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

Uvod. Prisustvo urođene trombofilije predstavlja dodatni faktor rizika od nastanka venskog tromboembolizma u trudnoći, ali i komplikacija same trudnoće kao što su ponavljani gubitak trudnoće, abrupcija placente, intrauterino zaostajanje u rastu i razvoju, te rana preeklampsija. Trudnice sa trombofilijom, a posebno one sa nedostatkom antitrombina, u riziku su od nastanka obe vrste komplikacija u trudnoći. Prikaz bolesnice. U radu je prikazana trudnica sa urođenim nedostatkom antitrombina u toku njene prve trudnoće, čija majka je četiri puta imala duboke venske tromboze, tokom trudnoće i puerperijuma. Uz redovno laboratorijsko praćenje hemostaznih parametara i redovne akušerske kontrole sa praćenjem važnog parametra placentne vaskularizacije, čitava trudnoća protekla je bez komplikacija. Profilaktička terapija niskomolekularnim heparinom uvedena je od 20. nedelje trudnoće, a supstituciona terapija primenom koncentrata antitrombina, neposredno pre porođaja. Porođaj je protekao bez komplikacija i u 37. nedelji rođena je zdrava muška beba telesne težine 3,6 kg i dužine 52 cm, sa Abgar skorom 9/10. Zaključak. Pravovremeno postavljena dijagnoza trombofilije, redovne akušerske kontrole i praćenje hemostaznih parametara u toku trudnoće, kao i primena adekvatne profilaktičke i supstitucione terapije, doprinele su prevenciji mogućih maternalnih ili komplikacija same trudnoće kod bolesnice sa urođenim nedostatkom antitrombina.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 earlyonset 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

Izmenjena struktura i antioksidativni kapacitet lipoproteinskih čestica visoke gustine u preeklampsiji

Background/Aim. One of the complications that can oc- cur during pregnancy is the development of preeclampsia (PE). The main characteristics of this condition are high blood pressure and very often signs of kidney damage or other organ damage. The condition affects 5–7% of all pregnant women and is one of the main factors of maternal and perinatal morbidity and mortality worldwide. The aim of this study was to investigate the structural and functional modifications of high-density lipoprotein (HDL) particles during high-risk pregnancies (HRP) for PE development. Methods. The longitudinal prospective study included a to- tal of 91 pregnant women with a HRP for developing PE. Out of this total number, 71 women did not develop PE until delivery, and this group was designated as the group without PE (WPE). The rest of the 20 HRP women devel- oped PE before delivery and were designated as the PE group. The blood was sampled toward the end of each tri- mester and before the delivery. The distribution of HDL particles was determined by the vertical 3–31% polyacryla- mide gradient gel electrophoresis method. The antioxidative capacity of HDL particles was measured by the activity of the HDL-associated enzyme – paraoxonase 1 (PON1). PON1 activity was determined by the method of kinetic spectrophotometry from serum samples. Results. The re- sults have shown that the proportions of HDL 2b particles significantly increased in the 2nd trimester (p ˂ 0.05) and remained increased until the end of pregnancy in the WPE group. PON1 activity was significantly higher in the 3 rd tri- mester (p < 0.05) of the WPE group. In the PE group, we found that the proportions of HDL 3a particles significantly decreased in the 2 nd trimester (p < 0.05) and remained de- creased until the end of pregnancy. PON1 activity has not changed in the PE group during pregnancy. Conclusion. Dyslipidemia in pregnancy could be associated with differ- ent modifications of HDL particles. The adaptive pregnancy mechanisms expressed as a functional modification of HDL particles in pregnant women who develop PE seem inade- quate and, therefore, lose their atheroprotective role.Uvod/Cilj. Jedna od komplikacija koja se može javiti tokom trudnoće je razvoj preeklampsije (PE). Glavne karakteristike ovog stanja su visok krvni pritisak i vrlo često znaci oštećenja bubrega ili drugih organa. Ovo stanje pogađa 5–7% svih trudnica i jedan je od glavnih faktora morbiditeta i mortaliteta trudnica i fetusa ili novorođenčadi. Cilj ovog rada bio je ispitivanje strukturnih i funkcionalnih modifikacija lipoproteinskih čestica visoke gustine (high- density lipoprotein – HDL) u trudnoćama sa visokim rizikom (TVR) za razvoj PE. Metode. U longitudinalnoj prospektivnoj studiji učestvovala je ukupno 91 trudnica sa TVR od razvoja PE. Od ukupnog broja trudnica, kod njih 71, PE se nije razvila do kraja trudnoće i ova grupa je označena kao grupa bez PE (BPE). Kod preostalih 20 žena sa TVR se razvila PE do porođaja, i one su svrstane u grupu PE. Krv je uzimana za analizu na kraju svakog trimestra i pred porođaj. Raspodela HDL čestica je određivana metodom vertikalne elektroforeze u 3–31% gradijentu poliakrilamidnog gela. Antioksidativni kapacitet HDL čestica je određivan na osnovu aktivnosti enzima paraoksonaze 1 (PON1) vezanog za HDL. Aktivnost PON1 u serumu je određivana metodom kinetičke spektrofotometrije. Rezultati. Rezultati su pokazali da se udeo HDL 2b čestica značajno povećao u drugom trimestru (p < 0,05) i ostao je povećan do kraja trudnoće u grupi BPE. Aktivnost PON1 bila je značajno veća u trećem trimestru (p < 0,05) kod ove grupe trudnica. Udeo HDL 3a čestica se značajno smanjio u drugom trimestru u PE grupi trudnica (p < 0,05) i ostao je snižen do kraja trudno će. Aktivnost PON1 enzima u PE gripi se nije menjala u toku trudnoće. Zaključak. Dislipidemija u trudnoći može biti posledica različitih modifikacija HDL čestica. Strukturne i funkcionalne modifikacije HDL čestica, kao jedan od adaptivnih mehanizama, kod trudnica kod kojih se razvila PE, nisu adekvatne i kao takve gube svoju ateroprotektivnu ulogu

Cholesterol homeostasis is dysregulated in women with preeclampsia

Introduction The link between preeclampsia and dyslipidemia has been established. Even though lipid profile parameters have been intensively investigated in the pathology of preeclampsia, their accurate molecular mechanisms of action have not been fully decoded. Objectives We aimed to identify the specifics of cholesterol metabolism in women affected by late‑onset preeclampsia and single out potential biomarkers associated with late‑onset syndrome. Patient s and methods A total of 90 pregnant women with a priori risk for preeclampsia were monitored at 4 time points during gestation and, based on the outcome of pregnancy, they were classified into the high‑risk group (70 women) and the preeclampsia group (20 women). Cholesterol metabolic profiling was done using liquid chromatography‑tandem mass spectrometry. Result s The only significant change in the preeclampsia group was an increase in the lathosterol level (P = 0.001). The first‑trimester lathosterol level was higher in the preeclampsia group compared with the high‑risk group (P = 0.02). Further, in the preeclampsia group, positive correlations were found between desmosterol and β‑sitosterol (ρ = 0.474; P = 0.03) in the third trimester, desmosterol and campesterol changes between the second and the first (ρ = 0.546; P = 0.02), and the third and first trimesters (ρ = 0.754; P <0.001), as well as between the desmosterol and β‑sitosterol differences between the third and first trimesters (ρ = 0.568; P = 0.01). No similar correlations were found in the high‑risk group. Conclusions Late‑onset preeclampsia could be associated with an altered lipid profile. By studying the quantitative metabolic signatures of cholesterol, we might assume that both cholesterol synthesis and absorption are increased, that is, there is an imbalance in the cholesterol homeostasis regulation in women affected by the disease

Supplementary data for the article: Stojsavljević, A.; Rovčanin, M.; Miković, Ž.; Perović, M.; Jeremić, A.; Zečević, N.; Manojlović, D. Analysis of Essential, Toxic, Rare Earth, and Noble Elements in Maternal and Umbilical Cord Blood. Environ Sci Pollut Res 2022. https://doi.org/10.1007/s11356-021-18190-y.

Supplementary material for: [https://doi.org/10.1007/s11356-021-18190-y]Related to published version: [https://cherry.chem.bg.ac.rs/handle/123456789/4879

Kombinovano prisustvo genskih polimorfizma faktora koagulacije XIII V34L i inhibitora plazminogen aktivatora 1 4G/5G značajno utiče na rizik od spontanog pobačaja u srpskoj populaciji

Background:Recurrent pregnancy loss (RPL) is a heterogeneous condition affecting up to 5% of women of reproductive age. Inherited thrombophilia have been postulated as one of the causes of RPL. Here we examined the prevalence of nine thrombophilic gene polymorphisms among women with history of recurrent miscarriages and fertile controls.Methods:The study included 70 women with history of at least three early pregnancy losses and 31 fertile controls with no miscarriages. We investigated mutations in genes responsible for clotting and fibrinolysis, including factor V(FV) Leiden, FV H1299R, factor II (FII) G20210A, methyl-ene tetrahydrofolate reductase (MTHFR) C677T and A1298C, factor XIII (FXIII) V34L, plasminogen activator inhibitor-1 (PAI-1) 4G/5G and endothelial protein C receptor (EPCR) H1 and H3 haplotypes using reverse polymerase chain reaction ViennaLab cardiovascular disease StrippAssays. Results:Our results showed no significant increase inprevalence of tested polymorphisms in women with RPL. However, relative risk for PRL among women heterozygousfor FXIII V34L was 2.81 times increased (OR 2.81, 95% CI1.15–6.87, P=0.023). Haplotype analysis showed that combined presence of high-risk genotypes for FXIII andPAI-1 significantly increases risk for RPL (OR 13.98, CI95% 1.11–17.46, P=0.044).Conclusions:This is the first study in Serbian population that investigated prevalence of FVR2, A1298C, FXIII V34Land EPCR gene variants. Compound heterozygosity forFXIII V34L and PAI-1 4G is significant risk factor for recur-rent miscarriage. Our results should be viewed in context of small case-control study, so further large prospective studies are need for confirmation of our findings.Uvod: Ponavljani spontani pobačaji (PSP) su etiološki heterogeni i javljaju se kod 5% parova u reproduktivnom period. Jedan od mogućih uzroka PSP su i nasledne trombofilije. U okviru ove studije analizirali smo učestalost devet trombofilnih polimorfizama kod pacijentkinja sa ponavljanim spontanim pobačajima. Metode: Ispitanici su u studiji podeljeni u dve grupe na osnovu anamnestičkih podataka o broju spontanih pobačaja (70 u grupi sa PSP i 31 u kontrolnoj grupi). Ispitivani su sledeći genski polimorfizmi: faktor V Lajden (FVL), FVR2, faktor II (FII) G21210A, metilentetrahidrofolat reduktaza (MTHFR) C677T i A1298C polimorfizmi, inhibitor aktivatora plazminogena 1 (PAI-1) 4G/5G, faktor XIII (FXIII) V34L i endotelni protein C receptor (EPRC) H1, H2 i H3 haplotipovi. Za detekciju navedenih polimorfizama je korišćena metoda multipleks reakcije lančanog umnožavanja i reverzne hibridizacije na ViennaLab stripovima. Rezultati: Dobijeni rezultati nisu pokazali povećanu učestalost ispitivanih polimorfizama u grupi sa PSP. Posmatrajući uticaj pojedinačnih polimorfizama na ishod trudnoće pokazano je da polimorfizam FXIII V34L povećava rizik za ponavljane spontane pobačaje (OR 2,81, 95%CI 1,15-6,87, P=0,023). Analizom haplotipova ustanovljeno je da kombinovano prisustvo V34L i PAI-1 4G varijanti značajno povećava rizik za PSP (OR 13,98, CI 95% 1,11-17,46, P=0,044). Zaključak: Ovo je prva studija koja je ispitivala prevalencu FVR2, A1298C, FXIII V34L and EPCR polimorfizama u populaciji žena iz Srbije. Složeni heterozigoti za FXIII V34L i PAI-1 4G polimorfizme imaju značajno povišen rizik sa ponavljane gubitke trudnoće. Radi potvrde dobijenih rezultata potrebne su veće prospektivne studije

Cholesterol Metabolic Profiling of HDL in Women with Late-Onset Preeclampsia

A specific feature of dyslipidemia in pregnancy is increased high-density lipoprotein (HDL) cholesterol concentration, which is probably associated with maternal endothelium protection. However, preeclampsia is most often associated with low HDL cholesterol, and the mechanisms behind this change are scarcely explored. We aimed to investigate changes in HDL metabolism in risky pregnancies and those complicated by late-onset preeclampsia. We analyze cholesterol synthesis (cholesterol precursors: desmosterol, 7-dehydrocholesterol, and lathosterol) and absorption markers (phytosterols: campesterol and β-sitosterol) within HDL particles (NCSHDL), the activities of principal modulators of HDL cholesterol’s content, and major HDL functional proteins levels in mid and late pregnancy. On the basis of the pregnancy outcome, participants were classified into the risk group (RG) (70 women) and the preeclampsia group (PG) (20 women). HDL cholesterol was lower in PG in the second trimester compared to RG (p < 0.05) and followed by lower levels of cholesterol absorption markers (p < 0.001 for campesterolHDL and p < 0.05 for β-sitosterolHDL). Lowering of HDL cholesterol between trimesters in RG (p < 0.05) was accompanied by a decrease in HDL phytosterol content (p < 0.001), apolipoprotein A-I (apoA-I) concentration (p < 0.05), and paraoxonase 1 (PON1) (p < 0.001), lecithin–cholesterol acyltransferase (LCAT) (p < 0.05), and cholesterol ester transfer protein (CETP) activities (p < 0.05). These longitudinal changes were absent in PG. Development of late-onset preeclampsia is preceded by the appearance of lower HDL cholesterol and NCSHDL in the second trimester. We propose that reduced capacity for intestinal HDL synthesis, decreased LCAT activity, and impaired capacity for HDL-mediated cholesterol efflux could be the contributing mechanisms resulting in lower HDL cholesterol

Novi biomarkeri u procjeni rizika za razvoj preeklampsije

Despite significant progress in improving pregnancy outcomes in recent decades, predicting the risk and treatment of preeclampsia are still major challenges in clinical practice (1). The aim of this study was to examine non-routine biomarkers in preeclampsia risk assessment. The study involved 90 women with high-risk pregnancies, 20 of whom developed preeclampsia by the end of pregnancy. Biochemical parameters were determined between the 12th and 13 th weeks of gestation. The results of the study showed that women who later developed preeclampsia had higher concentrations of lathosterol, cholesterol synthesis marker (p <0.05), inflammatory proteins - monocyte chemoattractant protein-1 (MCP-1), and resistin (p <0.01, both), as well as paraoxonase-1 (PON1) activity (p <0.05). Binary logistic regression analysis showed that higher concentrations of lathosterol, MCP-1, resistin, and PON-1 were associated with preeclampsia development. To determine whether the parameters significant in univariate analysis, are independent predictors of preeclampsia, we applied multivariate regression analysis. Clinical markers commonly used in risk assessment (maternal age and body mass index, mean arterial pressure, and uterine blood flow), lathosterol, MCP-1, resistin, and PON-1 were included in the model. MCP-1 and resistin stood out as significant independent predictors of preeclampsia. The diagnostic accuracy of the investigated model was excellent (AUC=0.859). The study results indicated the importance of a multi-marker approach in risk assessment for preeclampsia development.Uprkos značajnom napretku u poboljšanju ishoda trudnoće poslednjih decenija, predviđanje rizika i terapija preeklampsije su još uvijek veliki izazovi u kliničkoj praksi (1). Cilj ove studije je bio ispitivanje biomarkera koji se ne koriste u rutinskoj praksi u proceni rizika za razvoj preeklampsije. U studiji je učestvovalo 90 žena sa visokorizičnim trudnoćama, od kojih je 20 razvilo preeklampsiju do kraja trudnoće. Biohemijski parametri su određivani između 12. i 13. nedelje gestacije. Rezultati studije su pokazali da su žene koje su razvile preeklampsiju imale više koncentracije latosterola, markera sinteze holesterola (p <0,05), inflamatornih proteina - monocitnog hemoatraktantnog proteina-1 (MCP-1) i rezistina (p < 0,01, oba), kao i aktivnost enzima paraoksonaze-1 (PON1) (p <0,05). Binarna logistička regresiona analiza je pokazala da su više koncentracije latosterola, MCP-1, rezistina i PON-1 povezane sa razvojem preeklampsije. Da bi se utvrdilo da su parametri koji su se u univarijantnoj analizi pokazali značajnim, nezavisni prediktori preeklampsije, primjenili smo multivarijantnu regresionu analizu. U model su ušli klinički parametri koji se uobičajeno koriste u procjeni rizika (starost i indeks tjelesne mase majke, srednji arterijski pritisak i protok krvi kroz matericu), latosterol, MCP-1, rezistin i PON-1. MCP-1 i rezistin su se istakli kao značajni nezavisni prediktori preeklampsije. Pokazana je odlična dijagnostička tačnost ispitivanog modela (AUC=0,859). Rezultati ove studije su ukazali na značaj multimarkerskog pristupa u procjeni rizika za razvoj preeklampsije.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Examination of Trace Metals and Their Potential Transplacental Transfer in Pregnancy

With the ever-growing concern for human health and wellbeing, the prenatal period ofdevelopment requires special attention since fetuses can be exposed to various metals through themother. Therefore, this study explored the status of selected toxic (Pb, Cd, Ni, As, Pt, Ce, Rb, Sr, U)and essential trace metals (Mn, Co, Cu, Zn, Se) in the umbilical cord (UC) sera, maternal sera, andplacental tissue samples of 92 healthy women with normal pregnancies. A further aim focuses on thepotential transplacental transfer of these trace metals. Based on the obtained levels of investigatedelements in clinical samples, it was observed that all of the trace metals cross the placental barrierand reach the fetus. Furthermore, statistical analysis revealed significant differences in levels oftoxic Ni, As, Cd, U, Sr, Rb, and essential Mn, Cu, and Zn between all three types of analyzed clinicalsamples. Correlation analysis highlighted As to be an element with levels that differed significantlybetween all tested samples. Principal component analysis (PCA) was used to enhance these findings.PCA demonstrated that Cd, Mn, Zn, Rb, Ce, U, and Sr were the most influential trace metals indistinguishing placenta from maternal and UC serum samples. As, Co, and Cu were responsible forthe clustering of maternal serum samples, and PCA demonstrated that the Pt level in UC sera wasresponsible for the clustering of these samples. Overall, the findings of this study could contribute toa better understanding of transplacental transfer of these trace metals, and shed a light on overalllevels of metal exposure in the population of healthy pregnant women and their fetuses

Effects of Gestational Diabetes Mellitus on Cholesterol Metabolism in Women with High-Risk Pregnancies: Possible Implications for Neonatal Outcome

Metabolic disorders in pregnancy, particularly gestational diabetes mellitus (GDM), are associated with an increased risk for adverse pregnancy outcome and long-term cardiometabolic health of mother and child. This study analyzed changes of serum cholesterol synthesis and absorption markers during the course of high-risk pregnancies, with respect to the development of GDM. Possible associations of maternal lipid biomarkers with neonatal characteristics were also investigated. The study included 63 women with high risk for development of pregnancy complications. Size and proportions of small low-density (LDL) and high-density lipoprotein (HDL) particles were assessed across trimesters (T1–T3), as well as concentrations of cholesterol synthesis (lathosterol, desmosterol) and absorption markers (campesterol, β-sitosterol). During the study, 15 women developed GDM, while 48 had no complications (non-GDM). As compared to the non-GDM group, women with GDM had significantly higher triglycerides in each trimester, while having a lower HDL-C level in T3. In addition, they had significantly lower levels of β-sitosterol in T3 (p < 0.05). Cholesterol synthesis markers increased across trimesters in both groups. A decrease in serum β-sitosterol levels during the course of pregnancies affected by GDM was observed. The prevalence of small-sized HDL decreased in non-GDM, while in the GDM group remained unchanged across trimesters. Newborn’s size in the non-GDM group was significantly higher (p < 0.01) and inversely associated with proportions of both small, dense LDL and HDL particles (p < 0.05) in maternal plasma in T1. In conclusion, high-risk pregnancies affected by GDM are characterized by altered cholesterol absorption and HDL maturation. Advanced lipid testing may indicate disturbed lipid homeostasis in GDM

Lipidni status fiziološke nekomplikovane trudnoće

Specifically altered lipid profile and physiological hyperlipidemia during pregnancy are considered essential for the normal course of pregnancy and fetal development. This specific alteration of the lipid profile raises the questions about potential proaterogenic effect of these altered lipid parameters during pregnancy and its influence on the development of cardiovascular disease in women later in life. Research topic was also the association of altered lipid profile during pregnancy with the development of complications in pregnancy, especially gestational diabetes, hypertension and preeclampsia. Through the mediation of cholesterol ester transfer protein (CETP), the activity of which grows in mid-gestation, there are exchanges of the triglycerides between VLDL and LDL or HDL particle, which leads to increased accumulation of triglycerides in these particles, causes them to become smaller and denser with much greater atherogenic potential. These changes in lipid profile point out that a large number of pregnancies increase risk of development of cardiovascular diseases later in life. In order to optimize the predictive capacity of the lipid profile during pregnancy, it is recommended to determine the indexes of lipid.Specifično izmenjen lipidni profil i fiziološka hiperlipidemija tokom trudnoće smatraju se esencijalnim za normalan ishod trudnoće i razvoj fetusa, a upravo ova specifičnost promena parametara lipidnog profila otvara pitanja njihove potencijalne proaterogenosti tokom trudnoće i uticaja na rizik za razvoj kardiovaskularne bolesti u kasnijem životu žene. Takođe se ispituje i povezanost izmenjenog lipidnog profila tokom trudnoće sa razvojem komplikacija u trudnoći, pre svega sa razvojem gestacijskog dijabetesa, hipertenzije i preeklampsije. Posredovanjem holesterol estar transportnog proteina (CETP), čija aktivnost raste sredinom trudnoće, dolazi do izmene triglicerida i holesterola između lipoproteinskih čestica vrlo niske gustine (VLDL) i lipoproteinskih čestica male gustine (LDL) ili lipoproteinskih čestica velike gustine (HDL), tako da dolazi do povećanog nakupljanja triglicerida u LDL i HDL česticama, pri čemu one postaju manje i gušće, i kao takve imaju veći proaterogeni potencijal, što sve ukazuje i na proaterogeni potencijal trudnoće, posebno ukoliko se ona ponavlja više puta tokom života. Da bi se optimizirao prediktivni kapacitet lipidnog profila tokom trudnoće preporučuje se određivanje lipidnih indeksa