Rozprawy doktorskie na temat „Pregnancy trimester”

Abstract The aim of the present study was to evaluate the efficacy of the first trimester screening for Down syndrome (DS) in an unselected low-risk Finnish population. The study involved 4,617 women who attended screening between the 8th and 14th weeks of pregnancy in 1998-2000. They gave a blood sample for the measurement of pregnancy associated plasma protein A (PAPP-A) and free beta human chorionic gonadotrophin (β-hCG). Of these women, 3,178 also had an ultrasound examination for the measurement of fetal nuchal translucency (NT). The risk figure for every screened woman was calculated using a computerized risk figure program. The risk 1 in 250 was used as a cut-off. The subgroup of screen positives comprised 5.8% of the study group. There were 16 DS cases. The combined method (maternal age, NT and the biochemical markers) detected 77% of the affected pregnancies. NT combined with maternal age gave a detection rate of 69%. Serum markers without NT combined with maternal age found 75% of the Down's. In 49 consecutive singleton in-vitro-fertilization pregnancies, the β-hCG value was more often elevated compared to spontaneous pregnancies, increasing the false positive rate. In 67 twin pregnancies, the serum marker levels were approximately double those in singletons. Smoking reduced PAPP-A by 20% making the smokers more likely to get a positive screening result. To determine the impact of the screening on the live born incidence of DS, two historical populations were compared. The first group was screened by second trimester serum samples (β-hCG and AFP) and the second group by first trimester ultrasound examination. When detection rates were at the same level, the second trimester screening reduced the number of live born Down's children more effectively. In conclusion, the first trimester combined method (maternal age, NT, β-hCG and PAPP-A) for Down syndrome screening is efficient in an unselected low risk population. The biochemical screening is not recommended in IVF-pregnancies.

The study objective was to determine whether early 2 nd trimester amniotic fluid (AF) erythropoietin (EPO) was associated with and predictive of (a) development of maternal gestational diabetes (GDM) and (b) the infant outcome parameters of (i) gestational age at birth (GAAB) assessed exclusively among spontaneous vaginal deliveries or (ii) birth weight (measured in grams and percentiles). Enzyme-linked-immunosorbent assay was used to determine the EPO concentration of 170 biobanked AF samples. Student's t-test revealed no difference between GDM and non-GDM subjects. AF EPO was not predictive of GAAB despite being significantly greater among preterm infants compared to post-term infants. In contrast, AF EPO was significantly higher among the smallest infants using both birth weight classification schemes. However, following inclusion of known covariates AF EPO was predictive of gram birth weight only. Early 2nd trimester AF EPO may emerge as a useful biomarker of fetal nutritional status and/or growth.

In this thesis safety, efficacy and acceptability of early medical abortion with mifepristone and the prostaglandin analogue gemeprost are investigated in Chapters 2,3 and 5. In Chapter 4 the mechanism of abortion with these agents is explored. The use of a single dose of 400 mg, 500 mg or 600 mg of mifepristone followed 48 hours later by a half or a whole 1 mg gemeprost pessary was shown to induce complete abortion in 95% of women of £ 56 days amenorrhoea. No significant differences were demonstrated between the three treatment regimes. When 600 mg of mifepristone was given with either a half or a whole gemeprost pessary, women receiving the smaller dose of prostaglandin experienced significantly less severe pain. Abortion rates were not compromised by a reduction in the dose of prostaglandin with 98% of women receiving a half pessary aborting, compared with 100% of women receiving a whole pessary. Pretreatment with mifepristone or gemeprost 48 hours prior to the administration of 1 mg gemeprost was also studied. Measurement of uterine tone with an intrauterine pressure catheter showed that while pretreatment with gemeprost had no effect on uterine tone following a further dose of gemeprost, pretreatment with mifepristone exerted a significant effect. In addition, the pattern of uterine activity following gemeprost or mifepristone pretreatment was shown to differ. Blood loss was measured during and after the induction of abortion with mifepristone and gemeprost in 222 consecutively treated women of <63 days of amenorrhoea. The median loss <56 days amenorrhoea was 72 mls. Blood loss was found to increase with increasing gestation and was significantly greater in women treated between 56 and 63 days of amenorrhoea. Although the introduction of prostaglandins to gynaecological practice has improved midtrimester abortion techniques, it remains a long, unpleasant and relatively high risk procedure.

Introduction: In 2012, the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention expanded their recommendation for the Tdap vaccination to include the antepartum period. Regardless of immunization history, the recommendation states that medical practitioners should administer the Tdap vaccination to every pregnant woman in each occurring pregnancy (Munoz, et al., 2014; Shakib, et al., 2013; Goldfarb, Little, Brown, Riley, 2014). Methods: To describe treatment practices and uptake of Tdap vaccine, a cross-sectional descriptive survey design was utilized. The purpose of survey is to gather information regarding prevalence, distribution, and interrelations of variables within a population (Polit & Beck). In this study, the survey questionnaire was conducted in an online format. Results: Of the six HBM questions included in the study, except for question four, the results of the chi-squared analysis suggest that any single measured dimension of the HBM cannot predict a health behavior, in this case receipt of the Tdap vaccination. The population is split regarding infants' perceived susceptibility to pertussis infection. Strong agreement to the benefit of vaccination was revealed. Question six regarded available information, although the majority were satisfied a significant percentage indicated a desire for more information. Discussion: This Doctorate of Nursing Practice project developed a survey based on the Health Belief Model with the intention of assessing perceived susceptibility, perceived severity, perceived benefits and perceived barriers to the health care preventative action of receiving the Tdap vaccination in the third trimester of pregnancy. Through in-depth literature review, consideration of the updated ACIP guidelines, and support of a developed theoretical framework, an eight-question survey was developed. The data examined in this project may serve to illustrate limitations in provider care that can be immediately improved upon, such as information sharing. The primary limitation of the study is in the sample size of 44 eligible survey responses and the uniform demographics of the population. Despite these limitations, the survey design may be extended to other populations of interest, with greater demographic variation for further study.

Uterine decidual macrophages are present throughout pregnancy however, little is known of their phenotype or functional relevance. This study aimed to further the understanding of decidual macrophage phenotype and function across the first and early second trimester. In addition, this study aimed to compare decidual macrophages derived from normal pregnancies and those at increased risk of developing complications (pre-eclampsia, FGR and stillbirth). Macrophage phenotype was shown to differentially affect trophoblast behaviour, with pro-inflammatory (M1 -like) macrophages inducing trophoblast apoptosis and impairing trophoblast motility, proliferation and network formation, when compared with an anti-inflammatory (M2-like) phenotype. Decidual macrophages were found to become increasingly anti-inflammatory with gestation; with upregulation of CD206 expression and downregulation of CD86, TLR4 and CD11c expression between the 4th and 14th week of pregnancy. The relative risk of a pregnancy developing complications was calculated by uterine artery resistance indices (Rl) measured by Doppler Ultrasound scanning, enabling phenotypic and functional comparisons to be made between decidual macrophages from normal and higher risk pregnancies. Decidual macrophages from normal pregnancies and those with a higher risk were found to differ in their cytokine secretion profiles, with those from higher risk pregnancies having reduced TNF-a, IL-8, VEGF, IL-1 ra and M-CSF secretion. Decidual macrophages from pregnancies with a higher risk of developing complications were also found to increase trophoblast apoptosis, reduce trophoblast proliferation, and impair trophoblast chemotaxis and network formation, when compared to decidual macrophages from normal pregnancies. Vascular smooth muscle apoptosis, proliferation and motility was not found to be affected by decidual macrophages. When decidual NK cells were cultured with secreted factors from decidual macrophages no effect on decidual NK phenotype was observed. Conversely, decidual macrophages cultured with decidual NK cell secreted factors were found to have elevated expression of CD11c and TLR4. The shift in decidual macrophage phenotype with advancing gestation likely reflects the requirement for tolerance of the semi-allogeneic fetus to support a successful pregnancy. The differential regulatory effect of decidual macrophages from normal and higher risk pregnancies on trophoblast phenotype and function are particularly interesting given that aberrant trophoblast invasion and spiral artery remodelling is related to the pathology of pre-eclampsia. These observations suggest that pre­eclampsia is preceded by impaired decidual macrophage-trophoblast interactions.

Regulation of the growth and differentiation of trophoblast cells is critical for successful embryo implantation and placentation. Cytokines are key players in these processes, as well as modulating the maternal immune response to prevent rejection of the conceptus. This thesis focused on the investigation of the cytokine interleukin (IL) - 33 and its receptor, ST2. ST2 has two isoforms, a functional cell surface receptor (ST2L) and a soluble decoy receptor (sST2). Previous work in this laboratory had shown that the human placenta expresses both IL-33 and sST2 at term. The aim of this thesis was to investigate IL-33 and ST2 in early pregnancy, the time when trophoblast is at its most active, with a view to better understanding their role. IL-33 and ST2 mRNA and protein were examined in 14 first trimester placentas from 6-12 weeks of gestation. IL-33 was localized to cells in the villous stroma, whereas ST2 was present in the syncytiotrophoblast, villous cytotrophoblast and the invasive extravillous cytotrophoblast of the cell columns. Secretion of sST2, but not IL-33, by the placenta was found. Investigation of pre-implantation embryos showed the presence of ST2, but not IL-33 protein. Decidualized endometrium was investigated as a potential source of IL-33 and sST2 at the maternal-fetal interface and, although mRNA for both was present, no protein could be found. The key finding was that sST2, rather than ST2L, was the predominant isoform in the placenta. This led us to reconsider the hypothesis that IL-33/ST2 interactions in the placenta are important for successful pregnancy and raised the possibility that they may have independent roles. Using trophoblast cell lines as a model, it was shown that sST2 binds to trophoblast cells, significantly inhibits their proliferation and stimulates their invasion in vitro. This is the first report of this novel role for sST2 in pregnancy. Thus these studies have shown that sST2 may play an important role in implantation and placentation through controlling trophoblast invasion.

The aim of this thesis was to examine a large cohort of women undergoing pregnancy assessment before 12 weeks gestation, collecting demographic, symptom and ultrasound data. I aimed to examine the role of prior risk factors and initial ultrasound findings in the prediction of first trimester viability of these pregnancies. Further, I aimed to develop and validate models to counsel women in future about the likely chance of viability for any individual pregnancy. The hypotheses were: (1) There are prior risk and ultrasound factors that can predict likely pregnancy viability, (2) These factors can be used to predict pregnancy loss or ongoing viability in any particular pregnancy and (3) In predicting outcome, both mathematical models } and 'simple rules' (for everyday clinical use) can perform well. ) The prospective study included 1881 women, with median age 32 years and median gestational age at presentation of 50 days. 46% presented with bleeding and 36% with pain. The final outcome was an ongoing pregnancy in 885 (61.7%) and early pregnancy loss in 550 (38.3%) women. Both 'prior risks' (maternal age and bleeding score) and ultrasound factors (gestation and yolk sac size and fetal heart beat) predicted viability. Mathematical models developed showed that these factors used separately and when combined together predicted viability with accuracy. The final scoring system using both demographic and ultrasound variables together was proven to be highly accurate in prediction of pregnancy viability, performing with a sensitivity of 0.92, specificity of 0.73, positive predictive value of 84.7% and negative predictive value of 85.4%. All 3 study hypotheses were proven. The conclusion of this study is that using routinely collected demographic and ultrasound data an accurate individualised likelihood of ongoing viability can be offered to women in early pregnancy with and without symptoms of pain or bleeding.

Abstract The purpose of this study was to evaluate extended first trimester screening for severe chromosomal disorders and adverse pregnancy outcomes in singleton pregnancies among the general population in Finland. Maternal serum biochemical markers, pregnancy associated plasma protein-A (PAPP-A) and free beta human chorionic gonadotropin (fβ-hCG), and fetal nuchal translucency (NT) thickness were measured during the gestational weeks 8+0–13+6. A computerized risk figure program was used to calculate an individual risk figure for chromosomal disorders. It was investigated whether the screening parameter, PAPP-A, is associated with adverse pregnancy outcomes. The prevalence of Down syndrome (DS) cases in Finland during the years 2002–2006 was 1:364 (N=795). The proportion of women aged 35 years or older increased from 5–10% in the years 1980–1990 to 19.1% during the study period. Most DS cases (61.1%) presented in that age group. The first trimester combined screening for Down syndrome yielded a detection rate (DR) of 81.9% for a 4.3% false positive rate (FPR). The performance was evaluated among 76949 voluntary women during the study period of 01.05.2002–31.12.2008. There were 188 cases of DS. The screening worked better among the older women. The number of invasive procedures needed to detect one case of DS was higher among the younger women. Adding specific algorithms for screening of other chromosomal abnormalities yielded DR of 74.0% for trisomy 18 (T18) and 54.5% for trisomy 13 (T13) with an additional increase of 0.3% FPR. For chromosomal abnormalities other than T18 and T13, the specific algorithms did not improve the screening performance. Low first trimester maternal serum levels of PAPP-A (≤0.30 MoM) were significantly associated with small for gestational age (SGA) newborns and stillbirths (SBs). The combined screening method for DS works well in practice and has been standardized in Finland. In screening for trisomies 18 and 13 a specific algorithm is reasonable. Low first trimester levels of PAPP-A could be used as an independent marker for pregnancies at high risk for SGA babies and SBs
Tiivistelmä Tutkimuksen tarkoituksena oli arvioida laajennetun ensimmäisen raskauskolmanneksen kromosomipoikkeavuuksien seulonnan toimivuutta yksisikiöisissä raskauksissa suomalaisessa normaaliväestössä. Äidin seerumin biokemialliset merkkiaineet, raskauteen liittyvä valkuaisaine A (PAPP-A) ja raskaushormoni (fβ-hCG) sekä sikiön niskaturvotus mitattiin raskausviikoilla 8+0–13+6. Yksilöllinen riskiluku kromosomipoikkeavuuksille laskettiin käyttäen tietokoneen riskinlaskentaohjelmaa. Seulonnan merkkiaineen, PAPP-A:n, matalien pitoisuuksien yhteyttä epäsuotuisiin raskauden lopputuloksiin tutkittiin. Downin oireyhtymän esiintyvyys Suomessa oli 1:364 (N=795) vuosina 2002–2006. 35-vuotiaiden tai sitä vanhempien naisten osuus oli tutkimusaikana 19.1 %, mikä on huomattavasti suurempi kuin vuosien 1980–1990: 5–10 %. Näiden naisten sikiöiden joukosta löytyi suurin osa Down oireyhtymistä (61.1 %). Ensimmäisen raskauskolmanneksen yhdistelmäseulonnan toimivuutta tutkittiin aikana 01.05.2002–31.12.2008. Tutkimukseen osallistui 76 949 vapaaehtoista naista. Joukossa oli 188 Downin oireyhtymätapausta. Seulonnan herkkyys Downin oireyhtymälle oli 81.9 % ja tarkkuus 4.3 %. Seulonta toimi parhaiten vanhempien naisten joukossa. Niiden kajoavien toimenpiteiden määrä, jotka tarvittiin yhden Down-sikiön löytämiseksi, oli suurempi nuorten naisten joukossa. Tutkimuksessa Downin oireyhtymän algoritmiin lisättiin spesifiset algoritmit trisomioille 18 ja 13, jolloin saavutettiin 74.0 %:n herkkyys trisomialle 18 ja 54.5 %:n herkkyys trisomialle 13. Väärien positiivisten seulontatulosten määrä kasvoi 0.3  %:n verran. Seulonnan toimivuus muiden kromosomipoikkeavuuksien joukossa ei parantunut spesifisten algoritmien avulla. Lisäksi matalan PAPP-A-pitoisuuden yhteys pienipainoisuuten ja kuolleena syntyneisyyteen oli tilastollisesti merkittävä. Tutkimus osoitti, että esimmäisen raskauskolmanneksen yhdistelmäseulonta toimii hyvin käytännössä. Trisomioiden 18 ja 13 seulonnassa spesifisten algoritmien käyttö on järkevää. Matalaa ensimmäisen raskauskolmanneksen PAPP-A-arvoa voitaisiin käyttää itsenäisenä riskimerkkiaineena raskauksille, joissa pienipainoisuuden ja kuolleena syntymisen riski on kohonnut

Our objectives were to measure concentrations of glucose, insulin, insulin-like-growth-factor-binding-protein-1 (IGF BP1) and beta-hydroxybutyrate (BOHB) in amniotic fluid (AF), and establish if these concentrations were associated with emergence of maternal gestational diabetes mellitus (GDM). AF samples (n=408) were collected following routine amniocentesis (12-22 weeks gestation). Glucose and insulin concentrations were elevated in our GDM mother-infant pairs, where GDM was associated with a 176g increase in birth weight. Logistic regression showed that AF glucose but not insulin was associated with developing GDM. Non-linear Bayesian probability plots showed that when 2nd trimester glucose was plotted against insulin increases in both were predictive of the subsequent emergence of GDM. In conclusion, our findings show that: (1) AF glucose but not insulin predicts subsequent emergence of GDM and (2) these observed elevations provide evidence that the fetus of GDM mothers is being exposed early in-utero to metabolic perturbations (i.e. elevated glucose) that may have important long-term metabolic consequences for their future development.

Mental health disorder is the leading cause of disease burden in women worldwide. Pregnant women with mental disorder are especially at risk of having offspring with adverse outcomes. This study aimed to investigate risk factors of mental health disorder among Chinese pregnant women in the third trimester. A total of 462 pregnant women in their third trimester completed interviews at three hospitals in Shandong Province, China from July to December, 2010. The Symptom Checklist-90-R (SCL-90-R) was used to evaluate mental health disorder, and was defined as total score ≥160, or scores of any symptom dimensions ≥3, or total of positive symptoms ≥43. Multiple logistic regression was used to examine the risk factors of mental health disorder, and to adjust for covariates. The total score and scores of somatization, obsessive-compulsive, anxiety, and phobic anxiety were higher than corresponding national norm by SCL-90-R assessment (all p<0.05). Multiple logistic regression showed family income, relationship with parents-in-law, concerns about child's health, fear of delivery, and pregnancy complications were negatively associated with mental health disorder (all p<0.05). More specifically, relationship with parents-in-law, fear of delivery, preference on mode of delivery (Caesarean section), and body image concerns were positively associated with anxiety (all p<0.05); Fear of delivery was positively associated with depression (p=0.023). Family income, relationship with parents-in-law, concern about child's health, fear of delivery, and pregnancy complications were identified as potential risk factors of mental health disorder in this Chinese pregnant women population. Strategies to reduce mental health disorder are needed among Chinese pregnant women.

Acute promyelocytic leukemia (APL) is a clinically distinct and rare type of acute myeloid leukemia and represents an oncologic emergency. Even rarer is the incidence of APL in pregnancy with less than 60 cases described in the literature. A 33-year-old pregnant female at 34 week gestation presented to hospital with reports of abdominal pain. On admission she was found to have acute onset pancytopenia with a WBC count of 1.2, Hemoglobin of 9.7g/dl, and platelet count of 26000. Initial history, exam, and investigations including a peripheral smear, coagulation panel, liver function, vitamin b12 and folate levels did not reveal possible etiology of pancytopenia. Given worsening pancytopenia, bone marrow biopsy was done which showed 58% promyelocytes and 11% blasts with numerous Auer rods present. Cytogenetics showed abnormal female karyotype with t(15:17) and FISH analysis revealed PML/RARA fusion in 76.5% of analyzed cells. The above findings were diagnostic of APL. After multidisciplinary discussion with high risk obstetrics physician, it was decided to immediately induce labor for immediate initiation of treatment of APL. She had a prolonged labor requiring aggressive blood product support and initiation of All trans retinoic acid (ATRA) before delivery given concerns of coagulopathy. Induction treatment with Arsenic trioxide (ATO) was started the day after her delivery. Repeat bone marrow biopsy on day 24 showed complete morphologic remission. Shortly thereafter, she started cycle 1 of consolidation with ATRA and arsenic trioxide. APL is characterized by a translocation between chromosome 15 and 17. Coagulopathy is a pathognomonic feature of this leukemia and often the reason for high mortality in early course of disease. APL when treated with ATRA and ATO, has excellent remission rate and 99% overall survival at 2 years. APL in pregnancy is associated with increased risk of preterm delivery, perinatal mortality, and miscarriage. Following pregnancy, there is an increased risk of bleeding, infection, or placental abruption. ATRA, one of the pillars around which treatment of APL revolves, is highly teratogenic during the first trimester and has low risk later in pregnancy. Treatment is directed by the trimester of pregnancy. Termination of pregnancy or treatment with single agent conventional chemotherapy is preferred in the first trimester whereas treatment with ATRA prior to delivery and use of chemotherapy after delivery is the preferred approach in the 2nd and 3rd trimester. This case is an example of individualized approach with a multidisciplinary team need in the setting of scarce data.

Formålet med undersøgelsen var at finde ud af, hvorvidt gravide kvinder på Færøerne fik en kost, som er i overensstemmelse med rekommandationer der foreligger gravide. 148 kvinder deltog i undersøgelsen, hvor der blev gennemført tre 24 h recall og seks selvregistreringer, samt et food frequency qeistionnaire omhandlende de sidste 12 måneder. Resultatet af den samlede energi, energifordeling, A-, C-, D- og E-vitaminer, og folsyre, jern og calcium er sammenlignet med de rekommandationer der foreligger for gravide i de nordiske lande, specielt Danmark, idet Færøerne følger de danske anbefalinger. Det gennemsnitlige energiindtag var 10,0 MJ, som i gennemsnit fordelte sig i henhold til kostanbefalingerne med 15% proteiner, 52% kulhydrater og 33% fedt. Kostfiberindtaget var lavere end anbefalet, 17,4 gram per dag. Mættede og monoumættede fedtsyrer fulgte anbefalingerne, men indtaget af polyumættede fedtsyrer var lavt, 3,6%. Indtaget af n-3 fedtsyrer var 0,6%, som er lavere end anbefalet. Indtaget at C-vitaminer og calcium var tilstrækkeligt gennem kosten. Indtaget af de andre vitaminer og mineraler var mindre end anbefalingerne. 85% tager vitamintilskud og 64% tager jerntilskud. Indtaget af fisk var 280 gram per uge, kornprodukter 323 gram per dag, kød 193 gram per dag, sødesager 128 gram per dag, frugt og grønt 193 gram per dag, frugt juice 98 gram per dag. Resultatet fra denne opgave kan sætte større fokus på kost og graviditet, samt at der er et behov for en større og mere indgående kostundersøgelse blandt den generelle befolkning, hvis resultater kan bruges i sundhedsfremmende arbejde.
The purpose of this project was to find out whether pregnant women in the Faroe Islands had a dietary intake, which were in accordance with recommendations for pregnant women. 148 women participated in the survey, which involved three 24 hour recall and six days diary, and a food frequency questionnaire for the last 12 months. The results of total energy, the energy distribution of protein, carbohydrate and fat and the micronutrients vitamin-A, -C, -D, -E, folic acid, iron and calcium are compared with recommendations for pregnant women in the Nordic countries, especially from Denmark because the Faroe Islands follow the Danish recommendations. In average the total energy consumption per day was 10,0 MJ, and the distribution was 15% protein, 52% carbohydrates and 33% fat. Dietary fibre intake was 17,4 gram per day, which is lower than recommended. The intake of saturated and monounsaturated fatty acids followed the recommendations whereas the intake of polyunsaturated fatty acids and n-3 fatty acids was lower then recommended, 3,6% and 0,6%. Supply of vitamin-C and calcium through the food was sufficient, whereas the supply of the other micronutrients was too low compare to recommendations. 85% of the women took vitamin supplements and 64% took iron supplements. Intake of fish was 280 gram per week, cereal products 323 gram per day, meat 139 gram per day, sweets 128 gram per day, fruit and vegetables 193 gram per day, fruit juice 98 gram per day. The results from this project can put a focus on the connection between diet and pregnancy as well as there is a need for a detailed dietary survey among the general population, where the results can used in further health promotion

ISBN 91-7997-141-5

This study was conducted to determine whether or not a significant difference exists in pregnant women among those receiving therapeutic touch, mock therapeutic touch, or no touch on measurements of anxiety and well-being. Thirty third trimester primigravida subjects were tested pre- and postintervention using the State-Anxiety Inventory and a Well-Being Visual Analog; heart and respiratory rates were monitored before, during, and after the treatment. No significant differences were found using analysis of covariance with the pre-test scores as the covariate. The findings indicate that therapeutic touch may not be useful in reducing state anxiety or enhancing subjective well-being in pregnancy. Study limitations include a small sample size, use of an instrument without established reliability and validity, and a study environment that may have increased anxiety.

Mesenchymal stromal cells (MSC) are multipotent cells found in fetal, neonatal and adult tissues. Fetal MSC have advantageous characteristics over their adult counterparts, and the regenerative potential of fetal blood MSC has recently been shown in a model of skeletal dysplasia and renal failure. Although fetal blood MSC can be isolated during ongoing pregnancy, the clinical effectiveness of using fetal blood-derived MSC for prenatal fetal cell therapy is constrained by the invasive nature of blood sampling procedure. With amniocentesis and chorionic villus sampling (CVS), fetal MSC can be obtained with minimal invasion. The aim of this study was to characterise stem cells from 1st trimester amniotic fluid (AF) and placenta by comparing their phenotype with MSC from 1st trimester bone marrow and 2nd trimester AF. Cells from all sources have similar immunophenotype, express pluripotency markers and telomerase, but 1st trimester AF stem cells have higher kinetics. The cells can differentiate into 3 lineages (bone, fat and cartilage), form embryoid bodies (EB) in vitro and can be transfected with high efficiency using non-viral methods. The migration potential of fetal MSC was also investigated using in vitro migration assays, to recapitulate the in vivo mechanisms involved in donor cell recruitment to various tissues and delineate the pathways involved. Fetal blood MSC and AF stem cells were shown to express CXCR4, the stromal cell-derived factor-1 (SDF-1) receptor, intracellularly but not on the cell membrane and migrate to SDF-1 gradients and to osteoblast cultures derived from the Osteogenesis Imperfecta mouse (oim), but not wild type bones. Pre-stimulation with oim plasma up-regulated CXCR4 and increased chemotaxis to SDF-1 and oim bone. Conclusively, 1st trimester AF and placenta are a new source of stem cells with great potential for future cell therapy applications. Also, initial experiments indicate the importance of the SDF-1/CXCR4 axis for stem cell recruitment to the site of injury.

Height, skinfold, and circumference measurements were obtained from 29 normal weight and 17 overweight (>110% of desirable weight for height) healthy pregnant women every four weeks during their second trimester of pregnancy. The mean weight gain and food intake values were not significantly different for both groups. Measurements increased at a greater rate for the normal weight gravidas than for the overweight gravidas in almost every case. For both groups, increases in fat stores were greater in the central sites than in the peripheral sites. No clear relationship between age, prepregnant weight, and weight gain during the second trimester with the birthweight of the baby was found. The infant birthweights of both groups were at an optimal level ( >2500 grams) except for one (born to the mother 151% of her desirable weight for height). The similarity in results for the two groups is greatly due to there not being a large enough difference in prepregnant weights between the two groups. Nevertheless, the results do lend support to a 20 to 30 pound weight gain for an optimal outcome of pregnancy for healthy pregnant women with a wide range of prepregnancy weights. Those women 150% or more of their desirable weight for height may need to gain on the lower end of the spectrum due to their excess endogenous reserves and to possible harm to the fetus with large gains.
Master of Science

Résumé : L’aggravation de certaines caractéristiques cliniques des femmes enceintes (âge, poids) et l’augmentation de la prévalence du diabète gestationnel (DG) poussent à dépister le DG le plus tôt possible pour éviter chez la mère et le fœtus les complications à court et à long terme. Le dépistage du DG est recommandé à 24-28 semaines de grossesse, et le plus souvent un test de tolérance à 50g de glucose (TTG) est réalisé. Pour les femmes qui ont des facteurs de risque, ce test doit être effectué plus précocement, habituellement pendant le premier trimestre de la grossesse. Cette dernière recommandation est peu suivie, d’autant qu’il n’y a pas de consensus international sur le dépistage du DG pendant le premier trimestre de la grossesse. Objectifs. 1) Définir au premier trimestre de la grossesse la valeur de la glycémie du TTG qui prédit le diagnostic de DG à 24-28 semaines avec une sensibilité et une spécificité optimales à l’aide d’une courbe ROC. 2) Déterminer si la glycémie du TTG au premier trimestre est un facteur prédictif indépendant du DG. Méthodes. Étude prospective de cohorte. Les facteurs d'inclusion étaient : âge ≥ 18 ans et âge gestationnel entre 6 et 13 semaines après la dernière menstruation. Les TTG ont été effectués à la première visite prénatale. Une deuxième visite était programmée à 24-28 semaines pour faire une hyperglycémie provoquée par voie orale (HGPO) et donc un éventuel diagnostic de DG. Les critères utilisés pour ce diagnostic étaient ceux de l’Association américaine du diabète. Résultats. Les TTG ont été faits à 9,1±2,0 semaines et les HGPO à 26.5±1.1semaines chez 1180 femmes (28,2±4,4 ans, IMC : 25,2±5,5 kg/m[indice supérieur 2]). Un DG a été diagnostiqué chez 100 (8,4%) participantes. La valeur de glycémie du TTG à 5,6 mmol/L a prédit le DG avec une sensibilité de 84,1% et une spécificité de 62,3%, tandis que la valeur prédictive positive était de 0,121 et la valeur prédictive négative de 0,985. Cette valeur de 5,6 était indépendamment associée au DG (OR=2,806, IC 95%: 1,98 à 3,97, p <0,001). Comparé à d'autres facteurs de risque, le TTG était le plus puissant prédicteur indépendant du DG (OR=1,767, IC 95%: 1,52 à 2,05, p <0,001). Conclusions. Au premier trimestre, la valeur glycémie de 5.6 mmol/L du TTG prédit avec une bonne sensibilité et spécificité l’apparition d’un DG à 24-28 semaines. La glycémie du TTG au premier trimestre est le plus puissant prédicteur indépendant de DG.
Abstract : The changes in clinical characteristics of pregnant women and an increase in the prevalence of gestational diabetes mellitus (GDM) warrant the importance of screening as early as possible in order to possibly prevent short and long-term complications in both the mother and fetus. GDM screening is recommended at 24-28 weeks of pregnancy, using a 50g glucose challenge test (GCT) although women with multiple risk factors are expected to be assessed “early” in pregnancy, a recommendation poorly followed. Most importantly, there is no universal agreement currently in place for GDM screening, particularly during the first trimester of pregnancy. Objectives. 1) To define the cut-off value of GCT during the first trimester in order to predict GDM diagnosed at 24-28 weeks of gestation with optimal sensitivity and specificity using ROC curve. 2) To determine if GCT during the first trimester of pregnancy is an independent predictor of GDM diagnosed at 24-28 weeks gestation. Methods. This is a prospective cohort study. Women were recruited at their first prenatal visit. Inclusion factors were: age ≥ 18 years and gestational age between 6 and 13 weeks from their last menstrual period. GCT were performed at the first prenatal visit. The second visit was scheduled at 24-28 weeks for the diagnostic 75g oral glucose tolerance test (OGTT). GDM diagnosis was made in accordance with the American Diabetes Association guidelines. A variety of statistical analysis including multivariate logistic regression models and ROC curve were used to address the aims of the study. Results. Participants (n=1180, age: 28.2±4.4 years, BMI: 25.2±5.5 kg/m[superscript 2]) underwent GCT at 9.1±2.0 weeks and OGTT at 26.5±1.1 weeks of gestation. GDM was diagnosed in 100 (8.4%) women. The cut-off value of 5.6 mmol/L predicted GDM with 84.1% (75.4-92.7) sensitivity, 62.3% (59.5-65.1) specificity, while the positive predictive value was 0.121 (0.091-0.150) and the negative predictive value was 0.985 (0.975-0.994). This 5.6 value was independently associated with GDM (OR=2.806, 95% CI: 1.98-3.97, p<0.001). Compared to other risk factors, GCT was the strongest independent predictor of GDM (OR=1.767, 95% CI: 1.52-2.05, p<0.001). Conclusions. The cut-off value of 5.6 mmol/L has the optimal sensitivity and specificity for the GCT during the first trimester to predict GDM at 24-28 weeks of gestation according to ADA guidelines. GCT during the first trimester is the strongest independent predictor of GDM at 24-28 weeks of gestation.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado.
Antepartum suicidal behaviors are a leading cause of maternal injury and death. Previous research has not investigated associations between antepartum suicidal ideation and perinatal complications. Our study objective was to evaluate the relationship of antepartum suicidal ideation with low infant birthweight, small for gestational age, and preterm birth. A cohort study was conducted among 1,108 women receiving prenatal care in Peru. Suicidal ideation was measured using the Patient Health Questionnaire-9 during pregnancy. Birth outcomes were extracted from medical records. Linear regressions and multivariable logistic regressions were used to estimate were used to investigate associations between suicidal ideation and pregnancy outcomes. The prevalence of suicidal ideation was 8.7%, preterm delivery was 5.7%, low birthweight was 4.4%, and small for gestational age was 3.4%. In an adjusted model, infant birthweight was 94.2 grams lower for mothers with antepartum suicidal ideation (95% CI: −183.0, −5.5, p = 0.037) compared with those without suicidal ideation. After adjusting for confounders including depression, participants with suicidal ideation had a nearly four-fold increased odds of delivering a small for gestational age infant (OR: 3.73; 95% CI: 1.59–8.74). These findings suggest suicidal ideation during pregnancy is associated with adverse perinatal outcomes, especially low infant birthweight.
Revisión por pares

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado.
Antepartum suicidal behaviors are a leading cause of maternal injury and death. Previous research has not investigated associations between antepartum suicidal ideation and perinatal complications. Our study objective was to evaluate the relationship of antepartum suicidal ideation with low infant birthweight, small for gestational age, and preterm birth. A cohort study was conducted among 1,108 women receiving prenatal care in Peru. Suicidal ideation was measured using the Patient Health Questionnaire-9 during pregnancy. Birth outcomes were extracted from medical records. Linear regressions and multivariable logistic regressions were used to estimate were used to investigate associations between suicidal ideation and pregnancy outcomes. The prevalence of suicidal ideation was 8.7%, preterm delivery was 5.7%, low birthweight was 4.4%, and small for gestational age was 3.4%. In an adjusted model, infant birthweight was 94.2 grams lower for mothers with antepartum suicidal ideation (95% CI: −183.0, −5.5, p = 0.037) compared with those without suicidal ideation. After adjusting for confounders including depression, participants with suicidal ideation had a nearly four-fold increased odds of delivering a small for gestational age infant (OR: 3.73; 95% CI: 1.59–8.74). These findings suggest suicidal ideation during pregnancy is associated with adverse perinatal outcomes, especially low infant birthweight.
Revisión por pares

Doctor Pharmaceuticae - Dpharm
The use of efavirenz (EFV) in the first trimester of pregnancy remains controversial. In South Africa, the use of EFV-containing antiretroviral therapy (ART) as part of a Fixed Dose Combination (FDC) during the first trimester of pregnancy started in April, 2013. Literature to date has reported conflicting outcomes following the use of EFV-containing ART during the first trimester of pregnancy. The objectives of the study were to determine the prevalence of adverse pregnancy outcomes among HIV-positive pregnant women treated with EFV-containing ART and compare these results with those of pregnant women treated with NVP-containing ART and HIV-negative pregnant women in resource-limited settings. In addition, the study also aimed to determine the effect of the time of initiation of ART on the prevalence of adverse pregnancy outcomes.

CD4+CD25high regulatory T cells (Tregs) are implicated in the maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent, and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim of this study was to determine the frequency, phenotype, and function of circulating Tregs in the second trimester of human pregnancy and the influence of progesterone and 17β-estradiol on Treg phenotype and frequency. Based on expressions of Foxp3, CD127, and HLA-DR as determined by multicolor flow cytometry, we defined a proper CD4dimCD25high Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester of pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4+ population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17β-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4dimCD25highFoxp3+ cells in PBMC from nonpregnant women. By coculturing FACS-sorted Tregs and autologous CD4+CD25– responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as nonpregnant women in terms of suppressing IL-2, TNF-, and IFN- secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Furthermore, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need reevaluation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.
Background: Despite the large amount of research regarding prenatal care (PNC) in physicians’ offices, hospital outpatient clinics, and community health centers, there is a great paucity of information regarding the role the Emergency Department plays in PNC. Objective: To understand the factors associated with pregnant women’s choice to seek prenatal care in the Emergency Department. Methods: This study is an investigative examination of the attitudes towards and perceived barriers to PNC of women in the first trimester of pregnancy presenting to the Emergency Department at an urban level 1 trauma center. Survey questions examined demographic information and patient factors, such as how they found out about the pregnancy, if they had seen a doctor for this pregnancy, use of PNC in prior pregnancies, and whether they would utilize first trimester PNC in the future. Additionally, the survey contained a series of statements about the importance of PNC and factors affecting their utilization as rated on a 5 point Likert scale. All data was abstracted and coded into Excel. Descriptive statistics and 95% confidence intervals were calculated. Logistic regression was used to predict future PNC use. Results: A total of 74 patients who met the inclusion criteria were surveyed. Ninety‐three percent (CI 84‐97%) knew they were pregnant prior to presenting to the ED. Thirty‐seven percent (CI 27‐50%) had a prenatal visit prior to the index ED visit. Twelve percent (CI 6‐22%) reported they were at the ED for PNC, 70% (CI 59‐80%) for another OB/GYN issue, and 18% (CI 10‐28%) for a reason unrelated to pregnancy. However, 22% strongly agreed and 8% agreed that if they had PNC they would not have come to the ED that day. Predictors of future PNC use included knowledge of pregnancy prior to ED visit, number of pregnancies, belief that PNC is important for the mother’s health, knowledge of where to receive PNC, and belief that taking prenatal vitamins during pregnancy can help the baby. Conclusions: For the population of pregnant females presenting to an urban level 1 trauma emergency department during the first trimester of pregnancy, a large proportion (30%) reported they would not have come to the ED if they received PNC. This would represent a significant reduction in ED visits per year if these women received appropriate services. Future research would need to further delineate the perceived barriers to PNC in this population.

Objetivo: Calcular os valores preditivos da ultrassonografia de primeiro trimestre gestacional para a detecção da artéria umbilical única. Avaliar a relação dos marcadores ultrassonográficos de cromossomopatias do primeiro trimestre (translucência nucal, osso nasal e ducto venoso), além da idade gestacional do exame, CCN, sexo fetal, medida da bexiga fetal, alterações de morfologia e IMC da gestante, com a acurácia do diagnóstico no primeiro trimestre. Métodos: Estudo longitudinal prospectivo envolvendo 1.564 gestantes, que foram submetidas à ultrassonografia com avaliação do cordão umbilical entre 11 e 13 semanas e 6 dias, no período de novembro de 2007 a setembro de 2009. Posteriormente, realizaram a avaliação do cordão umbilical em ultrassonografia realizada no segundo ou terceiro trimestres. Foi verificada a concordância do diagnóstico de AUU no primeiro trimestre com o diagnóstico no segundo trimestre, calculando-se o coeficiente Kappa. Os testes qui-quadrado e exato de Fisher foram utilizados para verificar a existência de associação entre a acurácia da ultrassonografia de primeiro trimestre e as variáveis da ultrassonografia e da gestante (translucência nucal, osso nasal, ducto venoso, idade gestacional do exame, CCN, sexo fetal, medida da bexiga fetal, alterações de morfologia e IMC da gestante). Resultados: A concordância dos diagnósticos de AUU no primeiro e segundo trimestres foi moderada (Kappa = 0,609), sendo que a sensibilidade da ultrassonografia de primeiro trimestre em relação à ultrassonografia de segundo trimestre foi de 76%, a especificidade foi de 99%, o valor preditivo positivo foi de 51,6% e o valor preditivo negativo foi de 99,6%. A acurácia foi de 98,7%. Dentre as variáveis analisadas, que poderiam ter influenciado na acurácia da ultrassonografia de primeiro trimestre na detecção de AUU, a única que se mostrou estatisticamente significante foi o sexo fetal. Conclusão: A sensibilidade da ultrassonografia de primeiro trimestre na detecção da AUU é de 76%, o que é menor do que a observada no segundo ou terceiro trimestres.
Objective: To calculate the predictive values of first gestational trimester ultrasonography for detection of single umbilical artery. Assess the relation of ultrasound markers of chromosomal disease in the first trimester (nuchal translucency, nasal bone and ductus venosus) in addition to gestational age at exam, CRL, fetal gender, measurement of fetal bladder, morphological alterations and BMI of a pregnant woman, with accuracy of diagnosis in the first trimester. Methods: A prospective longitudinal study was conducted from November 2007 to September 2009 encompassing 1564 pregnant women submitted to ultrasound imaging for umbilical cord assessment between the 11 and 13 weeks and six days. Later they underwent evaluation of the umbilical cord by ultrasound performed in the second or third trimesters. Consistency of SUA diagnosis in the first trimester was verified with that of the second trimester by calculating the Kaplan coefficient. The Chi-square and Fisher\'s exact tests were used to verify if there was an association between accuracy of ultrasonography of the first trimester and the variables of ultrasonography and those of the pregnant woman (nuchal translucency, nasal bone, ductus venosus, gestational age at exam, CRL, fetal gender, measurement of fetal bladder and morphological alterations as well as pregnant woman\'s BMI). Results: SUA diagnoses in the first and second trimester disclosed moderate consistency (Kaplan=0.609) while sensitivity of first trimester ultrasound in relation to that of the second trimester was of 76% and specificity was of 99%, positive predictive value was of 51.6% and negative predictive value was of 99.6%. Accuracy was of 98.7%. Among the analyzed variables, fetal gender was the only one with a statistical significance that might bear influence on first trimester ultrasound accuracy for detection of SUA. Conclusion: Sensitivity of the first trimester ultrasound for detection of SUA is of 76%, that is to say, lower than that observed in the second or third trimesters

Gestational diabetes (GDM) occurs in up to 9% of pregnancies. Perinatal depression affects up to 20% of women during pregnancy, and can extend into the postpartum period. A number of studies have linked depression and diabetes, however, whether this applies to GDM or which might come first is less understood. The purpose of this study was to examine the potential relationship between depression identified in the first trimester of pregnancy and the subsequent development of GDM. Women without pre-existing Type I/II diabetes (n = 1021) were evaluated for depression during the first trimester of pregnancy, and medical records were reviewed to identify a positive history of diabetes. Women identified as depressed during the first trimester were more likely to have GDM compared to those not depressed. After controlling for demographic factors and weight-related variables level of depression in the first trimester still predicted later GDM development. Depression identified in early pregnancy may predict increased risk of subsequent GDM development. Due to the numerous maternal, fetal and neonatal complications associated with GDM, early recognition is essential to promote the best possible outcomes for mother and infant. Recognizing depression as a possible risk factor for GDM development could lead to earlier screening and preventative measures.

Summary Background: Previous studies report that women are failing to make informed choices with regard to antenatal screening, due to significant deficits in knowledge. However, current definitions dictate that informed choice occurs not merely as a result of sufficient knowledge, but by acting in line with one’s attitudes despite perceived social pressure (Dormandy et al., 2002). Objective: To investigate whether women are making informed choices with regard to Combined Ultrasound & Biochemical (CUB) screening, using more substantial criteria. Design: Prospective non-experimental. Setting: The Queen Mother’s Maternity Hospital in Glasgow. Sample: 63 women due attend their first antenatal appointment. Outcome measures: responses to a questionnaire constructed for the purposes of the study. Methods: A multidimensional questionnaire measure encompassing demographic factors, areas of knowledge recommended by The Royal College of Obstetricians and Gynaecologists (RCOG, 1993) and all aspects of the Theory of Planned Behaviour (TPB; Ajzen, 1985). Results: Women appeared to be well informed, though there were some worrying misconceptions. Women appeared to intend to act in line with their attitudes, although small numbers of women planning to refuse screening limited findings. Attitude was the strongest predictor of behavioural intention. Conclusions: There appears to be moderate support for the hypothesis that women would make ‘informed choices’, though this is limited by a number of factors which require further investigation.

Le placenta est un organe transitoire permettant les échanges nutritionnel et gazeux entre la mère et le fœtus. Son unité structurale et fonctionnelle est la villosité choriale (VC), constituée en son centre d'un axe mésenchymateux bordé par une couche cellulaire de cytotrophoblastes villeux (CTV) fusionnant pour former la couche la plus externe : le syncytiotrophoblaste (ST), sécréteur d'hormones indispensables au maintien de la grossesse, notamment l'hCG. Au premier trimestre de la grossesse (T1), le placenta se développe dans un environnement pauvre en O2 dû à l'obstruction des artères utérines spiralées par des bouchons cytotrophoblastiques empêchant le sang maternel oxygéné de pénétrer dans la chambre intervilleuse (CIV). Dès 10 semaines d'aménorrhée (SA), ces bouchons se délitent, laissant entrer le flux sanguin dans la CIV au contact direct du placenta. La pO2 passe alors de 20 mmHg à 60 mmHg. En présence d'O2, la cellule produit des espèces réactives de l'oxygène (ERO) jouant le rôle de seconds messagers dans de multiples processus physiologiques (prolifération, différenciation, apoptose). Ils peuvent être cytotoxiques dans le cas du stress oxydant : la cellule possède un système de défense antioxydant permettant de maintenir le taux d'ERO intracellulaire à un niveau physiologique faible. L'équilibre des espèce pro- et anti-oxydantes est appelé homéostasie redox. Au T1, le placenta est soumis à une transition environnementale requérant l'adaptation de sa balance redox pour assurer le bon développement du placenta. Les objectifs de ce travail sont : (i) Déterminer la source principale d'anion superoxyde O2.- avant et après l'augmentation de la pO2 dans la CIV et étudier les défenses antioxydantes associées. (ii) Etudier l'impact de l'oxygéno-transition sur les voies redox-sensibles, notamment les MAPKs impliquées dans la prolifération et la différentiation trophoblastique. (iii) De déterminer au T1 l'influence de l'activité de la NADPH oxydase (Nox) placentaire sur la sécrétion du sFlt-1, facteur anti-angiogénique impliqué dans la physiopathologie de la prééclampsie (PE) afin de proposer de nouvelles réflexions concernant l'implication de la Nox dans la genèse de cette pathologie d'origine placentaire. Dans la VC (7-9 SA et 12-14 SA), la mesure de la production d'O2.- alliée à l'utilisation d'inhibiteurs spécifiques des différentes sources d'ERO montre que la Nox est la source principale d'O2.- au T1. Cette production est plus importante avant 10 SA et est associée à une modification de la localisation de la sous-unité organisatrice de Nox2, p47phox. Cette activation de la Nox placentaire est associée à une activation de la voie p38MAPK. p38 est localisée essentiellement dans le CTV au T1. L'expression génique et protéique des différentes isoformes de Nox révèle la présence de Nox2, Nox4 et Nox5 dans le trophoblaste au T1. Nox1 est cependant indétectable. L'activité des enzymes antioxydantes (SOD1, catalase, Gpx1) est augmentée à 12-14 SA, témoin de l'adaptation du système antioxydant à l'oxygéno-transition. L'exposition de VC à 7-9 SA au TGF-B1, activateur de Nox4 et de p38MAPK, associée à un inhibiteur de la voie p38 (SB203580), montre que l'activation de la voie p38 par le TGF-B1 entraine une augmentation de la sécrétion de sFlt-1. Cet effet est aboli par l'utilisation de SB203580. Dans notre modèle, l'exposition au TGF-B1 n'influence pas l'activation de la Nox. Cependant, l'utilisation d'un inhibiteur de Nox (DPI) permet de diminuer la sécrétion de sFlt-1. Ce travail a permis de montrer que la Nox est la source principale d'O2.- dans le placenta au premier trimestre en association avec l'activation de la voie p38MAPK. Nos résultats montrent que la sécrétion du sFlt-1 par la VC au premier trimestre est dépendante de la voie p38MAPK. Ce travail permettra une meilleure compréhension de l'implication des sources d'ERO dans le développement placentaire précoce et leur(s) rôle(s) dans la pathogenèse de la PE
The placenta is a transitory organ allowing gas and nutrients exchanges between mother and fetus. The structural and functional unit of the human placenta is the chorionic villi (CV). It is composed by a mesenchymal axis covered with a cellular layer called villous cytotrophoblast (VCT), which merges to form the syncytiotrophoblast (ST). The ST secretes hormones essential to maintain pregnancy, especially hCG. During the first trimester of pregnancy (T1), placenta develops itself in a poor oxygenated environment because of the obstruction of uterine spiraled arteries by cytotrophoblastic plugs which restrain the entry of the oxygenated maternal blood into the intervillous space (IVS). Between 10-12 gestational weeks (GW), the plugs will gradually disappear allowing blood to enter IVS in direct contact with CV. The pO2 will increase from 20 mmHg to 60 mmHg. Exposed to O2, the cell produces reactive oxygen species (ROS). ROS play a role as second messenger in redox-sensitive signaling pathways involved in physiological processes (proliferation, differentiation, apoptosis). They may become cytotoxic when oxidative stress occurs: the cell has an antioxidant defense system responsible for keeping low physiological levels of intracellular ROS, enough to ensure signal transduction. The balance between pro- and antioxidant systems is called redox homeostasis. The first trimester placenta is submitted to an environmental transition requiring redox balance adaptation to allow correct placental development in early pregnancy. The aim of this works are: (i) to determine the principal source of superoxide anion O2.- before and after the increase of pO2 in the intervillous space and the associated antioxidant defenses. (ii) To study the impact of the O2 transition on the activity of redox-sensitive pathways, specifically MAPKs involved in trophoblastic proliferation, differentiation. (iii) To determine, during T1, the placental NADPH oxidase (Nox) activity influence on the secretion of the antiangiogenic factor sFlt-1, which is involved in the pathophysiology of preeclampsia (PE), to offer new insight about Nox involvement in genesis of this pathology with placental origin. We measured the O2.- production in CV (7-9 GW vs. 12-14 GW). The O2.- assay was performed with specific inhibitors of ROS sources. The results show that NADPH oxidase (Nox) is the major source of O2.- in first trimester CV. Nox activity is significantly higher before 10 GW. This is confirmed by the modification of the Nox2 organizer subunit location, p47phox. This Nox activation in early stage of pregnancy is associated with p38 MAPK activation. p38 protein is mainly located within the villous cytotrophoblast in first trimester CV. Genic and protein expression study reveals the expression of Nox2, Nox4 and Nox5 isoforms in T1 trophoblast. Nox1 expression remains undetectable. The antioxidant enzymes (SOD1, catalase, and Gpx1) activities are increased at 12-14 GW, revealing an antioxidant system adaptation to the oxygen transition. We exposed CV from 7 to 9 GW to TGF-B1, described as an activator of Nox4 and p38MAPK, and to p38 inhibitor (SB203580). The results showed that the activation of p38MAPK pathway in first trimester CV by TGF-B1 increases the level of secreted sFlt-1. This effect is abolished using SB203580. TGF-B1 exposure does not influence the activation of placental Nox in our model, but the use of a Nox inhibitor (DPI) decreases the secretion of sFlt-1. To conclude, our work shows that Nox is the main source of O2.- in first trimester placenta and is associated with the activation of the p38MAPK pathway. Our results also demonstrate that first trimester CV sFlt-1 secretion relies on the p38MAPK activation. This work allows a better understanding of the cellular sources of ROS involvement in early placental development and their role in pathogenesis of preeclampsia

Preeclampsia results from incomplete trophoblast invasion of the spiral arteries during early pregnancy. Vascular endothelial growth factor (VEGF) and plasminogen activator inhibitor-1 (PAI-1) are critical factors involved in angiogenesis, invasion and hemostasis at the maternal-fetal interface. Both factors are transcriptionally regulated by hypoxia inducible factor (HIF), a heterodimeric complex consisting of HIF-1[beta] and either HIF-1[alpha] or -2[alpha] whose specificity or redundancy in gene regulation is cell-type specific. This study uses siRNA technology to dissect the mechanisms of hypoxia-mediated regulation of PAI-1 and VEGF expression in first trimester trophoblasts. Immortalized first trimester human extravillous trophoblasts (HTR8/SVneo cells) were maintained in serum-free and serum-containing media for 4h (n=3-4), 8h (n=6), 24h (n=5) and 48h (n=5) under normoxic (21% O2) and hypoxic (1-2% O2) conditions to determine a time of maximum induction of both VEGF and PAI-1. Subsequently, cells were maintained for 48h in the presence or absence of siRNA for HIF-1[alpha], HIF-2[alpha], HIF-1[alpha] + -2[alpha], a non-targeting (NT) sequence or Cyclophilin B (CB). Media were then removed, cells lysed, and Western blotting used to assess HIF-[alpha] knockdown. VEGF and PAI-1 levels in the media were quantified by ELISA and results expressed as pg or ng/[micro]g protein. Results from 3 to 8 independent experiments were analyzed using unpaired t-tests. Under hypoxic conditions treatment of cells with HIF-1[alpha], HIF-2[alpha] or HIF -1[alpha] + -2[alpha] siRNA resulted in >90% HIF-Ñ protein knockdown as determined by Western blotting. 48h of hypoxic treatment caused a statistically significant increase in PAI-1 levels (p<0.01) and VEGF levels (p<0.001) compared to normoxic controls. Under hypoxic conditions, PAI-1 levels were 4.75 [plus-minus] 0.46 ng/[micro]g protein and VEGF levels were 7.27 [plus-minus] 1.08 pg/[micro]g protein. Treatment with siRNA to HIF-1[alpha], HIF-2[alpha] and HIF-1[alpha] + -2[alpha] significantly reduced PAI-1 levels to 3.3 [plus-minus] 0.35 (p<0.02), 3.1 [plus-minus] 0.38 (p<0.03) and 2.4 [plus-minus] 0.19 (p<0.003), respectively. No significant difference in PAI-1 reduction was noted between the three HIF siRNA conditions. Under hypoxic conditions, levels of VEGF in cells treated with siRNA to HIF-1[alpha] (5.79 [plus-minus] 0.55), HIF-2[alpha] (5.50 [plus-minus] 1.24) and HIF-1[alpha] + -2[alpha] (4.24 [plus-minus] 0.93) were reduced compared to the hypoxic control (7.27 [plus-minus] 1.08), yet these effects did not reach statistical significance. However, when compared with the levels observed in cells treated with NT siRNA (9.90 [plus-minus] .98), all HIF siRNA treatments promoted a significant reduction in VEGF expression (p<0.003, p<0.02 and p<0.003 for HIF-1[alpha], HIF-2[alpha] and HIF-1[alpha]+ -2[alpha], respectively). In conclusion, these results indicate that hypoxia-mediated changes in PAI-1 and VEGF expression in trophoblasts are regulated similarly by both HIF-1[alpha] and HIF-2[alpha]. This provides important insight into the molecular mechanisms regulating hemostasis and trophoblast invasion as well as their potential dysfunction in pregnancies complicated by preeclampsia

Objetivo: Determinar os valores dopplervelocimétricos normais do fluxo através da valva tricúspide em gestações únicas, entre 11 e 13 semanas e seis dias. Examinar a reprodutibilidade dos parâmetros avaliados e sua correlação com variáveis clínicas maternas e obstétricas. Métodos: Estudo prospectivo envolvendo 166 gestações únicas, com desfecho normal, examinadas entre 11 e 13 semanas e seis dias, no período de fevereiro de 2006 a agosto de 2008. Foram aferidas as velocidades máximas das ondas E e A, duração do ciclo cardíaco completo e sua fase diastólica e calculadas as relações onda E/onda A e diástole/ciclo. Os valores normais foram descritos pelas respectivas médias e desvio-padrão. Para análise da reprodutibilidade desses parâmetros foi calculado o coeficiente de correlação intra-classes em 12 casos examinados por dois examinadores. Regressão linear simples e multivariada foram empregadas para examinar a correlação dos parâmetros dopplervelocimétricos entre si e com a idade gestacional, a medida da translucência nucal e variáveis maternas. Resultados: Neste intervalo gestacional, os valores normais encontrados foram: onda E, 25 (± 4,6) cm/s; onda A, 42,9 (± 5,9) cm/s; relação E/A, 0,58 (± 0,07); ciclo cardíaco, 390 (± 21,1) ms; diástole, 147 (± 18) ms; relação diástole/ciclo, 0,38 (± 0,04). Entre as variáveis dopplervelocimétricas, foi observada correlação significativa entre o ciclo cardíaco e diástole (r=0,53; p<0,0001), diástole e onda A (r=-0,15; p=0,05), ondas E e A (r=0,77; p<0,0001), onda E e relação D/C (r=0,16; p=0,04), onda A e relação diástole/ciclo (r=-0,17; p=0,03). Todas as variáveis, exceto a velocidade da onda A, correlacionaram-se positivamente com a idade gestacional. Não foi observada correlação significativa das variáveis com a medida da translucência nucal, e, na comparação com as variáveis maternas, apenas a onda E e a idade materna apresentaram correlação significativa (r=-0,18, p=0,04). Os coeficientes de correlação intra-classes para a avaliação interobservador e intra-observador (examinadores um e dois) foram: onda E = 0,53 (0,53 e 0,64); onda A = 0,45 (0,46 e 0,49); ciclo cardíaco = 0,70 (0,79 e 0,84) e diástole = 0,63 (0,85 e 0,82). Conclusão: O presente estudo estabeleceu os valores normais dos parâmetros dopplervelocimétricos do fluxo através da valva tricúspide e demonstrou que tais parâmetros, com exceção da onda A, correlacionaram-se de forma positiva com a idade gestacional, e apresentaram reprodutibilidade boa/moderada.
Objective: To establish the measurements of normal tricuspid valve flow velocities at 11 to 13 weeks and 6 days to determine E-wave, A-wave, E/A ratio, cardiac cycle length, diastole length, diastole/cardiac cycle ratio, and their relationship with gestational age, nuchal translucency thickness, the characteristics of the study population, and to assess the reproducibility of flow measurements. Methods: Between February, 2006, and August, 2008, a total of 166 women with a singleton normal pregnancy between 11 and 13 + 6 weeks of gestation consented to participate in the study. Analysis of the waveforms consisted of calculation of peak velocity (cm/s) of the E-wave and A-wave, E-wave/A-wave ratio, cardiac cycle length (ms), diastole length (ms) and diastole/cardiac cycle ratio. To evaluate the intraobserver and interobserver agreement, a subgroup of 12 patients, chosen randomly, was examined twice by each examiner. For descriptive analysis of the results were calculated average and standard deviation. Simple and multivariate linear regression was used to establish the correlation between dopplervelocimetry among parameters and with gestational age, nuchal translucency thickness and the characteristics of the study population. Results: The average (± standard deviation) for transtricuspid flow-velocities waveforms parameters were: E-wave 25 (± 4.6) cm/s; A-wave 42.9 (± 5.9) cm/s; E/A ratio 0.58 (± 0.07); cardiac cycle length 390 (± 21.1) ms; diastole length 147 (± 18) ms; diastole/cardiac cycle length 0,38 (± 0.04). A statistically significant linear increase relative to gestational age was established for all parameters, except A-wave. Nuchal translucency thickness was not correlated with any parameter. A statistically significant negative regression coefficient was established for E-wave to maternal age (r=-0,18, p=0,04). A statistically significant relationship was established between: cardiac cycle length and diastole length (r=0.53; p<0.0001); diastole length and A-wave velocity (r=-0.15; p=0.05); E-wave and A-wave velocities (r=0.77; p<0.0001); E-wave velocity and D/C ratio (r=0.16; p=0.04); A-wave velocity and D/C ratio (r=-0.17; p=0.03). The intraclass correlation coeficients of interobserver and intraobsever evaluations (examiners 1 and 2) were: Ewave = 0.53 (0.53 and 0.64); A-wave = 0.45 (0.46 and 0.49); cardiac cycle = 0.70 (0.79 and 0.84) and diastole= 0.63 (0.85 and 0.82). Conclusions: These data determine normal parameters for tricuspid valve dopplervelocimetry and shows that these parameters, except A-wave, have positive correlation with gestational age, and good/moderate reproducibility.

INTRODUÇÃO: Pouco se sabe sobre parâmetros ultrassonográficos transvaginais possíveis de serem avaliados durante a gestação além do comprimento do colo uterino. A escassa literatura sugere que o volume calculado através da ultrassonografia tridimensional, a quantificação de sinal power Doppler em todo o órgão e o Doppler das artérias uterinas possam sofrer alterações de acordo com o comprimento cervical, e até mesmo anteceder seu encurtamento no processo que leva ao parto. OBJETIVOS: agregar novos parâmetros bi e tridimensionais ultrassonográficos à avaliação do colo uterino em gestações únicas. MÉTODO: Estudo transversal desenvolvido com dados de 2014 a janeiro de 2018 do projeto PROPE, no qual foi realizada ultrassonografia transvaginal em pacientes entre 20 e 23 semanas e 6 dias de gestação. Foram compilados e submetidos à análise secundária os dados de 162 gestantes com comprimento do colo uterino >= 25 mm (grupo Controle), 68 gestantes com comprimento do colo >= 15 mm e < 25 mm (grupo Colo Curto) e 18 gestantes com comprimento do colo < 15 mm (grupo Colo Muito Curto). Foram analisadas as características demográficas e antecedentes obstétricos das gestantes, e foram comparados entre os grupos os parâmetros cervicais de comprimento, volume e vascularização, além do Doppler de artérias uterinas bilateralmente. RESULTADOS: O comprimento médio (± DP) dos colos uterinos de cada grupo foi 35,28 ± 5,12 mm para o grupo Controle, 20,51 ± 2,47 mm para o grupo Colo Curto, e 10,72 ± 2,51 mm para o grupo Colo Muito Curto. Houve diferença entre os grupos quanto à idade materna, cor (etnia) e idade gestacional de inclusão. Quanto aos antecedentes obstétricos, houve associação somente entre a presença de colo curto na gestação atual e pelo menos um parto prematuro anterior em gestantes não nulíparas (p = 0,021). Em relação aos parâmetros ultrassonográficos, verificou-se correlação linear positiva moderada entre volume e comprimento do colo (coeficiente de Pearson=0.587, valor p < 0.0001). Os grupos Controle, Colo Curto e Colo Muito Curto foram estatisticamente diferentes em relação às médias (± DP) de volume (46,38 ± 13,60 cm vs. 32,15 ± 13,14 cm vs. 22,08 ± 11,10 cm, respectivamente)(p <= 0,001), e em relação às médias (± DP) de índice de fluxo (IF) (39,81 ± 6,42 cm vs. 38,73 ± 4,99 cm vs. 36,02 ± 5,34 cm, respectivamente) (p = 0,027), em que a diferença estatística ocorre entre os grupos Controle e Colo Muito Curto. Porém, na presença da informação do volume, após regressão linear, a associação entre os grupos e IF deixa de ser significativa. Também não houve relação entre os grupos estudados e o Doppler de artérias uterinas. CONCLUSÃO: Existe correlação linear positiva entre o volume e o comprimento do colo uterino. Na ausência de informações sobre o volume, comprimento cervical e índices de vascularização não se correlacionam. O comprimento cervical também não está relacionado a alterações no Doppler de artérias uterinas. Apesar das limitações de uma amostra pequena e escassez de dados comparativos na literatura, este estudo foi realizado com uma amostra homogênea da população e abre caminho para maiores pesquisas sobre o assunto
INTRODUCTION: Little is known about transvaginal ultrasound parameters other than cervical length that can be assessed during gestation. The literature suggests that changes in volume on three-dimensional ultrasound, quantification of power Doppler signal in the entire organ, and Doppler sonography of uterine arteries may be related to cervical length, and even precede its shortening during spontaneous delivery. OBJECTIVES: To include new two- and three-dimensional ultrasonographic parameters for evaluation of the uterine cervix in single pregnancies. METHODS: A crosssectional study of data from Project PROPE on transvaginal ultrasonography performed in patients between 20 and 23 weeks and 6 days of gestation from May 2014 to January 2018 was conducted. Secondary analysis of data from 162 pregnant women with uterine cervical length >= 25 mm (Control group), 68 pregnant women with cervical length >= 15 mm and < 25 mm (Short Cervix group), and 18 pregnant women with cervical length < 15 mm (Very Short Cervix group) was performed. The demographic characteristics and obstetric history of the pregnant women were analyzed, and the cervical length, volume, and vascularization were compared between the groups. In addition, Doppler velocimetry of the uterine arteries was performed bilaterally. RESULTS: The mean cervical length (± SD) was 35.28 ± 5.12 mm for the Control group, 20.51 ± 2.47 mm for the Short Cervix group, and 10.72 ± 2, 51 mm for the Very Short Cervix group. The groups differed in maternal age, ethnicity, and gestational age. When analyzing the obstetric history of only non-nulliparous patients we observed a significant association between the presence of a short cervix in the current pregnancy and at least one previous preterm birth (p = 0.021). With regard to the ultrasonographic parameters, we observed a moderate positive linear correlation between the volume and length of the cervix (Pearson coefficient = 0.587, p < 0.0001). The Control, Short Cervix, and Very Short Cervix groups showed differences in the mean (± SD) volume (46.38 ± 13.60 cm vs. 32.15 ± 13.14 cm vs. 22.08 ± 11.10 cm, respectively) (p <= 0.001) and mean (± SD) flow index (FI) parameter of cervical vascularization (39.81 ± 6.42 cm vs. 38.73 ± 4.99 cm vs. 36.02 ± 5.34 cm, respectively) (p = 0.027), and the difference between the Control and Very Short Cervix groups was statistically significant. However, after linear regression, in the presence of volume information, we found no association between the groups and FI. CONCLUSION: Cervical length and volume are positively correlated. When information about the volume is not provided, there\'s no association between cervical length and vascularization. Uterine artery Doppler is not related to cervical length. Despite the limitations of a small sample size and less comparative data in the literature, this study was performed with a homogeneous sample population and paves the way toward further research on the subject

En Afrique sub-Saharienne, les mesures préventives contre le paludisme pendant la grossesse ne sont mises en place qu'à partir du 2ème trimestre de la grossesse, laissant les femmes insuffisamment voire non protégées lors du 1er trimestre. Pourtant certaines études ont montré que les infections palustres survenant avant la 20ème semaine pourraient être délétères pour la santé de la mère et du fœtus. L'objectif de cette thèse était de décrire la prévalence des infections palustres au cours de la grossesse, notamment au 1er trimestre, et d'en évaluer les effets sur la morbidité de l'enfant à la naissance et sur la santé maternelle. Une cohorte de 411 femmes enceintes a été suivie depuis la période pré-conceptionnelle jusqu'à l'accouchement dans le sud du Bénin. L'infection palustre était dépistée mensuellement en utilisant une goutte épaisse. Nous avons montré que les infections palustres étaient plus fréquentes au 1er trimestre que pendant la période pré-conceptionnelle et aux 2ème et 3ème trimestres de grossesse. Les infections du 1er trimestre avaient un effet direct significatif sur le risque d'anémie en fin de grossesse. En revanche, aucune association directe n'a été mise en évidence entre la survenue d'une infection au 1er trimestre et le faible poids de naissance, la prématurité et le retard de croissance intra-utérin. Toutefois, les infectées de façon répétée au cours de la grossesse, avec une première infection au 1er trimestre, étaient significativement plus à risque de faibles poids de naissance. Les stratégies de prévention de paludisme devraient débuter dès le début de la grossesse, en complément aux mesures préventives existantes
In sub-Saharan Africa, preventive strategies against malaria during pregnancy are usually provided from the 2nd trimester of pregnancy. Consequently, pregnant women remain insufficiently or not protected during the first trimester. However, recentes studies have showed that malaria before 20 weeks of gestation would be deleterious for the mother and her fetus. The goal of this thesis was to describe the prevalence of malaria infections during pregnancy, particularly those occuring in the first trimester. For that purpose, we set up a cohort of 411 pregnant women followed from the preconception period to delivery in Southern Benin. Microscopic malaria infections were detected monthly using thick blood smear. We showed that microscopic malaria was more prevalent in early pregnancy than before conception and in comprarison to 2nd and 3rd trimester. We observed a significant direct effect of malaria infection in the first trimester on the maternal anaemia at the end of pregnancy whereas no direct effect was found on low birthweight, premature birth, and intrauterine growth restriction. However, women with repetead malaria infections starting in the frist trimester had highest risk to deliver lowbirthweight newborns. Preventives stratégies against malaria should clearly start from the first trimester of pregnancy and they should complement currently implemented measures by combining the administration of efficacious and safe drugs in the first trimester, associated to vector control interventions

OBJETIVO: Avaliar a influência dos efeitos da poluição atmosférica sobre o volume e a vascularização placentários no primeiro trimestre. MÉTODOS: O presente estudo é uma coorte prospectiva  realizada de outubro de 2011 a março de 2014, em São Paulo, Brasil. Os critérios de inclusão foram: feto único, idade gestacional entre 11 semanas e 13 semanas e 6 dias, ausência de doença materna, ausência de malformações e utilização correta do amostrador passivo individual de poluentes. Os critérios de exclusão foram: gestação gemelar, malformações e abortamento diagnosticados à ultrassonografia, mudança de endereço para fora da área de recrutamento, desistência da paciente, doença materna diagnosticada durante o acompanhamento. A exposição à poluição foi avaliada por 7 a 18 dias, antes da avaliação ultrassonográfica, utilizando-se amostrador passivo individual dos poluentes NO2 e de O3. Após uso do filtro, as gestantes eram avaliadas na Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina de São Paulo (FMUSP). Nesse local, elas foram submetidas à ultrassonografia morfológica entre 11 semanas e 13 semanas e 6 dias e à avaliação placentária pela técnica tridimensional associada ao power Doppler. Por meio desse exame foram avaliados quantitativamente o volume da placenta e seus índices vasculares placentários (com o software VOCAL), os quais compreendem: índice de vascularização (IV), índice de fluxo (IF) e índice de vascularização e fluxo (IVF). A influência dos níveis de poluentes na vascularização e volume placentários log-transformada foi analisada utilizando modelos de regressão linear múltipla que controlavam a idade gestacional, índice de massa corpórea, tabagismo, localização da placenta e paridade. RESULTADOS: Foram avaliadas 229 gestantes no primeiro. O aumento dos níveis de NO2 no primeiro trimestre teve um efeito negativo significativo sobre o IV (p = 0,012 e beta = 0,160) e IVF (p = 0,015 e beta = -0,159). Não houve influência de NO2 e O3 no volume placentário ou IF. CONCLUSÃO: A exposição materna ao NO2 foi significativamente associada com diminuição do índice de vascularização e do índice de vascularização e fluxo no primeiro trimestre da gravidez, o que sugere que esse poluente e outros poluentes primários e secundários, os quais estão associados ao NO2, influenciam na placentação, reduzindo sua vascularização
OBJECTIVE: To evaluate the influence of air pollution on the volume and placental vascularization in the first trimester. METHODS: This study is a prospective cohort conducted from October 2011 to March 2014 in São Paulo, Brazil. The inclusion criteria were single fetus, gestational age between 11 weeks and 13 weeks and 6 days, the absence of maternal disease, fetal defects and correct use of passive personal monitors pollutants. The exclusion criteria were twin pregnancy, abortion and malformations diagnosed on ultrasound, change of address out of the area of recruitment, patient abandonment, and maternal disease diagnosed during follow-up. The pollution exposure was evaluated by 7 to 18 days, before the ultrasound evaluation, using passive personal monitors pollutants of NO2 and O3. After using the filter, the pregnant women were evaluated at Obstetrics Department from Hospital das Clinicas of Faculdade de Medicina de São Paulo (FMUSP). In this place, they were subjected to morphological ultrasound between 11 weeks and 13 weeks and 6 days and placental evaluation by the three dimensional ultrasound power Doppler. Through the ultrasound examination were quantitatively evaluated the volume of the placenta and their placental vascular indices (with VOCAL software), which comprise the vascularization index (VI), flow index (FI) and vascularization flow index (VFI). The influence of pollutant levels on logtransformed placental vascularization and volume was analyzed using multiple linear regression models that controlled for gestational age, body mass index, smoking status, placental location and parity. RESULTS: In the first trimester 229 pregnant women were evaluation. NO2 levels increased in the first trimester had a significant negative effect on the VI (p=0.012 and beta= -0.160) and the VFI (p = 0.015 and beta= -0.159). No effect of NO2 and O3 on the log of placental volume or FI was observed. CONCLUSION: NO2 exposure was significantly associated with a diminished Vascularization Index and Vascularization and Flow Index in the first trimester of pregnancy, which suggests that this pollutant and other primary and secondary pollutants that are associated with NO2 influence placentation and decrease vascularization

UVOD Prenatalna dijagnostika predstavlja skup metoda i postupaka čiji je cilj da potvrde ili isključe postojanje kongenitalnih anomalija ploda. Prenatalni skrining može biti ne invazivni i invazivni. Ne invazivni skrining treba da ima visku senzitivnost i da omogući adekvatnu selekciju trudnica kojima će se predložiti genetsko ispitivanje ploda iz uzoraka dobijenih invazivnim metodama prenatalne dijagnostike. Prenatalni skrining prvog trimestra trudnoće obuhvata ultrazvučni pregled debljine nuhalne translucencije i laboratorijsku analizu dva biohemijska markera od 11 do 14 nedelje trudnoće, Prenatalni skrining drugog trimestra trudnoće koji se zasniva na biohemijskom skriningu i tripl testu iako je jedini koji se primenjuje zbog niske senzitivnosti od 20% do 40%, ne može se smatrati validnim. Integrativni biohemijski test prvog i drugog trimestra imaj veću senzitivnost (od 40 do 60%) ali ni on nije dao očekivane rezultate u adekvatnoj selekciji trudnica za genetsku analizu ploda zbog visoke stope lažno pozitivnih rezultata. Drugi trimestar trudnoće omogućava sonografskim pregledima i biohemijskim analizama dopunski način a u nekim slučajevima i jedini u proceni postojanja rizika Daunovog sindroma ili nekih drugih hromozomskih aberacija ploda Zato je primena integrativnih prenatalnih ne invazivnih metoda prvog i drugog trimestra trudnoće veoma značaja u poboljšanju dijagnostičkih vrednosti prenatalnih skrining testova i ima za cilj da smanji procenat invazivnih procedura zbog mogućih komplikacija i ne potrebnih finansijskih troškova. Daunov sindrom(trizomija 21 para hromozoma) je najčešća hromozomska numerička aberacija praćena mentalnom retardacijom dece (I.Q<70. ) Deca sa Daunovim sindromom su karakterističnog fenotipskog izgleda i sa čestim kongenitalnim anomailjama koje im onemogućavaju normalan život a često su i uzrok njihove prerane smrtnosti. Kongenitalne anomalije su zastupljene kod 2% do 5% živo rođene dece, predstavljaju 25 % perinatalne smrtnosti, četvrtina su uslovljnene hromozomskim aberacijama ili naslednom osnovom, od čega 0, 2%-0, 4% su sa Daunovim sindromom. CILJEVI Ciljevi četrorogodišnjeg istraživanja su bili da se poboljša dijagnostička vrednost postojećih prenatalnih testova, da se potvrdi značaj ultrazvučnog skrininga drugog trimestra trudnoće analizom debljine vratne brazde i dužine butne kosti ploda te da se poboljša njegova senzitivnost korporativnom sonografskom analizom cefaličnog indexa, intraorbitalnog rastojanja i dužine fronto-talamične distance. MATERIJAL I METODE Ukupan broj trudnica obuhvaćen četvorogodišnjim ispitivanjem koje su ultrazvučno pregledane i kojima je savetovano genetsko ispitivanje ploda blio je 4552. Tokom Retrospektivnog dvogodišnjieg ( 2010.2011)bila je 2169 dok je prospektivnom dvogodišnjom analizom (2012, 2013)je bilo obuhvaćeno 2383 trudnica. Ispitivana grupa su bile trudnice kod kojih je genetskom analizom otkriven patološki kariotip ploda, kontrolna grupa je obuhvatila sve ostale trudnice kod je kariotip ploda bio normalan od kojih su 124 trudnice odabrane metodom slučajnog izbora. Retrospektivnom studijom ultrazvučna je pregledana dužina vratne brazde(>6mm i dužina butne kosti<0, 6 od 14 do 22 nedelje trudnoće. Analizirana je cirkulacija fetalne krvi kroz duktus venosus ploda( a talas) i postojanje nosne kosti ploda(+, -). Prospektivnom analizom je ultrazvučnim pregledom ploda dodatno analiziran cefalični index(>85%), i intraorbitalna distanca i duzina fronto-talamične distance(<80%) ploda. Korišćene su metode deskriptivne statističke analize, aritmetička sredina, standardna devijacija, najmanja i najveća vrednost kod parametrijskih obeležja dok su za ne parametrijska postojanje nosne kosti i alfa talasa duktusu venozusu korišćene druge statističke metode, a komparativnim statističkim metodama kod normalnih, patoloških i kariotipova sa Daunovim sindromom ploda. Statistička značajnost je dokazana t testom a definisana nivoom p<0, 05 i p<0, 001 odnosom kod normalnih, patoloških kariotipova i Daunovog sindroma. Multifaktorskom regresivnom logističkom analizom je urađena procena senzitvnosti prenatalnog ultrazvučnog skrininga sa ispitivanim obeležjima drugog trimestra trudnoće REZULTATI I DISKUSIJA Od ukupnog broja ultrazvučno pregledaninh trudnica 4552 kojima je savetovano genetska analiza ploda citogenetskom analizom je otkriveno 66 patoloških kariotipova 1, 49%, sa Dunovim sindromom 31 0, 68%. Deskriptivnom statističkom obradom ultrazvučno ispitivanih obeležja od 14 do 22 nedelje trudnoće, uočeno je odstupanje i potvrđen značaj starije životne dobi trudnica, debljine vratne brazde i dužine frontotalamične distance u odnosu na normalne nalaze katiotipova ploda u predikciji Daunovog sindroma.Vrednosti dužine butne kosti, cefaličnog indeksa i intraorbitalnog rastojanja nisu imala veća odstupanja u poređenju patoškokih i normalnih nalaza kariotipova.Studentovim t testom je i dokazano p<0, 001 za debljinu vratne brazde i dužinu fronto-talamične distance, dok je za stariju životnu dob trudnice potvrđeno a;0, 001. Senzitivnost prenatalnog skrininga drugog trimestra analizom debljine vratne brazde i dužine butne kosti je veća u odnosu na standardno primenjivan biohemijski skrining drugog trimestra tripl testa (senzitivnost 40%-60) sa velikom stopom lažno pozitivnih rezultata.Dokazan je značaj poboljšanja senzitivnosti prenatalnih skrining testova dopunskom analizom tri ultrazvučna parametra, dužine fronto-talamične distance, cefaličnog indeksa i intraorbitalnog rastojanja u predikciji Daunovog sindroma, ali i kod ostalih hromozomskih aberacija ploda u periodu od 14 do 22 nedelje trudnoće primenomi multifaktorske logističke regresivne analize senzitivnost preko 93% sa 7% lažno pozitivnih rezultata. Postojanje korelacije između debljine vratne brazde i dužine fronto-talamične distance ploda poboljšavai senzitivnost prenatalnih ultrazvučnog skrininga. Integrativnim pristupom ultrazvučnog i biohemijskog skrininga drugog trimesra trudnoće, tripl testa očekuje se poboljšati dijagnostičkih vrednosti prenatalnog skrininga senzitivnost ne invazivnog skrininga u predikciji Daunovog sindroma i ostalih hromozomskih aberacija ploda. ZAKLJUČCI 1Potvrđen je značaj starije životne dobi trudnice u povećanju rizika Daunovog sindoma, i ostalih hromozomskih aberacija ploda ( p<0, 001) Potvrđen je značaj zadebljanja vratne brazde ploda >6mm(p<0, 001) i skraćenja butne kosti kod Daunovog sindroma ploda od 14 do 22 nedelje trudnoće u prenatalnom otkrivanju Dunovog sindroma i ostalih hromozomskih aberacija ploda i selekciji trudnica kojima će se predložiti genetsko ispitivanje ploda.Potvrđena je hipoteza da skraćenje fronto-talamične distance poboljšava senzitivnost ultrasonografskog skrininga, jer češće postoji kod Daunovog sindroma ploda ali i ostalih numeričkih hromozomskih aberacija tipa, nego kod normalnih nalaza kariotipa ploda( p<0, 001).Komparativnom analzom ultrazvučnim pregledom fronto-talamična distance debljine vratne brazde i dužine butne kosti ploda od 14 do 22 nedelje trudnoće može se značajno poboljšati vrednost dijagnostičkih prenatalnih testova u predikciji Daunovog sindroma. Postojanje korelacija između fronto-talamične distance i debljine vratne brazde dopunjuje ultrazvučni skrining i povećava njegovu senzitivnost na preko 90%, što je multifaktorskom regresivnom logaritamskom analizom i potvrđeno. Značaj multidisciplinarnog pristupa pogotovo je izražen u predikciji Daunovog sindroma, obzirom na različite specijalnosti koje u njemu učestvuju. Cost – benefit analiza. Visoka senzitivnost ne invazivnog prenatalnog skrininga u predikciji Daunovog sindroma, smanjuje troškove za pojedince i državu jer je njihova cena i do dest puta manja od cene citogenetskih analiza, a i trudnice se ne izlažu riziku mogućih komplikacija prilikom izvođenja invazivnih metoda
INTRODUCTIONS Prenatal diagnostic procedure represent a set of methods and techniques with the aim to afirmate or eliminate the presence of Down’s syndrome and other congenital anomalies Can be non-invasive and invasive methods. Non-invasive methods (laboratory or ultrasonographic) have the aim to make possible the most valid assessment of the risk of presence of an affected fetus in the pregnancy, selected pregnancy for invasive diagnostics procedures and citogenetics analisseskariotipingfoeti. Down’s syndrome, aneuploidy with trisomy 21 chromosomal, is the most common chromosomal numerical aberration associated with mental retardation of children (IQ< 70). Children with Down’s syndrome have characteristic phenotypic appearance with high frequent congenital anomalies that preclude a normal life and are frequently the cause of their earlier death. AIM The aim of the four year long investigation was to confirm the importance of ultrasound screening by the analyses of the basic ultrasound parameters for the second trimester, the thickness of the nuchal fold and the length of the femur of the fetus in the prediction of Down’s syndrome and other chromosomal aberrations of the fetus, as well as to improve other existing ultrasonic screenings of the first and second trimester of pregnancy by ultrasonic examination and analyses of the cephalic index and intraorbital space and the length of the fronto-thalamic distance. MATERIAL AND METODS Retrospective investigation (2010. 2011) and prospective investigation (2012.2013) includes 4655 pregnant women. For all pregnant women the genetic investigation of the fetus was performed. A total of 68 were found with chromosomal aberrations, 38 with Down’s syndrome. The method of haphazard choice in retrospective study and in prospective study ultrasound markers are examined. In retrospective analyses of the nuchal fold (<6mm and the length of femur <0.6, that represent basic ultrasound screening of the second trimester and are analyzed as parametric signs of the second trimester, and are analyzed as parametric markers, and analyses of the circulation of fetal blood through ductus venosus of the fetus. In the retrospective study the length of the nuchal fold (>6mm in length, that represent a basic ultrasound screening of the second trimester, and are analyzed as parametric markers in the prediction of Down’s syndrome and other chromosomal aberrations. RESULTS AND DISCUSION Cytogenetic analyses revealed 66 (1, 49%) pathologic karyotypes and Down syndrome were present in 31 (0, 68%) cases. All pathologic karyotypes were obtained after ultrasound examinations of 4552 pregnant women. Ultrasound markers for period 14th-22nd GW were analyzed with descriptive statistical methods and importance of pregnancy in older women, thickness of nuchal fold and lengths frontal thalamic distance were proofed in case of Down syndrome. Femoral bone lengths, cephalic index and intraorbital distances were similar for both groups, normal and pathologic karyotypes. Student’s t test revealed statistical significance with p<0, 001 values for nuchal fold thickness, frontal thalamic distance and older ages.Three additional ultrasound markers (frontal thalamic distance, cephalic index, intraorbital distance) improve prediction of Down syndrome and other chromosomal aberrations between 14th and 22nd GW as well. Multifactorial logistic regressive analyses revealed 93% sensitivity with 7% false positive results. Corelation between nuchal fold thickness and frontal thalamic distance improve prenatal ultrasound screening sensitivity. Using both ultrasound and biochemical screening (triple test) is way to improve sensitivity of non invasive screening in prediction of Down syndrome and other chromosomal aberrations. CONCLUSIONS Importance of pregnant women ages and higher risk for Down syndrome and other chromosomal aberrations was proofed (p<0, 001).Importance of nuchal fold thickness above 6mm (p<0, 001) and shorter femoral bone marker in period from 14th to 22nd GW in prediction of Down syndrome and other chromosomal aberrations are proofed (p<0, 001). Hypothesses that frontal thalamic distance improve ultrasound screening sensitivity was proofed was proofed (p<0, 001) since it is significantly shorter in Down syndrome and other chromosomal aberrations in comparison with fetuses with normal karyotypes. Comparative analyses of frontothalamic distance, nuchal fold thickness and femoral bone length in period from 14th to 22nd GW can signifi cantly improve prenatal diagnostic testing in Down syndrome prediction. Correlation between frontothalamic distance and nuchal fold thickness improve ultrasound screening sensitivity on 93% that is proofed with multifactorial logistic regressive analyses. Significance of multidisciplinary approach is high in Down syndrome prediction. Cost-benefit: High sensitivity of non invasive prenatal screening in Down syndrome prediction reduces costs for families and government since it costs ten time less than cytogenetic analyses and risk with invasive procedures is avoided.