Intra-amniotic inflammation in the mid-trimester of pregnancy is a risk factor for neuropsychological disorders in childhood.

OBJECTIVES: Intra-amniotic inflammation is a subclinical condition frequently caused by either microbial invasion of the amniotic cavity or sterile inflammatory stimuli, e.g., alarmins. An accumulating body of evidence supports a role for maternal immune activation in the genesis of fetal neuroinflammation and the occurrence of neurodevelopmental disorders such as cerebral palsy, schizophrenia, and autism. The objective of this study was to determine whether fetal exposure to mid-trimester intra-amniotic inflammation is associated with neurodevelopmental disorders in children eight to 12 years of age. METHODS: This is a retrospective case-control study comprising 20 children with evidence of prenatal exposure to intra-amniotic inflammation in the mid-trimester and 20 controls matched for gestational age at amniocentesis and at delivery. Amniotic fluid samples were tested for concentrations of interleukin-6 and C-X-C motif chemokine ligand 10, for bacteria by culture and molecular microbiologic methods as well as by polymerase chain reaction for eight viruses. Neuropsychological testing of children, performed by two experienced psychologists, assessed cognitive and behavioral domains. Neuropsychological dysfunction was defined as the presence of an abnormal score (<2 standard deviations) on at least two cognitive tasks. RESULTS: Neuropsychological dysfunction was present in 45% (9/20) of children exposed to intra-amniotic inflammation but in only 10% (2/20) of those in the control group (p=0.03). The relative risk (RR) of neuropsychological dysfunction conferred by amniotic fluid inflammation remained significant after adjusting for gestational age at delivery [aRR=4.5 (1.07-16.7)]. Of the 11 children diagnosed with neuropsychological dysfunction, nine were delivered at term and eight of them had mothers with intra-amniotic inflammation. Children exposed to intra-amniotic inflammation were found to have abnormalities in neuropsychological tasks evaluating complex skills, e.g., auditory attention, executive functions, and social skills, whereas the domains of reasoning, language, and memory were not affected in the cases and controls. CONCLUSIONS: Asymptomatic sterile intra-amniotic inflammation in the mid-trimester of pregnancy, followed by a term birth, can still confer to the offspring a substantial risk for neurodevelopmental disorders in childhood. Early recognition and treatment of maternal immune activation in pregnancy may be a strategy for the prevention of subsequent neurodevelopmental disorders in offspring.

Are bacteria, fungi, and archaea present in the midtrimester amniotic fluid?

OBJECTIVES: This study was conducted to determine whether bacteria, fungi, or archaea are detected in the amniotic fluid of patients who underwent midtrimester amniocentesis for clinical indications. METHODS: Amniotic fluid samples from 692 pregnancies were tested by using a combination of culture and end-point polymerase chain reaction (PCR) techniques. Intra-amniotic inflammation was defined as an interleukin-6 concentration >2,935 pg/mL. RESULTS: Microorganisms were detected in 0.3% (2/692) of cases based on cultivation, 1.73% (12/692) based on broad-range end-point PCR, and 2% (14/692) based on the combination of both methods. However, most (13/14) of these cases did not have evidence of intra-amniotic inflammation and delivered at term. Therefore, a positive culture or end-point PCR in most patients appears to have no apparent clinical significance. CONCLUSIONS: Amniotic fluid in the midtrimester of pregnancy generally does not contain bacteria, fungi, or archaea. Interpretation of amniotic fluid culture and molecular microbiologic results is aided by the assessment of the inflammatory state of the amniotic cavity. The presence of microorganisms, as determined by culture or a microbial signal in the absence of intra-amniotic inflammation, appears to be a benign condition.

Clinical chorioamnionitis at term X: microbiology, clinical signs, placental pathology, and neonatal bacteremia - implications for clinical care.

OBJECTIVES: Clinical chorioamnionitis at term is considered the most common infection-related diagnosis in labor and delivery units worldwide. The syndrome affects 5-12% of all term pregnancies and is a leading cause of maternal morbidity and mortality as well as neonatal death and sepsis. The objectives of this study were to determine the (1) amniotic fluid microbiology using cultivation and molecular microbiologic techniques; (2) diagnostic accuracy of the clinical criteria used to identify patients with intra-amniotic infection; (3) relationship between acute inflammatory lesions of the placenta (maternal and fetal inflammatory responses) and amniotic fluid microbiology and inflammatory markers; and (4) frequency of neonatal bacteremia. METHODS: This retrospective cross-sectional study included 43 women with the diagnosis of clinical chorioamnionitis at term. The presence of microorganisms in the amniotic cavity was determined through the analysis of amniotic fluid samples by cultivation for aerobes, anaerobes, and genital mycoplasmas. A broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry was also used to detect bacteria, select viruses, and fungi. Intra-amniotic inflammation was defined as an elevated amniotic fluid interleukin-6 (IL-6) concentration ≥2.6 ng/mL. RESULTS: (1) Intra-amniotic infection (defined as the combination of microorganisms detected in amniotic fluid and an elevated IL-6 concentration) was present in 63% (27/43) of cases; (2) the most common microorganisms found in the amniotic fluid samples were Ureaplasma species, followed by Gardnerella vaginalis; (3) sterile intra-amniotic inflammation (elevated IL-6 in amniotic fluid but without detectable microorganisms) was present in 5% (2/43) of cases; (4) 26% of patients with the diagnosis of clinical chorioamnionitis had no evidence of intra-amniotic infection or intra-amniotic inflammation; (5) intra-amniotic infection was more common when the membranes were ruptured than when they were intact (78% [21/27] vs. 38% [6/16]; p=0.01); (6) the traditional criteria for the diagnosis of clinical chorioamnionitis had poor diagnostic performance in identifying proven intra-amniotic infection (overall accuracy, 40-58%); (7) neonatal bacteremia was diagnosed in 4.9% (2/41) of cases; and (8) a fetal inflammatory response defined as the presence of severe acute funisitis was observed in 33% (9/27) of cases. CONCLUSIONS: Clinical chorioamnionitis at term, a syndrome that can result from intra-amniotic infection, was diagnosed in approximately 63% of cases and sterile intra-amniotic inflammation in 5% of cases. However, a substantial number of patients had no evidence of intra-amniotic infection or intra-amniotic inflammation. Evidence of the fetal inflammatory response syndrome was frequently present, but microorganisms were detected in only 4.9% of cases based on cultures of aerobic and anaerobic bacteria in neonatal blood.

The first thrombotic event in purely obstetric antiphospholipid syndrome patients and in antiphospholipid antibody carriers: comparison of incidence and characteristics.

PURPOSE: The long-term risk of thrombosis after pregnancy in women with purely obstetric antiphospholipid syndrome (OAPS) is not well defined. The current study's primary outcome was to evaluate the incidence and characteristics of the first thrombotic event in OAPS, identifying the risk factors for thrombosis in OAPS was its secondary one. METHODS: Patients with purely OAPS were consecutively enrolled between September 1999 and September 2019. Subjects without a history of pregnancy morbidity or thrombosis but with persistent positivity for one or more antiphospholipid antibodies (aPL carriers) made up the control group. The study groups included 94 OAPS patients and 124 aPL carriers who were matched for clinical and laboratory parameters. RESULTS: An event rate of 0.49/100 patient years was registered in OAPS patients during a mean follow-up of 8.7 years ± 5.5 SD. Kaplan-Meier survival analysis revealed that the cumulative incidence of thromboembolic events was not significantly different in OAPS patients vs aPL carriers. Arterial thrombosis and cerebrovascular events were the more frequent types of vascular involvement in the two groups. As far as risk factors for thrombosis were concerned, the presence of lupus anticoagulant significantly prevailed in both thrombotic OAPS patients and thrombotic aPL carriers with respect to purely OAPS patients and aPL carriers who did not develop thrombosis (p = 0.01 and p = 0.00, respectively). CONCLUSION: Just as for aPL carriers, closer monitoring and possibly, a pharmacological prophylaxis should be reserved for OAPS patients at highest risk of developing the first thrombotic event.

Therapeutic apheresis during pregnancy: A single center experience.

INTRODUCTION: Therapeutic apheresis (TA) represents a treatment option for pre-existing conditions or diseases occurring during gestation. Although pregnancy is not a contraindication per se, due to the lack of evidence-based guidelines and presumed risk of maternal/fetal adverse events there is a general resistance to its application. MATERIAL AND METHODS: Between January 2005 and August 2017, at the Apheresis Unit of the University Hospital of Padua 936 TA procedures were performed during 57 pregnancies in 48 patients: 813 Plasma Exchange sessions, 119 Immunoadsorptions, 4 Red Blood Cell exchanges. The treated disease were as follows: antiphospholipid syndrome (18 patients), autoimmune congenital heart block (18), myasthenia gravis (3), Rh alloimmunization (2), systemic sclerosis (1), suspected autoimmune encephalitis (1), severe hypertriglyceridaemia (1), post partum hemolytic-uremic syndrome (1), sickle cell disease (1), lupus nephritis (1) and thrombotic thrombocytopenic purpura (1). RESULTS: In the time period considered the apheresis sessions applied to pregnant women were 7.1% of the total (n = 13.251). The median age at the first treatment was 33 years. The median week of gestation (WG) at the beginning of treatments was 21. Twenty (2.1%) sessions were complicated by adverse events, none requiring or prolonging hospitalization. There were 50 live births, 5 spontaneous abortions and 2 voluntary terminations of pregnancy. Median WG at delivery was 35 and caesarean section was performed in 46 cases. CONCLUSIONS: Our data showed that TA in pregnancy is well tolerated. Close collaboration between clinician, obstetrician and TA specialist is crucial to ensure a good outcome of high-risk pregnancies.

Personalized treatment with immunoadsorption and intravenous immunoglobulin in a case of severe Rh alloimmunization during pregnancy unresponsive to plasma - exchange.

INTRODUCTION: Despite prophylaxis, a small proportion of RhD-negative women may develop anti-D antibodies after a sensitizing event occurring during pregnancy or delivery of a D-positive baby. Intrauterine transfusion (IUT) is the treatment of choice in case of fetal anemia, but it cannot be performed early during pregnancy. Combined treatment with therapeutic plasma-exchange (TPE) and intravenous immunoglobulin (IVIG) can avoid or delay IUT. Immunoadsorption (IA) could represent a more effective treatment in selected cases. CASE REPORT: We report a D-negative female with a history of induced abortion and hydrops fetalis, referred at 8 weeks of gestation with a high anti-D titer. Despite implementing a TPE-IVIG protocol, the patient experienced a spontaneous abortion. At the beginning of her fourth pregnancy, only after a partially effective intensive TPE course, cycles of IA-IVIG were performed. Despite a suboptimal response on the anti-D titer, Doppler ultrasonographic measurements of the fetal middle cerebral artery peak systolic velocity first showed evidence of anemia at 30 weeks of gestation and a IUT was required. After the IUT, anemia persisted with a subsequent dramatic rise in titer, requiring an emergent cesarean section. The infant subsequently underwent successful treatment with IVIG, phototherapy and exchange transfusion and was discharged 7 weeks later without neurological deficits. DISCUSSION: The treatment of high titer anti-D antibodies during pregnancy may require a multidisciplinary approach with utilization of different apheresis strategies in order to have a successful pregnancy outcome.

Evaluation of quantitative fFn test in predicting the risk of preterm birth.

OBJECTIVE: To evaluate diagnostic accuracy of quantitative fetal fibronectin (qfFN) test in predicting preterm birth (PTB) risk <34 weeks' gestation or within 14 days from testing. We explored the predictive potential of the test in five-predefined PTB risk categories based on predefined qfFN thresholds (<10, 10-49, 50-199, 200-499 and ≥500 ng/mL). METHODS: Measurement of cervicovaginal qfFN with Rapid fFN 10Q System (Hologic) in 126 women with singleton pregnancy (23-33 weeks' gestation) reporting signs and symptoms indicative of preterm labour (PTL). RESULTS: For PTB prediction risk <34 weeks' gestation, sensitivity decreased from 100% to 41.7% and specificity increased from 0% to 99.1% with increasing fFN thresholds. Positive predictive value (PPV) increased from 9.5% to 83.3% with increasing qfFN thresholds, while negative predictive value (NPV) was higher than 90% among the fFN-predefined categories. Diagnostic accuracy results showed an area under a receiving operator characteristic (ROC) curve of 84.5% (95% CI, 0.770-0.903). For delivery prediction within 14 days from the testing, sensitivity decreased from 100% to 42.8% and specificity increased from 0% to 100% with increasing fFN thresholds. Diagnostic accuracy determined by the ROC curve was 66.1% (95% CI, 0.330-0.902). CONCLUSIONS: The QfFN thresholds of tests are a useful tool to distinguish pregnant women for PTB prediction risk <34 weeks' gestation.

A Prospective Study of the Use of Fetal Intelligent Navigation Echocardiography (FINE) to Obtain Standard Fetal Echocardiography Views.

OBJECTIVE: To evaluate the performance of Fetal Intelligent Navigation Echocardiography (FINE) applied to spatiotemporal image correlation (STIC) volume datasets of the normal fetal heart in generating standard fetal echocardiography views. METHODS: In this prospective cohort study of patients with normal fetal hearts (19-30 gestational weeks), one or more STIC volume datasets were obtained of the apical four-chamber view. Each STIC volume successfully obtained was evaluated by STICLoop™ to determine its appropriateness before applying the FINE method. Visualization rates for standard fetal echocardiography views using diagnostic planes and/or Virtual Intelligent Sonographer Assistance (VIS-Assistance®) were calculated. RESULTS: One or more STIC volumes (total n = 463) were obtained from 246 patients. A single STIC volume per patient was analyzed using the FINE method. In normal cases, FINE was able to generate nine fetal echocardiography views using: (1) diagnostic planes in 76-100% of the cases, (2) VIS-Assistance® in 96-100% of the cases, and (3) a combination of diagnostic planes and/or VIS-Assistance® in 96-100% of the cases. CONCLUSION: FINE applied to STIC volumes can successfully generate nine standard fetal echocardiography views in 96-100% of cases in the 2nd and 3rd trimesters. This suggests that the technology can be used as a method of screening for congenital heart disease.

Whole blood thromboelastometry profiles in women with preeclampsia.

BACKGROUND: Preeclampsia (PE) is a pregnancy complication characterized by high blood pressure and significant amounts of protein in the urine. Various coagulation abnormalities have been described in pregnant women with PE. The aim of the present case-control study was to evaluate whole blood thromboelastometry profiles, performed by ROTEM(®), in women with PE in order to better characterize the PE-related discoagulopathy. METHODS: Standard ROTEM(®) (Tem International GmbH, Munich, Germany) parameters evaluating clot initiation [clotting time (CT)], propagation [clot formation time (CFT); α-angle], stability [maximum clot firmness (MCF)] and lysis [maximum lysis (ML)] in INTEM, EXTEM, NATEM, and FIBTEM assays were performed in 30 consecutive pregnant women with PE at diagnosis. Sixty (1:2 ratio with cases) healthy pregnant women, matched for gestational age (± 2 weeks) with the cases, acted as controls. Platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, antithrombin and D-Dimer were also evaluated. RESULTS: Preeclamptic women showed a significantly more rapid propagation phase in EXTEM assay than controls (CFT 62 ± 15 vs. 75 ± 15 s and α-angle 78 ± 4 vs. 75 ± 4°, p<0.01 in both cases). Moreover, MCF was significantly higher and ML significantly lower in women with PE than in healthy pregnant women (p=0.001 for all comparisons). CONCLUSIONS: ROTEM(®) profiles in women with PE were characterized by an increased tissue factor driven clot propagation capability. In addition, higher clot stability due both to the increase in clot firmness and the decrease in blood fibrinolysis was observed. Larger studies are needed to identify the clinical relevance of ROTEM(®) alterations in women with PE.

Therapeutic apheresis in pregnancy: General considerations and current practice.

It is widely known that pregnancy does not represent a contraindication to therapeutic apheresis (TA) techniques. In fact, since the first experiences of TA in pregnancy for the prevention of hemolytic disease of the newborn, several diseases are at present treated with TA, mainly within 6 clinical categories: (a) TA is a priority and has no alternative equally effective treatment (e.g., thrombotic thrombocytopenic purpura); (b) TA is a priority but there are alternative therapies not contraindicated in pregnancy (e.g., myasthenia gravis); (c) TA is an effective tool of saving/avoiding drugs contraindicated in pregnancy (e.g., systemic lupus erythematosus); (d) TA is a treatment of specific conditions/complications of pregnancy with maternal and/or fetal risk (e.g., antiphospholipid syndrome); (e) TA is a treatment of specific conditions of pregnancy with exclusive fetal risk (e.g., hemolytic disease of the newborn); (f) TA is a treatment of disease which is strongly indicated and can exceptionally occur during pregnancy (e.g., Goodpasture's syndrome). When dealing with TA pregnant patients, some technical aspects due to the physiological changes of gestation have to be carefully considered, in particular the increase of the circulating blood volume. Moreover a multidisciplinary medical team, including an obstetrician, a clinical consultant, specialist in TA and in transfusion medicine, and a neonatologist stand as a basic requirement for the proper management of some clinical conditions that may be characterized by high maternal and fetal risk.

Prenatal Diagnosis and Fetopsy Validation of Complete Atrioventricular Septal Defects Using the Fetal Intelligent Navigation Echocardiography Method.

(1) Background: Artificial Intelligence (AI) is a modern tool with numerous applications in the medical field. The case series reported here aimed to investigate the diagnostic performance of the fetal intelligent navigation echocardiography (FINE) method applied for the first time in the prenatal identification of atrioventricular septal defects (AVSD). This congenital heart disease (CHD) is associated with extracardiac anomalies and chromosomal abnormalities. Therefore, an early diagnosis is essential to advise parents and make adequate treatment decisions. (2) Methods: Four fetuses diagnosed with AVSD via two-dimensional (2D) ultrasound examination in the second trimester were enrolled. In all cases, the parents chose to terminate the pregnancy. Since the diagnosis of AVSD with 2D ultrasound may be missed, one or more four-dimensional (4D) spatiotemporal image correlation (STIC) volume datasets were obtained from a four-chamber view. The manual navigation enabled by the software is time-consuming and highly operator-dependent. (3) Results: FINE was applied to these volumes and nine standard fetal echocardiographic views were generated and optimized automatically, using the assistance of the virtual intelligent sonographer (VIS). Here, 100% of the four-chamber views, and after the VISA System application the five-chamber views, of the diagnostic plane showed the atrioventricular septal defect and a common AV valve. The autopsies of the fetuses confirmed the ultrasound results. (4) Conclusions: By applying intelligent navigation technology to the STIC volume datasets, 100% of the AVSD diagnoses were detected.

Midtrimester amniotic fluid concentrations of interleukin-6 and interferon-gamma-inducible protein-10: evidence for heterogeneity of intra-amniotic inflammation and associations with spontaneous early (<32 weeks) and late (>32 weeks) preterm delivery.

INTRODUCTION: Intra-amniotic inflammation is traditionally defined as an elevation of amniotic fluid interleukin (IL)-6. Previous case control studies have suggested an association between an elevated midtrimester amniotic fluid IL-6 and preterm delivery, although such an association has been recently challenged. Intra-amniotic inflammation can also be defined by an elevation of the T-cell chemokine, Interferon-gamma-inducible protein (IP)-10. An elevation in amniotic fluid IP-10 has been associated with chronic chorioamnionitis, a lesion frequently found in late spontaneous preterm birth and fetal death. In contrast, an elevation in amniotic fluid IL-6 is typically associated with acute chorioamnionitis and funisitis. This study was conducted to examine the relationship between an elevation in amniotic fluid IL-6 in the midtrimester and preterm delivery at or before 32 weeks of gestation, and the amniotic fluid concentration of IP-10 and preterm delivery after 32 weeks of gestation. MATERIALS AND METHODS: This cohort study included 847 consecutive women undergoing genetic midtrimester amniocentesis; in 796 cases, amniotic fluid and pregnancy outcome was available for study after exclusion of abnormal karyotype and/or fetal congenital anomalies. Spontaneous preterm delivery was defined as early (≤32 weeks) or late (after 32 completed weeks of pregnancy). The amniotic fluid and maternal blood concentrations of IL-6 and IP-10 were measured by specific immunoassays. RESULTS: 1) The prevalence of preterm delivery was 8.3% (66/796), while those of early and late spontaneous preterm delivery were 1.5% (n=12), and 4.5% (n=36), respectively; 2) patients who had a spontaneous preterm delivery after 32 weeks of gestation had a higher median amniotic fluid IP-10 concentration than those who delivered at term [median 713 pg/mL, inter-quartile range (IQR) 509-1427 pg/mL vs. median 589 pg/mL, IQR 402-953 pg/mL; P=0.006] and an elevation of amniotic fluid IP-10 concentration above 502 pg/mL (derived from an ROC curve) was associated with late spontaneous preterm delivery [odds ratio 3.9 (95% CI 1.6-9.9)]; 3) patients who had a spontaneous preterm delivery ≤32 weeks of gestation had a higher median amniotic fluid IL-6 concentration than those who delivered at term [median 2052 pg/mL, IQR 435-3015 pg/mL vs. median 414 pg/mL, IQR 209-930 pg/mL; P=0.006], and an elevated amniotic fluid IL-6 concentration above 1740 pg/mL (derived from an ROC curve) was associated with early spontaneous preterm delivery [odds ratio 9.5 (95% CI 2.9-31.1)]; 4) subclinical intra-amniotic inflammation, defined as an elevation of IL-6 (≥2.9 ng/mL) or IP-10 (≥2.2 ng/mL) concentration above the 95th percentile of patients who had uncomplicated term delivery (n=652 for IL-6 and n=633 for IP-10), was observed in 6.3% (50/796) and 5.8% (45/770) of cases, respectively. Although each type of inflammation is a risk factor for spontaneous preterm delivery, many patients had a term delivery without complication; 5) the amniotic fluid in the midtrimester did not contain microorganisms detectable with cultivation techniques. CONCLUSIONS: INTRA-amniotic inflammation is heterogeneous. Some patients have elevated amniotic fluid concentrations of IL-6, and are at risk for spontaneous preterm delivery before 32 weeks of gestation, while others have an elevated IP-10 (a chemotactic T-cell chemokine) and such patients are at risk for spontaneous preterm delivery after 32 weeks of gestation. A fraction of patients have subclinical intra-amniotic inflammation and deliver at term. The clinical significance of this condition remains to be determined.

Congenital pulmonary airway malformation (CPAM) [congenital cystic adenomatoid malformation] associated with tracheoesophageal fistula and agensesis of the corpus callosum.

Congenital pulmonary airway malformations (CPAM) are a family of hamartomatous disorders due to the uncontrolled overgrowth of the terminal bronchioles. Congenital pulmonary airway malformations can co-exist with cardiovascular and/or urogenital malformations, but their association with thoracopulmonary malformations is extremely rare. We report the first case of CPAM type I, co-existing with tracheo-esophageal fistula and corpus callosum agenesis.

Three-Dimensional Printing of Fetal Heart With d-Transposition of the Great Arteries From Ultrasound Imaging Data.

We reconstructed and printed a 3D model of the fetal heart affected by d-transposition of the great arteries from prenatal ultrasound images. Our 3D model revealed to be very helpful in showing the basic anatomical features of fetal complex Congenital Heart Disease (CHD) and represents an interesting additional diagnostic tool to the current standard imaging armamentarium, improving the quality of prenatal parental counseling.

Leptomeningeal Carcinomatosis of a Poorly Differentiated Cervical Carcinoma Caused by Human Papillomavirus Type 18.

Cervical cancer is caused by a persistent infection with high-risk types of Papillomaviruses (hrHPV); HPV16 and HPV18 are associated with about 70% of the cases. In the last decades the introduction of a cervical cancer screening has allowed a decrease in cervical cancer incidence and mortality; regular adhesion to the screening procedures, by pap test or HPV test, and colposcopy, according to the international guidelines, prevents cancer development and allows for diagnosis at the early stages. Nowadays, in industrialized countries, it is not common to diagnose this pathology in advanced stages, and this occurrence is frequently associated with patient's unattendance of cervical screening programs. We describe a case of delayed diagnosis of cervical cancer, posed only after the onset of the neurological symptoms caused by leptomeningeal metastases, despite a two-year history of abnormal cytology. The endocervical mass was analyzed by immunohistochemistry, and search and typing of HPV sequences was performed by PCR in the meningeal carcinomatous cells. A poorly differentiated squamous cell carcinoma was diagnosed, and HPV18 sequences were detected. This rapidly fatal case highlights the importance of following the evidence-based recommended protocols and the preventive role of the population-based cervical cancer screening programs.

Isolated Dissection of the Ductus Arteriosus Associated with Sudden Unexpected Intrauterine Death.

We report five cases of sudden intrauterine death due to premature closure of the ductus arteriosus. In four cases, this was caused by dissecting the hematoma of the ductus arteriosus with intimal flap and obliteration of the lumen. In one case, the ductus arteriosus was aneurysmatic, with lumen occlusion caused by thrombus stratification. No drug therapy or free medication consumption were reported during pregnancy. The time of stillbirth ranged between 26 and 33 gestational weeks. We performed TUNEL analysis for apoptosis quantification. The dissecting features were intimal tears with flap formation in four of the cases, just above the origin of the ductus arteriosus from the pulmonary artery. The dissecting hematoma of the ductus arteriosus extended downward to the descending aorta and backward to the aortic arch with involvement of the left carotid and left subclavian arteries. TUNEL analysis showed a high number of apoptotic smooth muscle cells in the media in two cases. Abnormal ductal remodeling with absence of subintimal cushions, lacunar spaces rich in glycosaminoglycans (cystic medial necrosis), and smooth muscle cell apoptosis were the pathological substrates accounting for failure of remodeling process and dissection.

The efficacy and safety of second-line treatments of refractory and/or high risk pregnant antiphospholipid syndrome patients. A systematic literature review analyzing 313 pregnancies.

OBJECTIVE: The most efficacious strategy to manage pregnant patients with antiphospholipid syndrome (APS) refractory to conventional heparin/low-dose aspirin treatment or at high risk of adverse pregnancy outcomes has not been determined with any degree of certainty. The study set out to evaluate the efficacy and safety of the second-line treatments most frequently used in addition to conventional therapy, and the data were analyzed to identify which is/are associated to the best pregnancy outcomes. METHODS: A systematic review of the literature on studies concerning second-line treatments for refractory and/or high risk pregnant APS women published between February 2006 and February 2020 was conducted. The records were retrieved by searching Medline via Pubmed, the Web of Science platform, the Cochrane library database and clinicaltrials.gov. RESULTS: Fourteen studies met the eligibility criteria of the review: six retrospective cohort studies, one case-control, one case-series and six case reports. The results of single treatment protocols based upon hydroxychloroquine (HCQ), low-dose steroids (LDS), intravenous immunoglobulins (IVIG), plasma exchange (PE) or pravastatin and of combination protocols based upon HCQ+LDS, IVIG+LDS, PE+LDS and PE+IVIG used during 313 pregnancies in 303 APS women were analyzed and compared. The second-line treatments produced 261/313 (83.4%) live births; severe pregnancy complications were registered in 75/313 (24%) pregnancies. Drug side-effects were observed in 3/313 (0.9%) pregnancies. Statistical analysis identified a significantly higher live birth rate and/or a significantly lower number of severe complications in the pregnancies treated with IVIG, HCQ, pravastatin, PE+IVIG and PE+LDS. CONCLUSION: Our results suggest using low-dose IVIG (< 2 g/Kg/month) or HCQ 400 mg/day starting before pregnancy in women with APS refractory to conventional therapy, while high-dose IVIG (2 g/Kg/month) associated with PE or alone in those with high risk±refractory APS.

Should bilateral uterine artery notching be used in the risk assessment for preeclampsia, small-for-gestational-age, and gestational hypertension?

OBJECTIVE: The purpose of this study was to determine the value of bilateral uterine artery notching in the second trimester in the risk assessment for preeclampsia, gestational hypertension, and small-for-gestational-age (SGA) without preeclampsia. METHODS: This prospective cohort study included 4190 singleton pregnancies that underwent ultrasound examination between 23 and 25 weeks' gestation. The 95th percentiles of the mean pulsatility index (PI) and resistive index (RI) of both uterine arteries were calculated. Multivariable logistic regression analyses were performed to determine if bilateral uterine artery notching is an independent explanatory variable for the occurrence of preeclampsia, early-onset preeclampsia (34 weeks), gestational hypertension, and delivery of an SGA neonate without preeclampsia, while controlling for confounding factors. RESULTS: (1) The prevalence of preeclampsia, early-onset preeclampsia, late-onset preeclampsia, SGA, and gestational hypertension were 3.4%, 0.5%, 2.9%, 10%, and 7.9%, respectively; (2) 7.2% of the study population had bilateral uterine artery notching; and (3) bilateral uterine artery notching was an independent explanatory variable for the development of preeclampsia (odds ratio [OR], 2.1; 95% confidence interval [CI],1.28-3.36), early-onset preeclampsia (OR, 4.47; 95% CI, 1.50-13.35), and gestational hypertension (OR, 1.50; 95% CI, 1.02-2.26), but not for late-onset preeclampsia or SGA. CONCLUSIONS: Bilateral uterine notching between 23 and 25 weeks' gestation is an independent risk factor for the development of early-onset preeclampsia and gestational hypertension. Thus, bilateral uterine artery notching should be considered in the assessment of risk for the development of these pregnancy complications.

Maternal plasma retinol binding protein 4 in acute pyelonephritis during pregnancy.

OBJECTIVE: Adipokines have been implicated in metabolic regulation and the immune response thus providing a molecular mechanism for the interaction between these two systems. Retinol binding protein 4 (RBP4) is a novel adipokine that plays a role in the pathophysiology of obesity-induced insulin resistance, as well as in the modulation of inflammation. The aim of this study was to determine whether there are changes in maternal plasma concentrations of RBP4 in pregnant women with acute pyelonephritis. STUDY DESIGN: This cross-sectional study included pregnant women in the following groups: 1) normal pregnancy (n=80); 2) pyelonephritis (n=39). Maternal plasma RBP4 concentrations were determined by enzyme-linked immunoassays. Non-parametric statistics were used for analyses. RESULTS: 1) The median maternal plasma RBP4 concentration was lower in patients with acute pyelonephritis than in those with a normal pregnancy (3709.6 ng/mL, interquartile range (IQR) 2917.7-5484.2 vs. 9167.6 ng/mL, IQR 7496.1- 10,384.1, P<0.001; 2) the median maternal plasma RBP4 concentration did not differ significantly between patients with acute pyelonephritis who had a positive blood culture and those with a negative culture (3285.3 ng/mL, IQR 2274.1-4741.1 vs. 3922.6 ng/mL, IQR 3126.8-5547.1, respectively, P=0.2); and 3) lower maternal plasma RBP4 concentrations were independently associated with pyelonephritis after adjustment for confounding factors. CONCLUSIONS: In contrast to what has been reported in preeclampsia, acute pyelonephritis during pregnancy is associated with lower maternal plasma RBP4 concentrations than in normal pregnancy. This finding suggests that the acute maternal inflammatory process associated with pyelonephritis is fundamentally different from that of the chronic systemic inflammatory process suggested in preeclampsia, in which RBP4 concentrations were found to be elevated.