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Genetic variation in the maternal vitamin D receptor FokI gene as a risk factor for recurrent pregnancy loss

Aim: The aim of this study was to evaluate the potential association between spontaneous or idiopathic PTB (SPTB) and DNMT3B gene polymorphisms in Slavic women, and their contribution to clinical characteristics of women with SPTB and their new-borns (family history of PTB, maternal smoking before pregnancy, maternal age, gestational week at delivery and fetal birth weight). Patients and methods: A total of 162 women with SPTB and 162 women with term delivery were included in a case-control study. Genotyping of DNMT3B rs1569686 and DNMT3B rs2424913 single nucleotide polymorphisms was performed using polymerase chain reaction and restriction fragment length polymorphism methods. Results: DNMT3B rs1569686 and rs2424913 minor alleles (T) were significantly more frequent in women with familial PTB than non-familial PTB, and contributed to a 3.30 and 3.54 increased odds for familial PTB under dominant genetic models (95 % CI = 1.53-7.14, P = 0.003 and 95 % CI = 1.56-8.01, P = 0.002). Furthermore, the DNMT3B rs1569686 and rs2424913 T alleles were significantly more frequent in women with SPTB who smoked before pregnancy, reaching the most significant association under additive genetic models (OR = 6.86, 95 % CI = 2.25-20.86, P ˂ 0.001 and OR = 3.77, 95 % CI = 1.36-10.52, P = 0.011). Conclusion: The DNMT3B rs1569686 and rs2424913 gene polymorphisms in Slavic women might be associated with a positive family history of PTB and smoking status before pregnancy.

Aim: Preterm birth (PTB) is a birth that occurs before the 37th week of gestation and is the leading cause of neonatal mortality and morbidity. DNA methyltransferases (DNMTs) establish DNA methylation patterns at specific genome regions and contribute to gene regulation. Previous studies have reported on an association between spontaneous PTB (SPTB ; birth with intact membranes) and epigenetic changes (i.e. methylation levels) in maternal blood, placenta and cord blood. Additionally, certain DNMT3B gene polymorphisms in women were found to be associated with an increased risk for SPTB. The aim of this study was to evaluate the potential association between SPTB and DNMT1, 3A, 3B and 3L gene polymorphisms in European Caucasian women, and their contribution to clinical characteristics of women with SPTB and their new-borns. Patients and methods: A total of 113 women with SPTB and 119 women with term delivery were included in a case-control study. Genotyping of DNMT1 rs2228611 A/G, DNMT3A rs1550117 A/G, DNMT3B rs1569686 G/T and DNMT3L rs2070565 A/G single nucleotide polymorphisms was performed using polymerase chain reaction and restriction fragment length polymorphism methods. Results: No statistically significant differences were found in the distribution of genotype or allele frequencies of tested polymorphisms between patients and controls. However, the DNMT3B rs1569686 minor allele (T) was more frequent in women with familial SPTB than women with non-familial SPTB (Χ2=7.65, P=0.006), contributing to a 4.02 increased odds for familial SPTB under the dominant genetic model (TG+TTvsGG) (95% CI=1.56-10.40, P=0.004). None of the other polymorphisms contributed to the clinical characteristics of women with SPTB and their new-borns (family history of SPTB, maternal and gestational age at delivery, fetal birth weight). Conclusion: The DNMT3B rs1569686 T allele in European Caucasian women might be associated with a positive family history of SPTB.

CILJ: Intraventrikularno krvarenje (IVH) jedno je od najznačajnijih uzroka oštećenja središnjeg živčanog sustava u prijevremeno rođene novorođenčadi. Niz je istraženih čimbenika rizika za nastanak IVH u prematurusa: genetski, prenatalni, faktori poroda, te čimbenici novorođenačkog razdoblja. Neki od njih jatrogene su prirode, što sugerira potrebu za znanstveno-istraživačkim pristupom u cilju detekcije istih.ISPITANICI I METODE: Retrospektivno su analizirani podaci iz medicinske dokumentacije Jedinice novorođenačkog intenzivnog liječenja, Klinike za ginekologiju i porodništvo, Kliničkog bolničkog centra Rijeka. Izdvojeni su podaci o prematurusima, u kojih je postavljena dijagnoza intraventrikularnog krvarenja (I.- IV. stupanj), tijekom 2013. i 2014. godine. Analizirani su podaci 60-ero djece koji se odnose na trudnoću, porod i novorođenačko razdoblje. Ispitanici su podijeljeni u skupine, u ovisnosti o stupnju IVH-a , a rezultati su statistički obrađeni.REZULTATI: Korioamnionitis majke u trudnoći, Apgar ocjene u 1. i 5 minuti, perinatalna asfiksija, gestacijska dob, prisutstvo respiratornog distresa, rodna masa, epizode hiper/hipokapnije, primjena reanimacije, svježe smrznute plazme (SSP), natrij-hidrogenkarbonata (NaHCO3) i filtriranih eritrocita (FE) u prvom tjednu života, pokazali su statistički značajnu razliku između grupa ispitanika s različitim stupnjevima IVH-a. Čimbenici koji su značajno utjecali na stupanj IVH jesu gestacijska dob (P=0,004) i primjena FE u 1. tjednu (P=0,001). Primjena FE u 1. tjednu života samostalno je doprinijela 11,74%, a gestacijska dob 7,80% u objašnjavanju stupnja IVH.ZAKLJUČCI: Osobito je važno da medicinsko osoblje, koje skrbi o prijevremeno rođenom novorođenčetu i trudnici, poznaje čimbenike rizika za javljanje IVH-a, posebice one jatrogene prirode, u cilju njihovog minimiziranja i/ili uklanjanja., OBJECTIVE: Intraventricular hemorrhage (IVH) is one of the most important causes of damage to the central nervous system in preterm infants. There are number of the investigated risk factors for IVH in premature infants: genetic, prenatal, delivery factors, and factors related to neonatal period. Some of them are of iatrogenic nature, suggesting the need for scientific-research approach to detect them. PATIENTS AND METHODS: We retrospectively analyzed data from medical records of Neonatal Intensive Care Unit, at the Department of Obstetrics and Gynecology, University Hospital Center Rijeka. Selected were the data on premature infants who were diagnosed with intraventricular hemorrhage (I- IV. degree), during 2013 and 2014. We analyzed the data of 60 children relating to pregnancy, childbirth and neonatal period. Subjects were divided into groups, depending on the degree of IVH, and the results were statistically analyzed. RESULTS: Chorioamnionitis during pregnancy, Apgar score at 1st and 5th minutes, perinatal asphyxia, gestational age, the presence of respiratory distress, birth weight, hyper- / hypocapnia, resuscitation, the use of fresh frozen plasma (FFP), sodium bicarbonate (NaHCO3) and the filtered red blood cells (FRBC) in the first week of life, showed a statistically significant association with the development of higher degree IVH. Factors that significantly influenced the degree of IVH are gestational age (P = 0.004) and the application of FE in the first week (P = 0.001). In explaining the degree of IVH, application of FE in the first week of life independently contributed with 11.74%, while gestational age with 7.80%.CONCLUSIONS: It is particularly important that the medical staff, which takes care of preterm newborn and pregnant woman, is familiar with the risk factors for developing IVH, particularly those of iatrogenic nature, for the purpose of their minimization and / or elimination.

Intraventrikualrno krvarenje najvažniji je uzrok oštećenja mozga u prematurusa. Unatoč razvoju neonatologije i neonatološke njege te posljedičnom smanjenju incidencije IVH, ono ostaje vrlo važnim čimbenikom morbiditeta i mortaliteta prematurusa. Cilj ovog rada bio je istražiti rizične čimbenike za razvoj IVH u prematurusa naše populacije. Istraživanje je provedeno retrospektivno i obuhvatilo je 60 djece rođene u KBC-u Rijeka u razdoblju 2013. - 2014. godine. Analizirana je banka podataka Zavoda za neonatologiju Klinike za ginekologiju i porodništvo Kliničkog bolničkog centra Rijeka. Dobiveni podatci su upisani u Microsoft Office Excel tablice i obrađeni metodama deskriptivne statistike. Niža gestacijska dob djeteta statistički je značajno povezana s većim stupnjem IVH, kao i primjena koncentriranih eritrocita u prvom tjednu. Primjena FE u 1. tjednu i gestacijska dob su statistički značajno utjecale na stupanj IVH, s udjelom od 64 %. Prema našim rezultatima nije bilo razlika u težini IVH s obzirom na način dovršenja poroda, prezentaciju u porodu te s obzirom na spol djeteta. Novorođenčad reanimirana po porodu, kao i novorođenčad s dijagnozom perinatalne asfiksije ima veću vjerojatnost za razvoj višeg stupnja IVH. Primjena bikarbonata povezana je s većom vjerojatnosti za viši stupanj IVH naše istraživane populacije. S obzirom na to da ne postoji specifična terapija za IVH, nužno je svu pažnju usmjeriti ka suportivnim mjerama - očuvanju cerebralne perfuzije, minimizaciji daljnjih ozljeda mozga i ranoj detekciji komplikacija Intraventricular hemorrhage is the most important cause of brain damage in premature infants and it remains a very important factor regardless the reducing incidence over the last decades. The aim oft his study was to investigate risk factors for development of IVH and their connection with the severity of IVH. The study was conducted retrospectively on 60 children born in the Hospital of Rijeka in the period from 2013. to 2014. We analyzed the data bank of the Clinic for Gynaecology and Obstetrics of the Clinical Hospital Centre and the Institute of Neonatology. The obtained data was stored in Microsoft Office Excell spreadsheet and analyzed by descriptive statistics. Application of FE in the first week and gestational age significantly influenced the degree of IVH, with a share of 64%. The lower gestational age of the child and application of concentrated blood cells int he first week are significantly associated with higher degree of IVH. According to our results, there was no difference int he severety of IVH in relation to the way of completion of delivery, presentation and the sex of the child. Newborns reanimated after birth and newborns with dignosed perinatal asphyxia are more likely to develop higher degree of IVH. Use of bicarbonates may increase the risk of a higher degree of IVH. That is why rationalization of use is necessary. Since there is no specific therapy, we must acces to supportive care that includes preserving cerebral perfusion, minimizing further brain injury and early detection of complications.