Preeclampsia transforms membrane N-glycome in human placenta.

Posttranslational modifications (PTM) which accompany pathological conditions affect protein structure, characteristics and modulate its activity. Glycosylation is one of the most frequent PTM influencing protein folding, localisation and function. Hypertension is a common gestational complication, which can lead to foetal growth restriction (IUGR) and even to foetal or maternal death. In this work we focused on the impact of preeclampsia complicated with IUGR on placental membrane N-glycome. Results have shown that preeclampsia reduced fucosylation of placental glycans, increased the appearance of paucimannosidic and mannosidic structures with lower number of mannose residues and decreased the amount of glycans with more mannose residues. Since preeclampsia is tightly connected to IUGR, glycosylation changes were investigated also on the functional membrane receptors responsible for growth: insulin receptor and the type 1 insulin-like growth factor receptor (IR and IGF1R). It was found that IR present in the IUGR placenta contained significantly less α2,6-Sia. Therefore, glycans on placental membranes alter due to preeclampsia, but changes seen at the level of the entire N-glycome may be different from the changes detected at the level of a specific glycoprotein. The difference recorded due to pathology in one membrane molecule (IR) was not found in another homologous molecule (IGF1R). Thus, besides studying the glycosylation pattern of the entire placental membrane due to preeclampsia, it is inevitable to study directly glycoprotein of interest, as no general assumptions or extrapolations can be made.

Screening performances of abnormal first-trimester ductus venosus blood flow and increased nuchal translucency thickness in detection of major heart defects.

OBJECTIVE: The aim of this study was to evaluate the screening performances of abnormal ductus venosus (DV) blood flow for the detection of heart defects in chromosomally normal fetuses with increased nuchal translucency (NT) thickness at 11-13 + 6 weeks' gestational in a population of singleton pregnancies. METHODS: During an 8-year period, all singleton pregnancies from 11 + 0 to 13 + 6 weeks were scanned for NT and DV blood flow assessment. Two groups of cases with abnormal NT were evaluated: NT ≥ 95th and NT ≥ 99th centile. DV waveforms were considered to be abnormal if the a-wave was reversed or absent (R/A). RESULTS: Addition of DV R/A a-wave to either NT ≥ 95th or NT ≥ 99th percentile increased specificity (p < 0.001 and p < 0.001, respectively), but not screening performances in detection of major heart defects (p = 0.73 and p = 0.91, respectively). Combination of DV R/A a-wave with NT ≥ 95th or NT ≥ 99th centile correlated with right heart defects (p = 0.024 and p = 0.013, respectively). CONCLUSIONS: In chromosomally normal fetuses, addition of abnormal DV a-wave to increased NT does not improve screening performances of NT in detection of major hearts defects in first trimester. However, there is correlation of such parameter with right heart defects and AV septal defects.

Oxidative status of maternal blood in pregnancies burdened by inherited thrombophilias.

Oxidative status of maternal blood represents an important parameter of pregnancy that is involved in both, regulation of physiological processes and (if significantly altered) development of different pregnancy complications. Inherited thrombophilias represent genetic disorders that increase the risk of thromboembolism in pregnancy. Little is known about the impact of thrombophilia on the oxidative status of maternal blood. In this study, we analyzed oxidative status of blood of 56 women with pregnancies burdened by inherited thrombophilias. The status was established at three different trimesters using biochemical assays and electrochemical measurements, and it was compared to 10 age- and trimester-matching controls. Activities of superoxide dismutase, catalase, and glutathione reductase in the 1st and the 2nd trimester of thrombophilic pregnancy were lower than controls. Also, there was less oxidation in the plasma, according to higher concentration of reduced thiols and lower oxidation-reduction potential. Therefore, it appears that thrombophilic mothers do not experience oxidative stress in the circulation in the first two trimesters. However, the rise in GPx, GR and SOD activities in the 3rd trimester of thrombophilic pregnancy implies that the risk of oxidative stress is increased during the late pregnancy. These results are important for developing antioxidative treatment that could tackle thrombophilia-related pregnancy complications.

Intrauterine treatment of large fetal neck lymphangioma with OK-432.

Lymphangiomas are benign vascular malformations of the lymphatic system and most commonly present in the neck area. Large lymphangiomas may compress and/or displace the larynx, trachea and esophagus and cause serious respiratory and feeding problems in neonates. Prenatal therapy could eliminate the risks of the mentioned complications. Prenatal therapy may include the EXIT (ex utero intrapartum treatment) procedure. As this procedure has certain risks for both the neonate and mother, the introduction of a safer method is justified. The use of OK-432, as a sclerosing agent, has shown positive results in several published cases of cystic hygroma, but there is no study about the prenatal use of this agent in the treatment of lymphangioma. The aim of this study was to present our experience with intrauterine intralesional injection of OK-432 in the treatment of neck lymphangiomas. Two cases of large multicystic neck lymphangiomas that were closely situated to the fetal airway were treated by single intralesional injection of OK-432. We noticed a progressive decrease in tumor volume throughout gestation. We did not experience any complications and there were no respiratory or feeding problems in the neonates. The esthetical appearance was satisfactory and both children were normal at the age of 2 years and 6 months, respectively. This report suggests that prenatal intralesional injection of OK-432 might be a safe and effective treatment in selected cases with large fetal neck lymphangiomas.

The influence of specific mutations in the AT gene (SERPINC1) on the type of pregnancy related complications.

BACKGROUND: Inherited antithrombin (AT) deficiency is a rare autosomal dominant disorder, caused by mutations in the SERPINC1 gene. The most common clinical presentation in AT deficient patients includes venous thrombosis and pulmonary embolism, while the association of AT deficiency and its effect on the development of pregnancy complications has been less studied. The aim of our research was to evaluate the effect of AT deficiency types, determined by genotyping, on pregnancy outcomes. METHODS: A retrospective cohort study included 28 women with AT deficiency, and their 64 pregnancies were analyzed. RESULTS: With regard to live birth rate, a significant difference was observed among women who were carriers of different SERPINC1 mutations, as the rate varied from 100% in cases of type I to the extremely low rate of 8% for women with type II HBS (AT Budapest 3) in the homozygous variant, P = 0.0005. All pregnancies from the type I group, even untreated ones, resulted in live births. In women with AT Budapest 3 in homozygous variant the overall live birth rate increased to 28.5% in the treated pregnancies. In this group the highest incidence of fetal death was observed of 62%; repeated fetal losses in 30%; fetal growth restriction in 22% and placental abruption in 7% of all pregnancies. CONCLUSION: Our study results indicate a difference between type I and type II AT deficiency. The risk of pregnancy related VTE was equally present in both groups, except for AT Budapest 3 in the heterozygous variant, while adverse pregnancy outcomes were strictly related to type II, especially AT Budapest 3 in the homozygous variant.

Neonatal Abstinence Syndrome - Diagnostic Dilemmas in the Maternity Ward.

INTRODUCTION: Neonatal abstinence syndrome (NAS) refers to a newborn neurological, gastrointestinal and/or respiratory disorder if a newborn was exposed to psychoactive substances in the intrauterine period. NAS is difficult to diagnose due to unreliability of the data on addictive substances use during pregnancy, limited possibilities of the prenatal exposure diagnosis and postnatal substance detection, which all lead to diagnostic dilemmas. OBJECTIVE: The aim of this study was to indicate the problems in patients with early NAS diagnosis in the maternity ward and the importance of clinical presentation used as a guide toward the diagnosis. METHODS: This retrospective study included five term eutrophic newborns with high Apgar score, good adaptation in the first day and with clinical presentation of NAS during the second day of life. The clinical presentation was dominated by irritability, increased wakefulness, increased muscle tone, shrilly crying, tremors, problems with accepting food, tachypnea, subfebrility and hyperhidrosis. Finnegan scale was introduced in order to diagnose NAS and apply the therapy. Single-medication therapy of phenobarbitone was applied in four cases and a combination of phenobarbitone and morphine in one case. For toxicological analysis newborns'urine samples were used. RESULTS: Conditions such as perinatal asphyxia, infection, hunger, polycythemia, hypoglycemia or hypocalcemia were excluded. Finnegan score implied that pharmacological treatment had to be administered. The discrepancy between the NAS anamnesis and toxicological analysis existed. Response to the treatment was positive in all cases. CONCLUSION: NAS is a multisystemic disorder and should be suspected when it is noticed that children exhibit characteristic signs. However, other pathological conditions have to be excluded. Quantification according to the adopted scales for NAS leads toward appropriate treatment and recovery of the newborns.

Erythropoietin in amniotic fluid as a potential marker in distinction between growth restricted and constitutionally small fetuses.

OBJECTIVE: To determine if there is any difference in amniotic fluid erythropoietin (EPO) concentration between fetuses small for gestational age (SGA) and appropriate for gestational age (AGA), and between the constitutionally small (CSF) and growth-restricted (GRF) fetuses. METHODS: EPO concentrations in the amniotic fluid samples were determined by EpoELISA test in 38 pregnancies with SGA and 15 pregnancies with AGA fetuses. In the SGA group we measured Ponderal index (PI) and skin-fold thickness (SFT). If PI and/or SFT were below 10th percentile the neonate was GRF. If both PI and SFT were above 10th percentile the neonate was CSF. RESULTS: Higher levels of EPO were detected in the SGA in comparison to the AGA fetuses (p < 0.01). EPO concentration was higher in GRF compared to CSF (p < 0.05). The EPO cut-off level between SGA and AGA was 6.81 IU/L (sensitivity 92.3%; specificity 73.3%), and between GRF and CSF was 9.8 IU/L (sensitivity 81%; specificity 80%). CONCLUSION: The preliminary results of this study suggest that amniotic fluid erythropoietin concentration is elevated in growth-restricted fetuses and could potentially be used for distinction between growth restricted and constitutionally small fetuses. Confirmation of these results on a larger group of pregnant women is needed.

Does anticoagulant therapy improve pregnancy outcome equally, regardless of specific thrombophilia type?

The study was conducted to evaluate the effect of anticoagulant therapy in women with thrombophilia and to detect the possible differences among carriers of mutations (factor V [FV] Leiden and FIIG20210) and those with natural anticoagulant deficiency. The 4-year prospective investigation included 85 pregnant women, with a history of recurrent fetal loss (RFL). They were treated with prophylactic doses of low-molecular-weight heparin (nadroparin) starting from 6 to 8 weeks of gestation. Pregnancy outcomes were evaluated based on the thrombophilia type. Carriers of thrombophilic mutations had a live birth rate of 93%, compared to 41.6% for women with natural anticoagulant deficiencies. Significant differences between the groups were also observed for intrauterine fetal death, intrauterine growth restriction, and postpartum thrombosis. The optimal therapy for women with natural anticoagulant deficiency and RFL remains unclear and future prospective study with a large number of patients is required to determine the best treatment for these severe thrombophilic conditions.

Clinical characteristics of first venous thrombosis among women under and over 45 years of age.

INTRODUCTION: Venous thromboembolism is a multifactorial disease defined by multiple interactions between genetic and acquired risk factors. After coronary heart disease and stroke, venous thromboembolism is the most common cause of cardiovascular death and disability. MATERIAL AND METHODS: In order to investigate the clinical characteristics of first venous thromboembolism, 447 women younger than 45 and 174 over 45 years of age with confirmed venous thromboembolism, who had been tested for the presence of thrombophilia in the period 1998-2012, were included in the study. RESULTS: Proximal deep vein thrombosis occurred most often among young women, while distal deep vein thrombosis was the most frequent in the older group. The most common reported risk for venous thromboembolism observed in 49.8% of the young women was pregnancy and puerperium, while 25.2% of them developed venous thromboembolism without any obvious cause. Among women over the age of 45, venous thromboembolism developed without an obvious cause in 38.5%, while malignant disease was identified as the most important risk factor in 23% of them. Thrombophilia was observed in 48.7% of the young women in comparison to 28.7% of the older ones (p < 0.0001). As for venous thromboembolism recurrence, it developed in 26.3% of young women and 17.8% of the older ones (p = 0.03). CONCLUSION: Younger women developed more severe forms of thrombosis than the older ones. Inherited risk factor for thrombosis was detected in almost half of all young women, and in every fourth elderly women. With the exception of factor V Leiden mutation, other types of congenital thrombophilia are almost negligible among older women. Therefore, thrombophilia testing in case of first thrombosis is fully justified only in young women.

Virtual reality aided visualization of fluid flow simulations with application in medical education and diagnostics.

Medical education, training and preoperative diagnostics can be drastically improved with advanced technologies, such as virtual reality. The method proposed in this paper enables medical doctors and students to visualize and manipulate three-dimensional models created from CT or MRI scans, and also to analyze the results of fluid flow simulations. Simulation of fluid flow using the finite element method is performed, in order to compute the shear stress on the artery walls. The simulation of motion through the artery is also enabled. The virtual reality system proposed here could shorten the length of training programs and make the education process more effective.

Segmental muscle vibration improves reaching movement in patients with chronic stroke. A randomized controlled trial.

BACKGROUND: Segmental muscle vibration (SMV) has been used to improve gait and to reduce spasticity in stroke patients. No data exist about the possibility to improve upper limb motor function by using SMV. METHODS: Forty-four patients with hemiparesis following chronic stroke were randomized to an experimental (n = 24) and a control group (n = 20). Patients in the experimental group received two weeks of general physical therapy and SMV over the biceps brachii and flexor carpi ulnaris muscles of the paretic side, while those in the control group received two weeks of general physical therapy. Kinematic analysis of reaching movement was performed at baseline and two weeks after treatment ended. RESULTS: Normalized jerk, indicating the smoothness of movement, significantly improved in the experimental group, with significant difference emerging between groups at the post-treatment evaluation. Patients in the experimental group also displayed a significant improvement for mean linear velocity, mean angular velocity at shoulder, distance to target at the end of movement and movement duration. No differences emerged between baseline and post-treatment evaluations in the control group. CONCLUSIONS: when added to general physical therapy, SMV is effective in improving, in a short-term period, upper limb motor performances of reaching movement in chronic stroke patients.

Screening for aneuploidies by maternal age, fetal nuchal translucency and maternal serum biochemistry at 11-13+6 gestational weeks.

INTRODUCTION: Aneuploidies are the major cause of perinatal death and early psychophysical disorders. OBJECTIVES: In this study, we analyzed detection and false-positive rates of screening for aneuploidies in the first trimester by the combination of maternal age, fetal nuchal translucency (NT) thickness and maternal serum free beta-human chorionic gonadotrophin (beta-hCG), and pregnancy-associated plasma protein-A (PAPP-A) at 11-13+6 weeks of gestation, using the appropriate software developed by the Fetal Medicine Foundation. METHODS: Our screening study for aneuploidies analyzed 4172 singleton pregnancies from January 2006 to December 2010. The sensitivities and false-positive rates using the combined aneuploidies determination for the risk cut-off of 1:275 were evaluated. RESULTS: In the trisomy 21 pregnancies, the fetal NT was higher than 95th centile, in 72.8%, serum free b-hCG concentration it was above the 95th centile in 55% and serum PAPP-A was below the 5th centile in 47% of the cases. In the trisomy 18 and 13, the fetal NT was above 95th centile in 66.6% and 44.4% of the cases, respectively.The serum free b-hCG concentration was above the 95th centile in 0 and 10%, but serum PAPP-A was below 5th centile in 80.9% and 88.8% of pregnancies. In the trisomy 21 pregnancies the median free beta-hCG was 2.3 MoM and the median PAPP-A was 0.45 MoM. Chromosomal abnormalities were detected in 169 fetuses: trisomy 21 (97), Turner syndrome (19), trisomy 18 (28), trisomy 13 (11) and others (14). Detection rate of combined screening for aneuploides were 86.0% with false positive rate of 5.3% (mean age 33 +/- 4.9 years, > 35 years in 35% of pregnancies). CONCLUSION: Our study suggests that the strategy of first-trimester combined screening of biochemical values and ultrasonographic parameters at 12 gestational weeks identifies higher percentage of aneuploidies with a lower false-positive rate than a single parameter strategy.

[Prenatal diagnosis of meconium ileus and meconium peritonitis: indications for cystic fibrosis testing].

INTRODUCTION: More recently, the regions of increased abdominal echogenicity such as echogenic bowel, meconium ileus and meconium peritonitis have been associated with an increased prevalence of a variety of unfavourable outcomes including chromosomal abnormalities, cytomegalovirus infection, intestinal obstruction, anorectal malformations and cystic fibrosis. Earlier prenatal examinations of these severe autosomal recessive diseases had been suggested only to families with history of cystic fibrosis. Recently, systemic examination has been introduced by ultrasound with bowel hyperechogenicity where the fetus is the index case for genetic disease. Risk for cystic fibrosis with this ultrasonography findings ranges from 0-33%. OUTLINE OF CASES: Two patients are presented, aged 24 and 29 years, both primigravide. The first one had ultrasonography finding of meconium peritonitis revealed at the 37th week of gestation and the other meconium ileus revealed on ultrasonography at the 29th week of gestation. Both patients had prenatal testing of foetal blood obtained by cordocenthesis, both had normal kariotype and were negative for cytomegalovirus infection. Parental DNA testing for the 2nd patient showed that parents were not carriers for the 29 most frequent mutations. Both neonates had intestinal obstruction, underwent surgery and early postoperative course was normal. Hystopathological finding suggested a possibility of cystic fibrosis for the 1st patient, but parents did not want to be tested and for the 2nd one congenital bowel stenosis as a cause of intestinal obstruction. CONCLUSION: Ultrasonographic echogenic bowel is an indication for invasive procedures for foetal blood testing for chromosomal abnormalities, congenital infections and parental testing for cystic fibrosis. Only if parental heterozygosity is proven foetus should be tested.

A successful outcome of pregnancy in a patient with congenital antithrombin deficiency.

BACKGROUND: Presence of inherited thrombophilia is an additional risk factor for maternal thromboembolism and certain adverse pregnancy outcomes, including recurrent fetal loss, placental abruption, intrauterine growth restriction and early-onset severe preeclampsia. Pregnant women with thrombophilia, especially those with antithrombin (AT) deficiency, are at high risk of both kinds of complications. CASE REPORT: We presented a pregnant women with congenital antithrombin deficiency in the first pregnancy, whose mother had had four times pregnancy-related deep vein thrombosis, and antithrombin deficiency. With the regular laboratory monitoring of hemostatic parameters and gynaecology surveillance including the follow-up of placental vascular flow, the whole pregnancy proceeded without complications. The prophylactic therapy with low molecular weight heparin was introduced from the 20th week of gestation and one dose of substitution therapy with antithrombin concentrate was administrated before delivery. Pregnancy and labour were terminated without complications at the 37th week of gestation, resulting in the delivery of a healthy male newborn of 3.6 kg body weight, 52 cm long, and with the Apgar scores of 9/10. CONCLUSION: A timely made diagnosis of thrombophilia, accompanied with regular obstetrics check-ups and follow-ups of hemostatic parameters during pregnancy, as well as the use of adequate prophylactic and substitution therapy, are the successful tools for the prevention of possible maternal complications and pregnancy itself in our patient with congenital AT deficiency.

The use of D-dimer with new cutoff can be useful in diagnosis of venous thromboembolism in pregnancy.

OBJECTIVE: D-dimer testing has an important role in the exclusion of acute venous thromboembolism (VTE) in the nonpregnant population. Establishing D-dimers role in the diagnosis of VTE in pregnancy is hampered because of the substantial increase of D-dimer throughout gestational age. STUDY DESIGN: In a prospective study we followed 89 healthy pregnant women to establish the reference range of D-dimer for each trimester. D-dimer testing was also performed in 12 women with clinical suspicion of VTE and their results were compared with the established new reference range of D-dimer, and with the recorded ultrasound findings. RESULTS: In the first trimester, 84% women from reference group had normal D-dimer, in the second 33%, and by the third trimester only 1%, which suggests that D-dimer has no practical diagnostic use in ruling out VTE if the threshold of 230 ng/mL for abnormal is used. All pregnant women with thrombosis who had positive ultrasound findings also had statistically significant elevation of the D-dimer level, considering the established reference range of the corresponding trimester. We found 100% sensitivity of D-dimer test. A women developed thrombosis in the first trimester had 6.7-7.6 time higher level of D-dimer than the mean value in the reference group, and in the third trimester thrombotic women had 2.0-3.8 time higher level of D-dimer, p<0.0001. CONCLUSION: D-dimer test with the new threshold for: the first of 286, the second of 457 and the third trimester of 644 ng/mL can be useful in diagnosis of pregnancy related VTE.

Type and location of venous thromboembolism in carriers of Factor V Leiden or prothrombin G20210A mutation versus patients with no mutation.

Factor V Leiden (FVLeiden) and prothrombin G20210A are the most common genetic causes of thrombophilia and established risk factors for different clinical manifestations of venous thromboembolism (VTE). This study investigated whether the clinical manifestation of VTE, the extension of deep vein thrombosis (DVT) and the presence of transient risk factors at the time of the first VTE, differed among patients with mutations (97 with FVLeiden; 33 with prothrombin G20210A) and in 109 patients without thrombophilia. Isolated pulmonary embolism (PE) was less prevalent in patients with FVLeiden (6%) and no thrombophilia (6%) than in those with prothrombin G20210A (15%). No difference was found in the incidence of distal DVT. Regarding the extension of proximal DVT, the lowest incidence for isolated popliteal vein and the highest for iliofemoral vein were observed in patients with prothrombin G20210A. No difference was observed between groups of patients with or without thrombophilia by unprovoked VTE. The pregnancy/puerperium was the most prevalent risk factor in carriers of prothrombin G20210A. Among FVLeiden carriers, the most prevalent risk factor was surgery, and in patients without thrombophilia, it was trauma (P < .05). Thrombosis of the upper limb was more frequent in a group without thrombophilia than in patients with mutations (P < .01). Transverse sinus venous thrombosis was present only in patients with prothrombin G20210A. Carriers of prothrombin G20210A have an increased risk of developing isolated PE and more severe clinical manifestations than those with FVLeiden or without thrombophilia.