; 95% confidence interval, 1.55-2.42), overweight or obesity (risk ratio, 1.20; 95% confidence interval, 1.06-1.37), and gestational diabetes mellitus (risk ratio, 1.21; 95% confidence interval, 0.99-1.46). The gestational diabetes mellitus association was specifically among women requiring insulin, whether they were of normal weight (risk ratio, 1.79; 95% confidence interval, 1.06-3.01) or overweight or obese (risk ratio, 1.77; 95% confidence interval, 1.28-2.45). A somewhat stronger association with COVID-19 diagnosis was observed among women with preexisting diabetes mellitus, whether they were of normal weight (risk ratio, 1.93; 95% confidence interval, 1.18-3.17) or overweight or obese (risk ratio, 2.32; 95% confidence interval, 1.82-2.97). When the sample was restricted to those with a real-time polymerase chain reaction test or an antigen test in the week before delivery or during the entire pregnancy, including missing variables using imputation or controlling for month of enrollment, the observed associations were comparable., Conclusion: Diabetes mellitus and overweight or obesity were risk factors for COVID-19 diagnosis in pregnancy, and insulin-dependent gestational diabetes mellitus was associated with the disease. Therefore, it is essential that women with these comorbidities are vaccinated., (Copyright © 2021. Published by Elsevier Inc.)

Women of childbearing age are largely affected by several autoimmune disorders (the estimates range between 1.5 and 10 per 10,000). The increasing number of effective biological agents has dramatically revolutionized the treatment of these clinical conditions, ameliorating the patient's quality of life. The use of these agents by women during pregnancy is growing to ensure the disease activity control and avoid adverse health outcomes. However, for many newer biological agents, the degree of information concerning their use in pregnancy is often incomplete to perform a conclusive risk assessment on fetal and maternal health given the exclusion of this specific population from pharmacological clinical trials. More recently, the COVID-19 pandemic has confirmed the unacceptable inequities of pharmacological research and medical treatment for pregnant and lactating women, exacerbating the need for filling the gaps of quantitative and qualitative pharmacology data in this sensitive population. ere we summarize (i) what is already known about safety and effectiveness of biological agents in this understudied population (with specific focus on pregnancy-related health outcomes), and what we are going to learn from the on-going studies among pregnant women treated with biological agents; (ii) the methodological and ethical considerations that characterize the pharmacological research in pregnancy, also discussing emerging evidence on the use of therapeutic drug monitoring (TDM) in this clinical setting., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: It is unclear whether the suggested link between COVID-19 during pregnancy and preeclampsia is an independent association or if these are caused by common risk factors., Objective: This study aimed to quantify any independent association between COVID-19 during pregnancy and preeclampsia and to determine the effect of these variables on maternal and neonatal morbidity and mortality., Study Design: This was a large, longitudinal, prospective, unmatched diagnosed and not-diagnosed observational study assessing the effect of COVID-19 during pregnancy on mothers and neonates. Two consecutive not-diagnosed women were concomitantly enrolled immediately after each diagnosed woman was identified, at any stage during pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed until hospital discharge using the standardized INTERGROWTH-21 st protocols and electronic data management system. A total of 43 institutions in 18 countries contributed to the study sample. The independent association between the 2 entities was quantified with the risk factors known to be associated with preeclampsia analyzed in each group. The outcomes were compared among women with COVID-19 alone, preeclampsia alone, both conditions, and those without either of the 2 conditions., Results: We enrolled 2184 pregnant women; of these, 725 (33.2%) were enrolled in the COVID-19 diagnosed and 1459 (66.8%) in the COVID-19 not-diagnosed groups. Of these women, 123 had preeclampsia of which 59 of 725 (8.1%) were in the COVID-19 diagnosed group and 64 of 1459 (4.4%) were in the not-diagnosed group (risk ratio, 1.86; 95% confidence interval, 1.32-2.61). After adjustment for sociodemographic factors and conditions associated with both COVID-19 and preeclampsia, the risk ratio for preeclampsia remained significant among all women (risk ratio, 1.77; 95% confidence interval, 1.25-2.52) and nulliparous women specifically (risk ratio, 1.89; 95% confidence interval, 1.17-3.05). There was a trend but no statistical significance among parous women (risk ratio, 1.64; 95% confidence interval, 0.99-2.73). The risk ratio for preterm birth for all women diagnosed with COVID-19 and preeclampsia was 4.05 (95% confidence interval, 2.99-5.49) and 6.26 (95% confidence interval, 4.35-9.00) for nulliparous women. Compared with women with neither condition diagnosed, the composite adverse perinatal outcome showed a stepwise increase in the risk ratio for COVID-19 without preeclampsia, preeclampsia without COVID-19, and COVID-19 with preeclampsia (risk ratio, 2.16; 95% confidence interval, 1.63-2.86; risk ratio, 2.53; 95% confidence interval, 1.44-4.45; and risk ratio, 2.84; 95% confidence interval, 1.67-4.82, respectively). Similar findings were found for the composite adverse maternal outcome with risk ratios of 1.76 (95% confidence interval, 1.32-2.35), 2.07 (95% confidence interval, 1.20-3.57), and 2.77 (95% confidence interval, 1.66-4.63). The association between COVID-19 and gestational hypertension and the direction of the effects on preterm birth and adverse perinatal and maternal outcomes, were similar to preeclampsia, but confined to nulliparous women with lower risk ratios., Conclusion: COVID-19 during pregnancy is strongly associated with preeclampsia, especially among nulliparous women. This association is independent of any risk factors and preexisting conditions. COVID-19 severity does not seem to be a factor in this association. Both conditions are associated independently of and in an additive fashion with preterm birth, severe perinatal morbidity and mortality, and adverse maternal outcomes. Women with preeclampsia should be considered a particularly vulnerable group with regard to the risks posed by COVID-19., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: During pregnancy, SARS-CoV-2 infection may cause an abnormal development of the placenta, thus influencing maternal and fetal outcomes. Few studies have reported data on placental morphology and histology in infected pregnant patients, although not compared with carefully matched controls. The aim of this study is to compare placental morphology and histology of pregnant women affected by SARS-CoV-2 to non-infected controls., Methods: This is a prospective multicenter case-control study on 64 pregnant women affected by SARS-CoV-2 who delivered at term or late-preterm. Data were collected about pregnancy course, maternal and fetal outcomes, placental biometry and macro- and microscopical morphology. 64 not-infected women were identified as controls, matched by age, body mass index and ethnicity., Results: Cases and controls had similar fetal and maternal outcomes. No significant differences were observed in placental macro- or microscopical morphology between the two groups. In the cases treated with antivirals, chloroquine, LMWH or antibiotics, placentas were heavier but not more efficient than the non-treated, since the fetal/placental weight ratio did not differ. Moreover, delayed villous maturation was more frequent in treated women, although not significantly. The newborns whose mothers received oxygen therapy as treatment had higher levels of umbilical cord pO₂ at birth., Discussion: In this prospective case-control study, SARS-CoV-2 infection during the third trimester did not influence placental histological pattern. Pharmacological and oxygen therapy administered to women affected by this viral infection could impact maternal and fetal outcomes and be associated to placental histological alterations., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: Because observational studies often use imperfect measurements, results are prone to misclassification errors. We used as a motivating example the possible teratogenic risks of antiemetic agents in pregnancy since a large observational study recently showed that first-trimester exposure to doxylamine-pyridoxine was associated with significantly increased risk of congenital malformations as a whole, as well as central nervous system defects, and previous observational studies did not show such associations. A meta-analysis on this issue was carried out with the aim to illustrate how differential exposure and outcome misclassifications may lead to uncertain conclusions., Methods: Medline, searched to October 2019 for full text papers in English. Summary Odds Ratios (ORs) with confidence intervals (CIs) were calculated using random-effect models. Probabilistic sensitivity analyses were performed for evaluating the extension of differential misclassification required to account for the exposure-outcome association., Results: Summary ORs were 1.02 (95 % CI, 0.92-1.15), 0.99 (0.82-1.19) and 1.25 (1.08-1.44) for overall congenital, cardiocirculatory, and central nervous system malformations respectively. By assuming exposure and outcome bias factor respectively of 0.95 (i.e., newborns with congenital defects had exposure specificity 5% lower than healthy newborns) and 1.12 (i.e., exposed newborns had outcome sensitivity 12 % higher than unexposed newborns), summary OR of central nervous system defects became 1.13 (95 % CI, 0.99-1.29) and 1.17 (95 % CI, 0.99-1.38)., Conclusion: Observational investigations and meta-analyses of observational studies need cautious interpretations. Their susceptibility to several, often sneaky, sources of bias should be carefully evaluated., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Maternal pregestational obesity is a significant risk factor for adverse pregnancy outcomes, such as gestational diabetes. Both these conditions can have an impact on placental development and affect maternal-fetal exchanges, compromising fetal metabolic status. The aim of the study is to investigate the influence of pre-pregnancy BMI on placental size and to evaluate the role of obesity and gestational diabetes mellitus (GDM) on fetal oxygenation in overweight and obese pregnant women., Methods: 208 normal weight (NW), 57 overweight (OW) and 69 obese (OB) women were studied at elective cesarean section (CS) at term. 10 OW and 24 OB women were affected by GDM. Maternal, fetal and placental data were collected. Respiratory gases and acid-base balance were measured in umbilical venous and arterial blood., Results: Placental weight and thickness were higher in OB pregnancies. Lower fetal-placental ratios (F/P) were found in GDM pregnancies, both OW and OB. Fetuses from OB mothers were more hypoxic and acidemic compared to NW, particularly when complicated by GDM., Discussion: In agreement with previous studies, our data show that placentas from OB and GDM pregnancies are heavier and thicker, suggesting that an unbalanced pregestational nutritional status can decrease the placental efficiency in maternal-fetal exchanges. Fetuses from obese women are also hypoxic and acidemic, while fetuses from gestational diabetic mothers are hypoxic, reflecting that an altered pre-pregnancy BMI can affect fetal oxygenation, and GDM can play an additional detrimental role, thus worsening placental function and fetal oxygenation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Albeit rarely, different spinal pathologies may require surgical treatment during pregnancy. The management of such cases poses a series of challenges, starting with adequate body positioning., Objective: To illustrate limits and indications of the different surgical positioning strategies for pregnant women undergoing spine surgery., Methods: We performed a systematic review of literature about the described surgical positioning strategies used for spinal surgery during pregnancy, discussing advantages, indications, and limits. We also describe of a novel three-quarters prone positioning for dorsal pathology., Results: The surgical strategy may vary according to several factors, such as the location and the nature of the underlying pathology, the stage of the pregnancy, and the clinical condition of mother and fetus. During the second trimester, the habitus begins to raise issues about both the abdominal and the aortocaval compressions. The third trimester implies neonatal and ethical challenges: both fetal monitoring and the possibility of urgently proceeding to delivery should be guaranteed. The prone position is feasible during the second trimester provided an adequate frame is supplied. The lateral or three-quarters prone positioning may offer the safest option in the last stages of pregnancy, whereas both supine and sitting positionings are anecdotal., Conclusions: Gestational age, surgical comfort and maternofetal safety should be balanced by a multidisciplinary team to tailor an adequate positioning plan for each individual case. The early third trimester is the more limiting period because of the womb hindrance favoring lateral or three-quarters positionings., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Metabolomics identifies phenotypical groups with specific metabolic profiles, being increasingly applied to several pregnancy conditions. This is the first preliminary study analyzing placental metabolomics in normal weight (NW) and obese (OB) pregnancies., Methods: Twenty NW (18.5 ≤ BMI< 25 kg/m 2 ) and eighteen OB (BMI≥ 30 kg/m 2 ) pregnancies were studied. Placental biopsies were collected at elective caesarean section. Metabolites extraction method was optimized for hydrophilic and lipophilic phases, then analyzed with GC-MS. Univariate and PLS-DA multivariate analysis were applied., Results: Univariate analysis showed increased uracil levels while multivariate PLS-DA analysis revealed lower levels of LC-PUFA derivatives in the lipophilic phase and several metabolites with significantly different levels in the hydrophilic phase of OB vs NW., Discussion: Placental metabolome analysis of obese pregnancies showed differences in metabolites involved in antioxidant defenses, nucleotide production, as well as lipid synthesis and energy production, supporting a shift towards higher placental metabolism. OB placentas also showed a specific fatty acids profile suggesting a disruption of LC-PUFA biomagnification. This study can lay the foundation to further metabolomic placental characterization in maternal obesity. Metabolic signatures in obese placentas may reflect changes occurring in the intrauterine metabolic environment, which may affect the development of adult diseases., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Intrauterine growth restriction (IUGR) and preeclampsia (PE) are pregnancy disorders characterized by placental insufficiency with oxygen/nutrient restriction and oxidative stress, all influencing mitochondria functionality and number. Moreover, IUGR and PE fetuses are predisposed to diseases later in life, and this might occur through epigenetic alterations. Here we analyze content and methylation of mitochondrial DNA (mtDNA), for the first time in IUGR and PE singleton fetuses, to identify possible alterations in mtDNA levels and/or epigenetic control of mitochondrial loci relevant to replication (D-loop) and functionality (mt-TF/RNR1: protein synthesis, mt-CO1: respiratory chain complex)., Methods: We studied 35 term and 8 preterm control, 31 IUGR, 17 PE/IUGR and 17 PE human singleton pregnancies with elective cesarean delivery. Fetal cord blood was collected and evaluated for biochemical parameters. Extracted DNA was subjected to Real-time PCR to assess mtDNA content and analyzed for D-loop, mt-TF/RNR1 and mt-CO1 methylation by bisulfite conversion and pyrosequencing., Results: mtDNA levels were increased in all pathologic groups compared to controls. Mitochondrial loci showed very low methylation levels in all samples; D-loop methylation was further decreased in the most severe cases and associated to umbilical vein pO 2 . mt-CO1 methylation levels inversely correlated to mtDNA content., Discussion: Increased mtDNA levels in IUGR, PE/IUGR and PE cord blood may denote a fetal response to placental insufficiency. Hypomethylation of D-loop, mt-TF/RNR1 and mt-CO1 loci confirms their relevance in pregnancy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The aim of this metaanalysis was to evaluate the risk of the development of obstetric complications in women with celiac disease. We searched electronic databases from their inception until February 2015. We included all cohort studies that reported the incidence of obstetric complications in women with celiac disease compared with women without celiac disease (ie, control group). Studies without a control group and case-control studies were excluded. The primary outcome was defined a priori and was the incidence of a composite of obstetric complications that included intrauterine growth restriction, small for gestational age, low birthweight, preeclampsia and preterm birth. Secondary outcomes included the incidence of preterm birth, intrauterine growth restriction, stillbirth, preeclampsia, small for gestational age, and low birthweight. The review was registered with PROSPERO (CRD42015017263) before data extraction. All authors were contacted to obtain the original databases and perform individual participant data metaanalysis. Primary and secondary outcomes were assessed in the aggregate data analysis and in the individual participant data metaanalysis. We included 10 cohort studies (4,844,555 women) in this metaanalysis. Four authors provided the entire databases for the individual participant data analysis. Because none of the included studies stratified data for the primary outcome (ie, composite outcome), the assessment of this outcome for the aggregate analysis was not feasible. Aggregate data analysis showed that, compared with women in the control group, women with celiac disease (both treated and untreated) had a significantly higher risk of the development of preterm birth (adjusted odds ratio, 1.35; 95% confidence interval, 1.09-1.66), intrauterine growth restriction (odds ratio, 2.48; 95% confidence interval, 1.32-4.67), stillbirth (odds ratio, 4.84; 95% confidence interval, 1.08-21.75), low birthweight (odds ratio, 1.63; 95% confidence interval, 1.06-2.51), and small for gestational age (odds ratio, 4.52; 95% confidence interval, 1.02-20.08); no statistically significant difference was found in the incidence of preeclampsia (odds ratio, 2.45; 95% confidence interval, 0.90-6.70). The risk of preterm birth was still significantly higher both in the subgroup analysis of only women with diagnosed and treated celiac disease (odds ratio, 1.26; 95% confidence interval, 1.06-1.48) and in the subgroup analysis of only women with undiagnosed and untreated celiac disease (odds ratio, 2.50; 95% confidence interval; 1.06-5.87). Women with diagnosed and treated celiac disease had a significantly lower risk of the development of preterm birth, compared with undiagnosed and untreated celiac disease (odds ratio, 0.80; 95% confidence interval, 0.64-0.99). The individual participant data metaanalysis showed that women with celiac disease had a significantly higher risk of composite obstetric complications compared with control subjects (odds ratio, 1.51; 95% confidence interval, 1.17-1.94). Our individual participant data concurs with the aggregate analysis for all the secondary outcomes. In summary, women with celiac disease had a significantly higher risk of the development of obstetric complications that included preterm birth, intrauterine growth restriction, stillbirth, low birthweight, and small for gestational age. Since the treatment with gluten-free diet leads to a significant decrease of preterm delivery, physicians should warn these women about the importance of a strict diet to improve obstetric outcomes. Future studies calculating cost-effectiveness of screening for celiac disease during pregnancy, which could be easily performed, economically and noninvasively, are needed. In addition, further studies are required to determine whether women with adverse pregnancy outcomes should be screened for celiac disease, particularly in countries where the prevalence is high., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Placental biometry at birth has been shown to predict chronic disease in later life. We hypothesized that maternal overweight/obesity, a state of low-grade inflammation and risk factor for adverse pregnancy outcome, could negatively influence placental development and that differences would be sex-specific., Methods: 696 women (537 normal-weight, NW; 112 overweight, OW; 47 obese, OB) with singleton uncomplicated pregnancies were prospectively enrolled at term delivery. Gestational age, maternal (age, height, pre-pregnancy BMI, gestational weight gain -GWG, hemoglobin, hematocrit and glycemia), fetal (weight, length, ponderal index, cranial circumference) and placental (weight, diameters) data were collected. Placental area, thickness and efficiency (fetal/placental weight ratio, F/P) were calculated., Results: GWG was within standard recommendations in OB, while OW exceeded it. Placental weight was significantly higher in OW versus NW, but not in OB, leading to significantly higher placental thickness and lower F/P in this group. In the total population, a significant interaction effect between maternal BMI and fetal sex on placental weight and efficiency was found. Indeed, differences in placental parameters were present only in female offspring., Discussion: In our population of OW and OB uncomplicated pregnancies only OW women, presenting GWG over standard recommendations, had thicker and less efficient placentas. We also reported different placental adaptation depending on fetal sex, with significant changes only in female fetuses. This may be part of a female-specific strategy aiming to ensure survival if another adverse event occurs. Customized counseling according to maternal BMI and fetal sex should be evaluated in clinical care., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: A common challenge in medicine, exemplified in the analysis of biomarker data, is that large studies are needed for sufficient statistical power. Often, this may only be achievable by aggregating multiple cohorts. However, different studies may use disparate platforms for laboratory analysis, which can hinder merging., Methods: Using circulating placental growth factor (PlGF), a potential biomarker for hypertensive disorders of pregnancy (HDP) such as preeclampsia, as an example, we investigated how such issues can be overcome by inter-platform standardization and merging algorithms. We studied 16,462 pregnancies from 22 study cohorts. PlGF measurements (gestational age ⩾20 weeks) analyzed on one of four platforms: R&D Systems, AlereTriage, RocheElecsys or AbbottArchitect, were available for 13,429 women. Two merging algorithms, using Z-Score and Multiple of Median transformations, were applied., Results: Best reference curves (BRC), based on merged, transformed PlGF measurements in uncomplicated pregnancy across six gestational age groups, were estimated. Identification of HDP by these PlGF-BRCs was compared to that of platform-specific curves., Conclusions: We demonstrate the feasibility of merging PlGF concentrations from different analytical platforms. Overall BRC identification of HDP performed at least as well as platform-specific curves. Our method can be extended to any set of biomarkers obtained from different laboratory platforms in any field. Merged biomarker data from multiple studies will improve statistical power and enlarge our understanding of the pathophysiology and management of medical syndromes., (Copyright © 2015 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Introduction: This study investigates the hypothesis that placenta works differently in oocyte donation (OD) compared to spontaneous pregnancies. To verify this hypothesis we examine the first trimester maternal serum levels of free β-hCG and pregnancy-associated plasma protein-A (PAPP-A). Then we evaluated for potential differences of Down syndrome screening between OD pregnancies, in vitro fertilization/intracytoplasmic sperm injection pregnancies with autologous oocytes (IVF/ICSI) and spontaneous pregnancies., Methods: We analyze 13624 spontaneously conceived pregnancies (Controls), 171 oocyte donation pregnancies (OD IVF/ICSI) and 76 IVF pregnancies with autologous oocytes (Autologous IVF/ICSI). Furthermore, we collect a cohort of 802 spontaneously conceived age-matched pregnancies, in order to evaluate how older uteri contribute to explain the changes in markers concentrations (Age-matched controls We compare the multiples of the median (MoM) of free β-hCG and PAPP-A and nuchal translucency., Results: Free β-hCG levels are significantly higher both in OD IVF/ICSI pregnancies (1.44 ± 1.06 MoM) and Autologous IVF/ICSI (1.48 ± 1.02 MoM) compared to Controls (1.15 ± 0.84 MoM; p < 0.05) and Age-matched Controls (1.18 ± 0.98 MoM; p < 0.05). PAPP-A levels do not significantly differ among the four groups. Significantly lower nuchal translucency is detected in Controls (1.41 ± 0.36 mm) compared to OD IVF/ICSI (1.46 ± 0.44 mm; p < 0.05), in Autologous IVF/ICSI (1.51 ± 0.34 mm; p < 0.05) and Age-matched Controls (1.44 ± 0.42 mm; p < 0.05)., Discussion: Oocyte donation pregnancies (OD IVF/ICSI) are significantly related to altered maternal serum placenta marker levels. These alterations might be due to the IVF technique., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Rheumatic diseases (RDs) occur preferentially in women, often during the childbearing age. The interaction of pregnancy and the RD is varied, ranging from spontaneous improvement to aggravation of disease symptoms or life-threatening flares. Risks for the mother with RD and the child differ in regard to the presence of organ manifestations, organ damage, disease activity, presence of specific autoantibodies, and therapy. Pregnancy complications comprise hypertension, preeclampsia, premature delivery, and side effects of therapy. Adverse pregnancy outcomes include recurrent miscarriage, intrauterine growth restriction, and fetal demise, and they are frequently encountered in RD with organ manifestations and harmful autoantibodies. Because of the difference in the prevalence of RDs, knowledge on the gestational course of disease and pregnancy outcome is limited to the fairly common RDs such as rheumatoid arthritis, systemic lupus erythematosus, and antiphospholipid syndrome. Pregnancies in RD are connected with increased risks for mother and child and need interdisciplinary care and management., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Throughout the last decade, increasing awareness has been raised on issues related to reproduction in rheumatic diseases including basic research to clarify the important role of estrogens in the etiology and pathophysiology of immune/inflammatory diseases. Sub- or infertility is a heterogeneous condition that can be related to immunological mechanisms, to pregnancy loss, to disease burden, to therapy, and to choices in regard to family size. Progress in reproductive medicine has made it possible for more patients with rheumatic disease to have children. Active disease in women with rheumatoid arthritis (RA) affects their children's birth weight and may have long-term effects on their future health status. Pregnancy complications as preeclampsia and intrauterine growth restriction are still increased in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS), however, biomarkers can monitor adverse events, and several new therapies may improve outcomes. Pregnancies in women with APS remain a challenge, and better therapies for the obstetric APS are needed. New prospective studies indicate improved outcomes for pregnancies in women with rare diseases like systemic sclerosis and vasculitis. TNF inhibitors hold promise for maintaining remission in rheumatological patients and may be continued at least in the first half of pregnancy. Pre-conceptional counseling and interdisciplinary management of pregnancies are essential for ensuring optimal pregnancy outcomes., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Introduction: Circulating endothelial progenitor cells (EPCs) may play a crucial role during pregnancy by sustaining adequate placentation and fetal growth. Unambiguous demonstration of EPC increase during pregnancy has been hampered so far by lack of standardized methods for EPC quantification. In this study we used the currently most accepted phenotype for EPC detection for investigating whether maternal circulating EPCs might increase during normal pregnancy and whether they may fail to increase in pregnancy complicated by idiopathic intrauterine growth restriction (IUGR), a leading cause of perinatal mortality and morbidity characterized by insufficient placental perfusion., Methods: Twenty-one non-pregnant women, 44 women during healthy pregnancy progression (9, 13 and 22 women in the first, second and third trimester, respectively) and 11 with pregnancy complicated by idiopathic IUGR were recruited in a cross-sectional study. EPCs in maternal blood were identified as CD45(dim)/CD34+ / KDR+ cells by flow cytometry. Plasmatic cytokines were measured by ELISA., Results: We observed a significant and progressive increase of EPCs in normal pregnancy, yet detectable in early pregnancy but even more pronounced in the third trimester. The increase of EPCs was impaired in IUGR-complicated pregnancies at comparable gestational age. The circulating levels of placental growth-factor and stromal-derived-factor-1 were significantly lower in IUGR than normal pregnancies, possibly contributing to EPC impairment., Conclusions: EPC count in maternal circulation may have a great potential as a novel biomarker for pregnancy monitoring and may represent the target of novel therapeutic strategies designed to prevent adverse pregnancy outcomes often occurring in IUGR., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Fetal growth restriction (FGR) results from placental insufficiency to adequately supply the fetus. This insufficiency involves impaired cytotrophoblast functions, including reduced migration and invasion, proliferation, and syncytium formation. Membrane-type matrix metalloproteinase 1 (MT1-MMP) is a key enzyme in these cellular processes. MT1-MMP exists in various forms: a 63-kDa proenzyme is synthesized as primary translation product, which is cleaved into a 57-kDa membrane-anchored active form. We hypothesized that reduced placental MT1-MMP in FGR impairs trophoblast functions. MT1-MMP mRNA and active enzyme was quantified in placentas from FGR and age-matched control pregnancies. MT1-MMP protein was localized in first-trimester and term placentas. Putative MT1-MMP functions in trophoblasts were determined using two blocking antibodies for measuring migration and proliferation, as well as fusion of primary trophoblasts and trophoblast-derived cells. MT1-MMP was expressed predominantly in the syncytiotrophoblast and the villous and extravillous cytotrophoblasts. In FGR placentas, levels of MT1-MMP mRNA and of active MT1-MMP protein were reduced (-34.2%, P < 0.05, and -21.5%, P < 0.01, respectively), compared with age-matched controls. MT1-MMP-blocking antibodies diminished migration, proliferation, and trophoblast fusion. We conclude that reduced placental MT1-MMP in FGR may contribute to the impaired trophoblast functions associated with this pathology., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Circulating angiogenic factors are potential markers for preeclampsia, but heterogeneous studies have failed to identify precise predictive/diagnostic properties. The Global CoLaboratory is investigating how to merge published data of angiogenic factors for meta-analysis on an individual sample basis., Objective: To amalgamate pregnancy angiogenic factor studies, investigate diagnostic and predictive properties of these markers in preeclampsia and placenta-related pregnancy complications, and to test if measures from disparate platforms can be standardised. This is the first report using PlGF measures to diagnose preeclampsia., Methods: Data were derived from 15 cohorts, within and outside the CoLaboratory network. Women were classified as either case (confirmed diagnosis of preeclampsia at sampling) or non-case (no preeclampsia at sampling). Individual PlGF measurements from four different analytical platforms were used, along with transformations of the data (e.g. log-transformations, transformations to a baseline platform). Transformed measurements were standardised both for specific platforms and globally, stratifying on gestational age. Different statistical techniques were compared., Results: The database currently contains 1442 cases and 11,512 non-cases, which were used to define an algorithm to merge PlGF measurements from different platforms. Non-case distributions were used to standardise case results. Diagnostic PlGF measurements in relation to preeclampsia will be presented and confirm feasibility., Conclusions: Future studies can extend this approach to other angiogenic factors, prediction as well as diagnosis and to other placenta-related disorders., (Copyright © 2013. Published by Elsevier B.V.)

Introduction: The state of activation of dendritic cells (DCs) at the feto-maternal interface critically contributes to optimal decidual immune responses needed to support fetal-placental development. We recently demonstrated that during healthy pregnancy also peripheral blood DCs (PBDCs), which are easily accessible, are activated as well. In this study, to investigate a possible involvement of DCs in intrauterine growth restriction (IUGR), we evaluated whether PBDCs in pregnancy complicated by IUGR may be altered compared with PBDCs in healthy pregnancy., Methods: PBDCs from 12 pregnant women with primary IUGR, 21 healthy pregnant and 19 nonpregnant women were analyzed by flow cytometric analysis of whole-blood samples collected at a single time point., Results: The number of plasmacytoid PBDCs was significantly reduced in women with IUGR pregnancy. Myeloid and plasmacytoid PBDCs in IUGR lacked the state of activation (assessed as CD80, CD86, CD40 expression) and the shift to a proinflammatory pattern of cytokine production occurring during healthy pregnancy., Discussion: To our knowledge, this is the first study investigating the state of PBDC activation in IUGR pregnancy. Our results are in accordance with a previous study reporting a lower expression of activation and maturation markers by decidual DCs in IUGR placentas., Conclusions: The reduced activation of PBDCs in IUGR pregnancy may possibly reflect a reduced activation of decidual DCs. If confirmed at the feto-maternal interface, the alterations of DCs described in IUGR pregnancy have the potential to negatively impact on vascular development during gestation. These observations may therefore broaden our understanding of IUGR pathogenesis., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Endothelial dysfunction typical of preeclampsia (PE) is the result of an excessive maternal inflammatory response to pregnancy. We investigated PTX3 in maternal, fetal and placental compartments in complicated pregnancies. Maternal blood samples were collected during the third trimester in 53 PE, 43 IUGR (intrauterine growth restriction) and 50 normal pregnancies. Fetal samples were collected from the umbilical vein in 26 PE, 23 IUGR and 26 normal pregnancies at elective cesarean section. Pattern and site of expression of PTX3 were studied by immunohistochemistry (IHC) on placenta, decidual bed and maternal peritoneum. PE and IUGR pregnancies had significantly higher maternal PTX3 levels compared to normal pregnancies, with IUGR significantly lower than PE. Maternal peritoneum expressed a significantly higher signal in the endothelium of pathological compared to normal pregnancies. The maternal increase of PTX3 correlated with the severity of disease with higher PTX3 concentrations in severe PE. Increased PTX3 levels in PE and IUGR mothers, together with IHC data represent the expression of altered endothelial function on the maternal side. IUGR fetuses had higher PTX3 values than controls and the increase was related to IUGR severity, likely reflecting the hypoxic environment. These data confirm the relevance of PTX3 in support the hypothesis that PE is a disease associated with altered maternal endothelial function. The PTX3 increase in IUGR fetuses deserves further investigation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Introduction: Early onset placenta Preeclampsia (ePE) with Intrauterine Growth Restriction (IUGR) is associated with insufficient placental function, leading to decreased nutrient and oxygen (O2) availability for the fetus [1]. Mitochondria (mt) are the cell energy producers. Mt dysfunctions could be involved in altered placental metabolism leading to ePE and IUGR. We previously demonstrated higher levels of mtDNA in human IUGR placentas [2]., Objectives: Here we investigate mtDNA levels in ePE and PE without IUGR placentas, and we present an innovative technique, High Resolution Respirometry (HRR), on cytotrophoblast cells (CTC) from PE, IUGR and control placentas (C), measuring cell O2 consumption which represents respiratory chain efficiency., Methods: mtDNA was measured by Real-Time PCR in 20 PE placentas, with (n=14) or without (n=6) IUGR, and 45 C. CTC were isolated from 4 PE, 4 IUGR and 6 C and characterized by flow cytometry, staining samples with anti-cytokeratin-7 and anti-vimentin antibodies. Cells were located in chambers with atmospheric O2levels; 2 different protocols were used, with or without digitonin permeabilization, allowing to measure the O2 consumption of the respiratory chain complexes singularly or all together. Substrates and inhibitors of different respiratory chain complexes were sequentially administered (succinate, ADP, oligomycin, FCCP, rotenone, antimycin A, glutamate, malate, myxothiazol, TMPD, ascorbate, pyruvate, cytochrome C, differently combined depending on the protocol) and O2 consumption levels were recorded. Data were normalized by Citrate Synthase (CS) activity and CTC mtDNA content., Results: PE placentas: mtDNA content was significantly increased in ePE+IUGR (p=0.02) vs C; opposite to this, mtDNA was decreased in PE without IUGR (p=0.03). CTC: single mt O2 consumption (obtained by normalizing data both by CS activity and mtDNA) was slightly increased both in PE and IUGR. The global cell respiration was increased, though not significantly. The trend towards higher O2 consumption studied on permeabilized cells  was confirmed for all the respiratory chain complexes., Conclusion: Our study showed that mtDNA is increased also in ePE with IUGR and added the novel observation that mtDNA is decreased in PE without IUGR. In both conditions placental mitochondria present an altered respiratory chain activity, with a trend to a higher respiratory capacity. This could lead to higher ATP production likely as an attempt to compensate for other aspects of placental disease due to small or inefficient exchange capabilities. Further data are needed to confirm these preliminary results, together with specific enzymatic assays to asses the respiratory chain complexes functionality. Supported by Fondazione Giorgio Pardi, Associazione Studio Malformazion(ASM) and by a Grant COFIN (Italian Ministry of Research) on: New markers for preterm deliveries., (Copyright © 2012. Published by Elsevier B.V.)

To assess whether antithrombotic prophylaxis with low-molecular-weight heparin effectively prevents recurrence of late pregnancy complications, 135 women with previous history of preeclampsia, hemolytic anemia, elevated liver enzymes and low platelet count syndrome, intrauterine fetal death, fetal growth restriction, or placental abruption who had been referred within the 12th gestational week were randomized to medical surveillance alone (n = 68) or combined to open-label nadroparin (3800 IU daily subcutaneous injections) treatment (n = 67) in the setting of a randomized, parallel-group, superiority trial, run in Italy from April 2007 to April 2010. Primary outcome was a composite end point of late-pregnancy complications. Analysis was by intention to treat. The study was stopped for futility at the time of the first planned interim analysis. Among the 128 women eventually available for final analyses, 13 of the 63 (21%) randomized to nadroparin compared with 12 of the 65 (18%) on medical surveillance alone progressed to the primary end point. The absolute event risk difference between treatment arms (2.2; -1.6 to 16.0) was not statistically significant (P = .76). Thus, nadroparin did not prevent late-pregnancy complications in women at risk of recurrence. This finding challenges the role of antithrombotic prophylaxis with low-molecular-weight heparin in the prevention of recurrent late pregnancy complications The trial was registered at http://ricerca-clinica.agenziafarmaco.it as EudraCT 2006-004205-26.

Objective: To investigate maternal thrombophilia in cases of Stillbirth (SB), also an uncertain topic because most case series were not characterised for cause/associated conditions of death., Study Design: In a consecutive, prospective, multicentre design, maternal DNA was obtained in 171 cases of antenatal SB and 326 controls (uneventful pregnancy at term, 1:2 ratio). Diagnostic work-up of SB included obstetric history, neonatologist inspection, placenta histology, autopsy, microbiology/chromosome evaluations. Results audited in each centre were classified by two of us by using CoDAC. Cases were subdivided into explained SB where a cause of death was identified and although no defined cause was detected in the remnants, 64 cases found conditions associated with placenta-vascular disorders (including preeclampsia, growth restriction and placenta abruption - PVD). In the remnant 79 cases, no cause of death or associated condition was found. Antithrombin activity, Factor V Leiden, G20210A Prothrombin mutation (FII mutation) and acquired thrombophilia were analysed., Results: Overall, the presence of a thrombophilic defect was significantly more prevalent in mothers with SBs compared to controls. In particular, SB mothers showed an increased risk of carrying Factor II mutation (OR=3.2, 95% CI: 1.3-8.3, p=0.01), namely in unexplained cases. Such mutation was significantly associated also with previous SB (OR=8.9, 95%CI 1.2-70.5). At multiple logistic regression, Factor II mutation was the only significantly associated variable with SB (adj OR=3.8, 95% CI: 1.3-13.5)., Conclusion: These data suggest that Factor II mutation is the only condition specifically associated with unexplained SB and could represents a risk of recurrence. PVD-associated condition is unrelated to thrombophilia., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Micronutrient status is increasingly recognized to play an important role in the health and well-being of pregnant women and in the development and long-term health of the offspring. On 26th - 28th February 2009, The Child Health Foundation invited leading experts in this area to a scientific workshop at Obergurgl, Austria to review and critically discuss current knowledge, to identify issues that may need to be addressed in future recommendations, and to highlight priorities and opportunities for future research. This report summarizes updated key conclusions of the workshop with regards to micronutrients' intake and physiological role related to mother, placenta and fetus, as well as relevance for adverse pregnancy and long-term outcomes., (2011 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Objective: The objective of the study was to determine the feasibility of detecting fetal brain lactate, a marker of fetal metabolic acidemia, using a noninvasive technique, proton magnetic resonance spectroscopy ((1)H MRS), in intrauterine growth-restricted (IUGR) fetuses., Study Design: In vivo human fetal brain lactate detection was determined by (1)H MRS in 5 fetuses with IUGR. Oxygenation and acid-base balance data were obtained at birth., Results: (1)H MRS analysis showed the presence of a lactate peak in the brain of the most severely affected IUGR fetus, with abnormal umbilical artery Doppler and fetal heart rate tracing. This finding was consistent with the low oxygen content and high lactic acid concentration observed in umbilical blood obtained at delivery., Conclusion: (1)H MRS allows the noninvasive detection of cerebral lactate in IUGR fetuses. Lactate detected by (1)H MRS may represent a possible marker of in utero cerebral injury or underperfusion., (Crown Copyright © 2011. Published by Mosby, Inc. All rights reserved.)

The Pregenesys Consensus Meeting held in Cambridge on 13 July 2009 was organized by the Pregenesys Consortium to review and critically discuss current knowledge regarding early markers of preeclampsia, to identify priorities and opportunities for future research, to consider issues that may need to be addressed in future recommendations and to highlight key issues in cost effectiveness and national policies concerning prediction and early screening for the risk of developing preeclampsia. This report summarizes the outcome of the Consensus Meeting and draws attention to issues for further investigation with specific regard to single versus multiple markers, early versus late risk identification, and the long-term effects on both maternal and perinatal health and the need to include these in any future cost-benefit assessment., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Iron (Fe) deficiency in pregnancy is associated to low birth weight and premature delivery while in adults it can result in increased blood pressure and cardiovascular disease. Cellular Fe uptake is mediated by the Transferrin Receptor 1 (TFRC), located in the trophoblast membranes. Here, we measured TFRC mRNA expression (Real Time PCR) and TFRC protein expression and localization (Western Blotting and immunohistochemistry) in IUGR compared to control placentas. A total of 50 IUGR and 56 control placentas were studied at the time of elective cesarean section. IUGR was defined by ultrasound in utero, and confirmed by birth weight <10th percentile. Three different severity groups were identified depending on the umbilical artery pulsatility index and fetal heart rate. TFRC mRNA expression was significantly lower in IUGR placentas compared to controls (p < 0.05), and this was confirmed for TFRC protein levels. In both experiments the most severe IUGR group presented lower expression compared to the other groups, and this was also related to umbilical venous oxygen levels. TFRC protein localization in the villous trophoblast did not differ in the groups, and was predominantly present in the syncytiotrophoblast. In conclusion, these are the first observations about TFRC expression in human IUGR placentas, demonstrating its significant decrease in IUGR vs controls. Thus, Fe transport could be limited in IUGR placentas. Further studies are needed to study components of the placental Fe transport system and to clarify the regulation mechanisms involved in TFRC expression, possibly altered in IUGR placentas., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objective: We investigated mitochondrial DNA (mtDNA) content in the maternal circulation of normal pregnancies of different gestational ages and in pregnancies complicated by intrauterine growth restriction (IUGR)., Study Design: We examined 70 maternal blood samples: 13 nonpregnant women; 45 normal pregnancies, divided into the 3 trimesters; and 12 pregnancies complicated by IUGR. MtDNA content was determined by real-time quantitative polymerase chain reaction, using a genomic control and a target gene., Results: A highly significant progressive reduction in circulating mtDNA was observed in pregnant women of first, second, and third trimesters and compared to nonpregnant women (mean value: 237, 188, 144, and 283, respectively; P < .001). Moreover, mtDNA was significantly increased in women carrying IUGR fetuses compared to women with normal pregnancies (430 vs 144; P < .001)., Conclusion: MtDNA could provide new insight into the mechanisms that occur during physiological gestation. Furthermore, mtDNA content may help recognize the IUGR disease in pregnancy., (Copyright © 2010 Mosby, Inc. All rights reserved.)

Objective: We report the first tularemia epidemic occurring in Tokat Province, located in the Middle Black Sea Region of Turkey, and some features of the cases. This epidemic has allowed the calculation of the attack rate of this disease because of its appearance in a single large family., Methods: The clinical and laboratory features of patients were examined. For serological diagnosis, microagglutination assays were done on serum samples from patients and other members of the family., Results: Seven members of the family developed overt clinical disease (one ulceroglandular, six oropharyngeal). Three patients had conjunctivitis in addition to oropharyngeal involvement. All patients had a microagglutination titer above 1/160. As eight out of 16 members of the extended family were found to be positive for tularemia serology, the attack rate was calculated to be 50%., Conclusions: Tularemia is highly infectious and different clinical forms can occur in a single epidemic.

Intrauterine growth restriction (IUGR) correlates with a specific placental phenotype, associated with defects in placental transport functions, that lead to fetal undernutrition. Both placental metabolism and transport may be affected, thus modifying the normal supply of nutrients. Models to investigate placental function may either couple or separate metabolism and transport. In human pregnancies, nutrient concentrations can be measured at the time of delivery or at cordocentesis in the umbilical vessels connecting the fetus to the placenta. The kinetics of placental transport can be evaluated in vivo using stable isotopes, i.e. infusing (13)C labelled nutrient in the mother by bolus or steady state techniques prior to cordocentesis or cesarean section. In vitro studies, using the model of the dually perfused human placenta or investigating the activity of transporters in the placental membranes have also significantly contributed to our understanding of placental function. In IUGR, the placental supply of amino acids is significantly reduced independently from the severity of growth restriction and from the presence of hypoxia. Moreover, maternal-fetal gradients of glucose are increased in severe IUGR fetuses, i.e. those with alterations of umbilical blood flows, and reduced conversion ratios of long chain-polyunsaturated fatty acids (LC-PUFA) from their parent fatty acids have been demonstrated. This review summarizes the current knowledge about placental metabolism and transport in IUGR pregnancies and the relationship with severity of the disease.

Information about the variations of the origins of subclavian and vertebral arteries and their course is of great importance for head and neck surgery. The normal vertebral arteries arise as the first branches of the corresponding subclavian arteries. In a minority of cases, the left vertebral artery could arise directly from the aortic arch between the left common carotid and the left subclavian arteries. An aberrant right subclavian artery arising as the last branch of the aortic arch is also a frequently seen aortic arch anomaly. Here, we present a case with common trunks of the subclavian and vertebral arteries, demonstrated by cardiac catheterization.

IUGR has been associated to a specific placental phenotype with reduced uptake of specific nutrients. Recently, it has been hypothesized that IUGR may be determined during early gestation. This period is characterized by decidual trophoblast invasion and by intense cellular growth, replication and differentiation. Since a huge energetic availability is required during gestation, we hypothesize that mitochondria may play a crucial role in this process being the main energetic producer in the cell. The aim of this study was to investigate the role of mitochondria in IUGR pathogenesis, evaluating the number of mitochondrial DNA copies (mtDNA) in IUGR placentae compared to controls. Placental samples were collected from 50 singleton pregnancies at the time of elective caesarean section. Twenty-six pregnancies were controls with normal intrauterine growth (AGA) and 24 were studied after the in utero diagnosis of IUGR. All samples were analyzed by real-time quantitative PCR and statistical analysis was performed by non-parametric tests. The median value of mitochondrial DNA content (IQR) in AGA and IUGR placentae was significantly different (455 and 698, respectively, p=0.004). The cell types responsible for the difference observed is unknown and it is possible that changes observed in the proportion of cell types may influence this measurement. Moreover, a significant negative relationship was observed between mtDNA and umbilical venous pO(2), with the highest levels detected in the most severe IUGR cases according to Doppler findings and to the presence of preeclampsia. These data suggest a relationship between the pathogenesis of IUGR and increased placental mtDNA copies. From our results we can speculate that increased mtDNA represents an adaptation of the metabolic placental mechanism to the calorie restriction of the fetus. Furthermore, we found that this rise was inversely related to oxygen tension in the umbilical vein. Although no specific pathogenetic role can be implied, mtDNA increases with hypoxia in placentas of IUGR.

Ovarian, endometrial and breast cancers are associated with several risk factors, such as low parity, infertility, early age at menarche, and late age at menopause. Frequently most of these risk factors coexist in infertile patients and some studies suggested that the different infertility causes can be involved in cancer risk development. In particular case-control and cohort studies investigated the possible role of ovulatory disorders, endometriosis and unexplained infertility in increasing the risk of this disease. Most studies have shown no overall increased risk in invasive ovarian cancer in subfertile patients, although nulliparity has been consistently associated with increased rates of ovarian tumor, in particular with borderline and endometrioid cancers in patients with a history of endometriosis. Different studies reported that infertile women are not at risk for breast cancer. However, women affected by infertility may be more at risk for endometrial cancer, particularly if affected by ovulatory disorders. Moreover, infertility is now often treated with medical devices that could by themselves modify the hormonal environment and be cofactors in the cellular changes towards cancer development. However, although early studies suggested that infertility medications were associated to increased risk in ovarian cancer, subsequent studies have been mainly reassuring, although suggesting that type and duration of medical treatment can increase the malignancy risk. An increased risk of endometrial cancer in patients undergoing infertility treatment has been reported, as expected by the similar structure shared by clomiphene and tamoxiphene. Since breast cancer is widely recognized as having a hormonal etiology, a possible role of fertility medications to promote cancer has been hypothesized. However, many large studies were not able to find an associated risk of breast cancer. In conclusion, nowadays, firm answers about the precise effects of infertility and its treatment on cancer risk are not available but findings are generally reassuring. Further studies about fertility drug treatments on larger populations may offer in the future longer follow-up and more precise data with better adjustments for confounding factors.

Unexplained intrauterine growth restriction of the fetus (IUGR) results from impaired placental development, frequently associated with maternal malperfusion. Some cases are complicated further by preeclampsia (PE+IUGR). Here, we provide the first evidence that placental protein synthesis inhibition and endoplasmic reticulum (ER) stress play key roles in IUGR pathophysiology. Increased phosphorylation of eukaryotic initiation factor 2alpha suggests suppression of translation initiation in IUGR placentas, with a further increase in PE+IUGR cases. Consequently, AKT levels were reduced at the protein, but not mRNA, level. Additionally, levels of other proteins in the AKT-mammalian target of rapamycin pathway were decreased, and there was associated dephosphorylation of 4E-binding protein 1 and activation of glycogen synthase kinase 3beta. Cyclin D1 and the eukaryotic initiation factor 2B epsilon subunit were also down-regulated, providing additional evidence for this placental phenotype. The central role of AKT signaling in placental growth regulation was confirmed in Akt1 null mice, which display IUGR. In addition, we demonstrated ultrastructural and molecular evidence of ER stress in human IUGR and PE+IUGR placentas, providing a potential mechanism for eukaryotic initiation factor 2alpha phosphorylation. In confirmation, induction of low-grade ER stress in trophoblast-like cell lines reduced cellular proliferation. PE+IUGR placentas showed elevated ER stress with the additional expression of the pro-apoptotic protein C/EBP-homologous protein/growth arrest and DNA damage 153. These findings may account for the increased microparticulate placental debris in the maternal circulation of these cases, leading to endothelial cell activation and impairing placental development.