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STUDY QUESTION Is morphologic development of the first-trimester utero-placental vasculature associated with embryonic growth and development, fetal growth, and birth weight percentiles? SUMMARY ANSWER Using the utero-placental vascular skeleton (uPVS) as a new imaging marker, this study reveals morphologic development of the first-trimester utero-placental vasculature is positively associated with embryonic growth and development, fetal growth, and birth weight percentiles. WHAT IS KNOWN ALREADY First-trimester development of the utero-placental vasculature is associated with placental function, which subsequently impacts embryonic and fetal ability to reach their full growth potential. The attribution of morphologic variations in the utero-placental vascular development, including the vascular structure and branching density, on prenatal growth remains unknown. STUDY DESIGN, SIZE, DURATION This study was conducted in the VIRTUAL Placental study, a subcohort of 214 ongoing pregnancies, embedded in the prospective observational Rotterdam Periconception Cohort (Predict study). Women were included before 10 weeks gestational age (GA) at a tertiary referral hospital in The Netherlands between January 2017 and March 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS We obtained three-dimensional power Doppler volumes of the gestational sac including the embryo and the placenta at 7, 9, and 11 weeks of gestation. Virtual Reality-based segmentation and a recently developed skeletonization algorithm were applied to the power Doppler volumes to generate the uPVS and to measure utero-placental vascular volume (uPVV). Absolute vascular morphology was quantified by assigning a morphologic characteristic to each voxel in the uPVS (i.e. end-, bifurcation-crossing-, or vessel point). Additionally, total vascular length (mm) was calculated. The ratios of the uPVS characteristics to the uPVV were calculated to determine the density of vascular branching. Embryonic growth was estimated by crown-rump length and embryonic volume. Embryonic development was estimated by Carnegie stages. Fetal growth was measured by estimated fetal weight in the second and third trimester and birth weight percentiles. Linear mixed models were used to estimate trajectories of longitudinal measurements. Linear regression analysis with adjustments for confounders was used to evaluate associations between trajectories of the uPVS and prenatal growth. Groups were stratified for conception method (natural/IVF-ICSI conceptions), fetal sex (male/female), and the occurrence of placenta-related complications (yes/no). MAIN RESULTS AND THE ROLE OF CHANCE Increased absolute vascular morphologic development, estimated by positive random intercepts of the uPVS characteristics, is associated with increased embryonic growth, reflected by crown-rump length (endpoints β  = 0.017, 95% CI [0.009; 0.025], bifurcation points β  = 0.012, 95% CI [0.006; 0.018], crossing points β  = 0.017, 95% CI [0.008; 0.025], vessel points β  = 0.01, 95% CI [0.002; 0.008], and total vascular length β  = 0.007, 95% CI [0.003; 0.010], and similarly with embryonic volume and Carnegie stage, all P -values ≤ 0.01. Density of vascular branching was negatively associated with estimated fetal weight in the third trimester (endpoints: uPVV β = −94.972, 95% CI [−185.245; −3.698], bifurcation points: uPVV β = −192.601 95% CI [−360.532; −24.670]) and birth weight percentiles (endpoints: uPVV β = −20.727, 95% CI [−32.771; −8.683], bifurcation points: uPVV β −51.097 95% CI [−72.257; −29.937], and crossing points: uPVV β = −48.604 95% CI [−74.246; −22.961])), all P -values < 0.05. After stratification, the associations were observed in natural conceptions specifically. LIMITATION, REASONS FOR CAUTION Although the results of this prospective observational study clearly demonstrate associations between first-trimester utero-placental vascular morphologic development and prenatal growth, further research is required before we can draw firm conclusions about a causal relationship. WIDER IMPLICATIONS OF THE FINDINGS Our findings support the hypothesis that morphologic variations in utero-placental vascular development play a role in the vascular mechanisms involved in embryonic and fetal growth and development. Application of the uPVS could benefit our understanding of the pathophysiology underlying placenta-related complications. Future research should focus on the clinical applicability of the uPVS as an imaging marker for the early detection of fetal growth restriction. STUDY FUNDING/COMPETING INTEREST(S) This research was funded by the Department of Obstetrics and Gynecology of the Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. There are no conflicts of interest. TRIAL REGISTRATION NUMBER Registered at the Dutch Trial Register (NTR6854). [ABSTRACT FROM AUTHOR]

STUDY QUESTION Is there a difference in embryonic morphological development between ongoing pregnancies and live pregnancies ending in a miscarriage? SUMMARY ANSWER Embryonic morphological development, assessed by the Carnegie stages, is delayed in live pregnancies ending in a miscarriage compared to ongoing pregnancies. WHAT IS KNOWN ALREADY Pregnancies ending in a miscarriage tend to have smaller embryos and slower heart rates. STUDY DESIGN, SIZE, DURATION Between 2010 and 2018, 644 women with singleton pregnancies, in the periconception period, were enrolled in a prospective cohort study with follow up until 1 year after delivery. A miscarriage was registered as a non-viable pregnancy before 22 weeks gestational age, defined by an absent heartbeat by ultrasound for a previously reported live pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS Pregnant women with live singleton pregnancies were included and serial three-dimensional transvaginal ultrasound scans were performed. Embryonic morphological development was assessed by the Carnegie developmental stages and evaluated using virtual reality techniques. The embryonic morphology was compared to clinically used growth parameters (i.e. crown-rump length (CRL) and embryonic volume (EV)). Linear mixed models were used to evaluate the association between miscarriage and the Carnegie stages. Logistic regression with generalized estimating equations was used to calculate the odds of a miscarriage after a delay in Carnegie stages. Adjustments were made for potential confounders or covariates and include age, parity, and smoking status. MAIN RESULTS AND THE ROLE OF CHANCE A total of 611 ongoing pregnancies and 33 pregnancies ending in a miscarriage were included between 7 + 0 and 10 + 3 weeks gestational age, resulting in 1127 assigned Carnegie stages for evaluation. Compared to an ongoing pregnancy, a pregnancy ending in a miscarriage is associated with a lower Carnegie stage (βCarnegie = −0.824, 95% CI −1.190; −0.458, P  <   0.001). A live embryo of a pregnancy ending in a miscarriage will reach the final Carnegie stage with a delay of 4.0 days compared to an ongoing pregnancy. A pregnancy ending in a miscarriage is associated with a smaller CRL (βCRL = −0.120, 95% CI −0.240; −0.001, P  =   0.049) and EV (βEV = −0.060, 95% CI −0.112; −0.007, P  =   0.027). The delay in Carnegie stage increases the odds of a miscarriage by 1.5% per delayed Carnegie stage (ORCarnegie = 1.015, 95% CI 1.002; 1.028, P  =   0.028). LIMITATIONS, REASONS FOR CAUTION We included a relatively small number of pregnancies ending in a miscarriage from a study population that is recruited from a tertiary referral centre. Furthermore, results of genetic testing on the products of the miscarriages or information on the karyotype of the parents were not available. WIDER IMPLICATIONS OF THE FINDINGS Embryonic morphological development, assessed by the Carnegie stages, is delayed in live pregnancies ending in a miscarriage. In the future, embryonic morphology may be used to estimate the likelihood of a pregnancy continuing to the delivery of a healthy baby. This is of crucial importance for all women but in particular for those at risk of a recurrent pregnancy loss. As part of supportive care, both women and their partners may benefit from information on the prospective outcome of the pregnancy and the timely identification of a miscarriage. STUDY FUNDING/COMPETING INTEREST(S) The work was funded by the Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Background Early detection of vulnerability during or before pregnancy can contribute to optimizing the first 1000 days, a crucial period for children's development and health. We aimed to identify classes of vulnerability among pregnant women in the Netherlands using pre-pregnancy data on a wide range of social risk and protective factors, and validate these classes against the risk of adverse outcomes. Methods We conducted a latent class analysis based on 42 variables derived from nationwide observational data sources and self-reported data. Variables included individual, socioeconomic, lifestyle, psychosocial and household characteristics, self-reported health, healthcare utilization, life-events and living conditions. We compared classes in relation to adverse outcomes using logistic regression analyses. Results In the study population of 4172 women, we identified five latent classes. The largest 'healthy and socioeconomically stable'-class [ n  = 2040 (48.9%)] mostly shared protective factors, such as paid work and positively perceived health. The classes 'high care utilization' [ n  = 485 (11.6%)], 'socioeconomic vulnerability' [ n  = 395 (9.5%)] and 'psychosocial vulnerability' [ n  = 1005 (24.0%)] were characterized by risk factors limited to one specific domain and protective factors in others. Women classified into the 'multidimensional vulnerability'-class [ n  = 250 (6.0%)] shared multiple risk factors in different domains (psychosocial, medical and socioeconomic risk factors). Multidimensional vulnerability was associated with adverse outcomes, such as premature birth and caesarean section. Conclusions Co-existence of multiple risk factors in various domains is associated with adverse outcomes for mother and child. Early detection of vulnerability and strategies to improve parental health and well-being might benefit from focussing on different domains and combining medical and social care and support. [ABSTRACT FROM AUTHOR]

Study Question: Is periconceptional maternal smoking associated with embryonic morphological development in ongoing pregnancies?Summary Answer: Smoking during the periconceptional period is associated with a delayed embryonic morphological development which is not fully recuperated beyond the first trimester of pregnancy.What Is Known Already: Smoking during pregnancy decreases prenatal growth, increasing the risk of preterm birth, small for gestational age (GA) and childhood obesity.Study Design, Size, Duration: Between 2010 and 2018, 689 women with ongoing singleton pregnancies were periconceptionally enrolled in a prospective cohort study with follow-up until 1 year after delivery.Participants/materials, Setting, Methods: Between 7 + 0 and 10 + 3 weeks, GA serial three-dimensional transvaginal ultrasound scans were performed. Embryonic morphological development as assessed by the Carnegie developmental stages was evaluated using Virtual Reality techniques. In the absence of fetal morphology classification methods beyond the embryonic period, fetal ultrasound measurements at around 20 weeks' GA, and birth weight were used to assess fetal growth. Linear mixed models were used to evaluate the association between smoking and the Carnegie stages. Regarding first-trimester morphological development, we additionally stratified our findings for mode of conception. Multiple linear regression models were used to study the association between smoking, fetal growth and birth weight. To investigate to which extent delayed embryonic morphological development mediated the effect of smoking, contemporary mediation analysis was used. Adjustments were made for potential confounders and other covariates.Main Results and the Role Of Chance: A total of 689 singleton ongoing pregnancies were included and 1210 Carnegie stages were determined. Maternal periconceptional smoking represented by the number of cigarettes/day was associated with a slight non-significant delay of the Carnegie stages (βcigarettes/day = -0.058, 95% CI -0.122; 0.007, P = 0.080). Smoking of ≥10 cigarettes/day showed the strongest association (β≥10 cigarettes/day = -0.352, 95% CI -0.648; -0.057, P = 0.019), as reflected by a 0.9-day delay in reaching the final Carnegie stage. Stratification for mode of conception showed a stronger negative association between the number of cigarettes/day in the IVF/ICSI group (βcigarettes/day = -0.126, 95% CI -0.200; -0.051, P = 0.001) compared to naturally conceived pregnancies (βcigarettes/day = 0.009, 95% CI -0.093; 0.111, P = 0.867). In the IVF/ICSI group, periconceptional smoking of ≥10 cigarettes/day was associated with in a 1.6 day delay in reaching the final Carnegie stage (β≥10 cigarettes/day = -0.510, 95% CI -0.834; -0.186, P = 0.002). In the second trimester, periconceptional smoking was associated with a smaller femur length (βcigarettes/day = -0.077, 95% CI -0.147; -0.008, P = 0.029) and a larger head circumference (β1-9 cigarettes/day = 0.290, 95% CI 0.065; 0.514, P = 0.012). Smoking was associated with a lower birth weight, with a dose-response effect (βcigarettes/day = -0.150, 95% CI -0.233; -0.068, P < 0.001). Furthermore, using the unadjusted model, 40-60% of the association between smoking and fetal ultrasound parameters and 6.3% of the association between smoking and birth weight can be explained by a delayed embryonic morphology.Limitations, Reasons For Caution: The study population was recruited from a tertiary referral center. Smoking habits were explored using self-reported questionnaires and checked for consistency by trained researchers.Wider Implications Of the Findings: This study shows that the association of periconceptional maternal smoking and human morphological development can already be detected early in the first trimester of pregnancy using embryonic morphology as outcome. One of the key messages of this study is that the delay, or dysregulation, in embryonic morphology is associated with allometric growth reflected by smaller fetal measurements at 20 weeks gestation and lower weight at birth. The delay in embryonic morphology, measured in early pregnancy, cannot be recuperated during the pregnancy. The results of this study emphasize the importance of smoking intervention programs prior to conception. More research is warranted to assess the association between periconceptional smoking cessation and embryonic development.Study Funding/competing Interest(s): The work was funded by the Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. The authors declare no conflicts of interest.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Study Question: What is the clinical association of maternal thyroid function with placental hemodynamic function?Summary Answer: A higher free thyroxine (FT4) concentration in early pregnancy is associated with higher placental vascular resistance.What Is Known Already: Suboptimal placental function is associated with preeclampsia (which, in turn, further deteriorates placental hemodynamics and impairs the fetal blood supply), fetal growth restriction and premature delivery. Studies have suggested that thyroid hormone (TH) has a role in placental development through effects on trophoblast proliferation and invasion.Study Design, Size, Duration: This study was embedded in The Generation R cohort, a population-based prospective study from early fetal life onwards in Rotterdam, the Netherlands. In total, 7069 mothers with expected delivery date between April 2002 and January 2006 were enrolled during early pregnancy.Participants/materials, Setting, Method: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) concentrations were measured during early pregnancy (median 13.4 weeks, 95% range 9.7-17.6 weeks). Placental function was assessed by Doppler ultrasound via measurement of arterial vascular resistance, i.e. umbilical artery pulsatility index (PI) and uterine artery resistance index (RI) (both measured twice, between 18-25th and after 25th gestational weeks) and the presence of uterine artery notching (once after the 25th gestational week) in 5184 pregnant women.Main Results and the Role Of Chance: FT4 was positively linearly associated with umbilical artery PI in the second and third trimesters as well as with uterine artery RI in the second trimester and the risk of uterine artery notching in the third trimester (P < 0.05 for all). The association of thyroid function with preeclampsia and birth weight was partially mediated through changes in placental function, with the percentages of mediated effects being 10.4% and 12.5%, respectively.Limitations, Reasons For Caution: A potential limitation is the availability of only a single time point for TH measurements and different numbers of missing placental ultrasound measurements for the adverse outcomes.Wider Implications Of the Findings: A higher FT4 concentration in early pregnancy is associated with higher vascular resistance in the second and third trimesters in both the maternal and fetal placental compartment. These effects on placental function might explain the association of FT4 with adverse pregnancy outcomes, including preeclampsia and fetal growth restriction.Study Funding/competing Interest(s): This work was supported by a fellowship from ERAWEB, a project funded by the European Commission (to M.B.) and by clinical fellowship from The Netherlands Organization for Health Research and Development (ZonMw), Project 90700412 (to R.P.P.). The authors have no conflict of interest.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

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Study Question: Can growth trajectories of the human embryonic head be created using 3D ultrasound (3D-US) and virtual reality (VR) technology, and be associated with second trimester fetal head size and periconceptional maternal conditions? Summary Answer: Serial first trimester head circumference (HC) and head volume (HV) measurements were used to create reliable growth trajectories of the embryonic head, which were significantly associated with fetal head size and periconceptional maternal smoking, age and ITALIC! in vitro fertilization (IVF)/intra-cytoplasmic sperm injection (ICSI) treatment. What Is Known Already: Fetal growth is influenced by periconceptional maternal conditions. Study Design, Size, Duration: We selected 149 singleton pregnancies with a live born non-malformed fetus from the Rotterdam periconception cohort. Participants/materials, Setting, Methods: Bi-parietal diameter and occipital frontal diameter to calculate HC, HV and crown-rump length (CRL) were measured weekly between 9 + 0 and 12 + 6 weeks gestational age (GA) using 3D-US and VR. Fetal HC was obtained from second trimester structural anomaly scans. Growth trajectories of the embryonic head were created with general additive models and linear mixed models were used to estimate associations with maternal periconceptional conditions as a function of GA and CRL, respectively. Main Results: A total of 303 3D-US images of 149 pregnancies were eligible for embryonic head measurements (intra-class correlation coefficients >0.99). Associations were found between embryonic HC and fetal HC ( ITALIC! ρ = 0.617, ITALIC! P < 0.001) and between embryonic HV and fetal HC ( ITALIC! ρ = 0.660, ITALIC! P < 0.001) in ITALIC! Z-scores. Maternal periconceptional smoking was associated with decreased, and maternal age and IVF/ICSI treatment with increased growth trajectories of the embryonic head measured by HC and HV (All ITALIC! P < 0.05). Limitations, Reasons For Caution: The consequences of the small effect sizes for neurodevelopmental outcome need further investigation. As the study population consists largely of tertiary hospital patients, external validity should be studied in the general population. Wider Implications Of the Findings: Assessment of growth trajectories of the embryonic head may be of benefit in future early antenatal care. Study Funding/competing Interests: This study was funded by the Department of Obstetrics and Gynaecology, Erasmus MC University Medical Centre and Sophia Foundation for Medical Research, Rotterdam, The Netherlands (SSWO grant number 644). No competing interests are declared. [ABSTRACT FROM AUTHOR]

STUDY QUESTION: What are the effects of maternal and fetal soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PIGF) concentrations on fetal and childhood growth patterns? SUMMARY ANSWER: An angiogenic profile that is characterized by both low early pregnancy maternal sFlt-1 and PIGF concentrations and higher sFlt-1 concentrations, lower PIGF concentrations or a higher sFlt-1:PIGF ratio in umbilical cord blood is associated with a reduced fetal and childhood growth. WHAT IS KNOWN ALREADY: An imbalance in maternal and fetal sFlt-1 and PIGF concentrations has been suggested to affect pregnancy outcomes. However, their effects on longitudinal fetal and childhood growth remain largely unknown. STUDY DESIGN, SIZE, DURATION: This study was performed in 5980 mothers and 4108 of their children, participating in the Generation R Study; a population-based prospective cohort study from fetal life onwards in Rotterdam, the Netherlands (2001-2005). PARTICIPANTS/MATERIALS, SETTING, METHODS: Blood samples were obtained from mothers in early and mid-pregnancy and from the umbilical vein at delivery. Fetal and childhood growth characteristics (weight and length) were measured repeatedly by ultrasound and physical examinations until the age of 6 years. We assessed the associations of maternal and fetal angiogenic factors with fetal and childhood growth using repeated measurement regression models. Logistic regression models were used to determine associations between angiogenic factors and small for gestational age at birth (SGA). MAIN RESULTS AND THE ROLE Of CHANCE: Compared with early pregnancy maternal sFlt-1 concentrations in the lowest quintile, early pregnancy maternal sFlt-1 concentrations in the highest quintile were associated with a higher fetal weight growth resulting in a higher birth- weight (difference in birthweight 0.33 standard deviation score (SDS); 95% Confidence Interval (CI) 0.25-0.41), a lower risk of SGA (Odds Ratio (OR) 0.36; 95% CI 0.27-0.48) and a subsequent higher weight growth until the age of 6 years. Early pregnancy maternal PIGF concentrations in the lowest quintile were associated with a reduced weight growth pattern resulting in a smaller birthweight (difference in birthweight -0.34SDS;95% CI -0.44, -0.25), an increased risk of SGA (OR 3.48; 95% CI 2.39-5.08) and a lower weight growth throughout childhood. An early pregnancy maternal sFlt-1:PIGF ratio in the highest quintile was associated with a higher fetal weight growth pattern from 30 weeks onwards, resulting in a higher weight at birth (difference in birthweight 0.09 SDS; P-value <0.05), which remained present until the age of 2 years. Newborns with higher umbilical cord sFlt-1 concentrations, lower PIGF concentrations or a higher sFlt-1:PIGF ratio showed a lower fetal and childhood weight growth from 30 weeks gestation onwards until the age of 6 years (P-value <0.05). Similar patterns were observed in relation to fetal and childhood length growth. LIMITATIONS, REASONS FOR CAUTION: The study is an observational study. Therefore, no causal relationships can be established. WIDER IMPLICATIONS OF THE FINDINGS: Both a maternal and fetal angiogenic imbalance may affect fetal and childhood growth. Changes in angiogenic profiles may be involved in the pathways linking fetal growth restriction with the long-term risk of vascular disease in adulthood. STUDY FUNDING/COMPETING INTEREST(S): The first phase of the Generation R Study is made possible by financial support from The Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam, and the Netherlands Organization for Health Research and Development (ZonMw 21000074). V.W.V.J. received additional grants from the Netherlands Organization for Health Research and Development (ZonMw VIDI). M.I.B.-B. is financially supported by the Bo Hjelt foundation (grant 2009). The authors have no competing interests. [ABSTRACT FROM AUTHOR]

Background: The recent introduction of virtual reality (VR) enables us to use all three dimensions in a three-dimensional (3D) image. The aim of this prospective study was to evaluate an innovative VR technique for automated 3D volume measurements of the human embryo and yolk sac in first trimester pregnancies. Methods: We analysed 180 3D first trimester ultrasound scans of 42 pregnancies. Scans were transferred to an I-Space VR system and visualized as 3D 'holograms' with the V-Scope volume-rendering software. A semi-automatic segmentation algorithm was used to calculate the volumes. The logarithmically transformed outcomes were analysed using repeated measurements ANOVA. Interobserver and intraobserver agreement was established by calculating intraclass correlation coefficients (ICCs). Results: Eighty-eight embryonic volumes (EVs) and 118 yolk sac volumes (YSVs) were selected and measured between 5(+5) and 12(+6) weeks of gestational age (GA). EV ranged from 14 to 29 877 mm(3) and YSV ranged from 33 to 424 mm(3). ANOVA calculations showed that when the crown-rump length (CRL) doubles, the mean EV increases 6.5-fold and when the GA doubles, the mean EV increases 500-fold (P < 0.001). Furthermore, it was found that a doubling in GA results in a 3.8-fold increase of the YSV and when the CRL doubles, the YSV increases 1.5-fold (P < 0.001). Interobserver and intraobserver agreement were both excellent with ICCs of 0.99. Conclusion: We measured the human EV and YSV in early pregnancy using a VR system. This innovative technique allows us to obtain unique information about the size of the embryo using all dimensions, which may be used to differentiate between normal and abnormal human development. [ABSTRACT FROM AUTHOR]

BACKGROUND: Innovative imaging techniques, using up-to-date ultrasonic equipment, necessitate specific biometry. The aim of our study was to test the possibility of detailed human embryonic biometry using a virtual reality (VR) technique. [ABSTRACT FROM PUBLISHER]

For diagnostic purposes we assessed peripheral natural killer (NK) cell cytotoxicity and NK and T cell numbers to assess their putative predictive value in recurrent spontaneous abortion (RSA). A total of 43 women with subsequent pregnancy, 37 healthy controls and 39 women successfully partaking in an in-vitro fertilization (IVF) procedure, were included in the study. We show that before pregnancy, levels of NK cytotoxicity and numbers of both single CD56(pos) and double CD56(pos)CD16(pos) cells were similar between RSA women and controls. But notably, within the RSA group, NK cell numbers of <12% were strongly associated with a subsequent pregnancy carried to term. Supplementation of folic acid led to an increase of single CD56(pos) cells, but cytotoxic function appeared unaffected. The expression pattern of killer inhibitory receptors on CD56(pos) cells was not different between patients and controls. A longitudinal study revealed that, compared with controls, in RSA women higher numbers of double CD56(pos)CD16(pos) cells were present during early pregnancy, paralleled by an increase in cytotoxic NK cell reactivity. The single CD56(pos) population decreased in number. In conclusion, the analysis of peripheral NK cell characteristics appears a suitable diagnostic tool in RSA. Immunomodulation aimed at NK cell function appears a promising therapeutic measure. [ABSTRACT FROM AUTHOR]

Defective chorionic villous vascularization has been suggested to be associated with embryonic death. There are no reports, however, describing chorionic vascular profiles in spontaneous miscarriage tissue. Therefore, we investigated chorionic villous vascularization by both histopathology and an image analysis system combined with CD34 immunohistochemistry in spontaneous miscarriage tissue of 19 women with recurrent early pregnancy loss (REPL). Subsequently, we studied the vascular profile parameters (median vascular area, perimeter, number of vascular elements per measured chorionic area, and the median area, perimeter and diameter per vascular element) in relation to the maternal plasma total homocysteine concentrations (an independent risk factor for REPL). The histopathological scores and the measured number of vascular elements per mm(2) chorionic tissue were not significantly different between women with elevated and those with normal total homocysteine concentrations. However, women with elevated total homocysteine concentrations (fasting >18.3 micromol/l and/or 6 h after methionine load >61.5 micromol/l) showed (per measured chorionic area) significant smaller median vascular areas and perimeters. The single chorionic vascular elements in these women had significant smaller median areas, perimeters and diameters. Furthermore, the fasting total homocysteine was negatively correlated with the perimeter of the vascular element (r = -0.54: P <0.05). In conclusion, in REPL, elevated maternal total homocysteine concentrations are associated with defective chorionic villous vascularization. [ABSTRACT FROM AUTHOR]

Glutathione S-transferases (GST) are a family of enzymes involved in the detoxification of xenobiotics. In humans, GST are divided into four different classes, alpha, mu, pi and theta, with partly overlapping substrate specificity and a tissue-specific expression pattern. We studied the cellular distribution of GST alpha and pi in a variety of human embryonic organs obtained from an extra-uterine monozygotic twin pregnancy at 8 weeks' gestational age. Tissues were fixed in 4% paraformaldehyde and embedded in paraffin. Three 4 microm thick sections were used, one for routine haematein and eosin staining, the others for immunohistochemical determination using monoclonal and polyclonal antibodies against GST alpha and pi, respectively. Both GST alpha and pi were present in hepatocytes, gastrointestinal epithelium, adrenal gland medulla, and tela chorioidea in the telencephalon. GST pi, but not alpha, was found in the epithelium of pancreatic and pulmonary glands, trachea, nephrons and urinary collecting ducts, as well as in the pia mater of the telencephalon and in developing nerve tissue in the gastrointestinal muscularis mucosae. In summary, we have demonstrated that immunoreactive protein for both GST alpha and pi is expressed in the human embryo at 8 weeks' gestational age. The early expression of GST alpha and pi in the epithelia of the urinary and digestive tracts and the respiratory system supports the importance of GST in the detoxification of potentially toxic or carcinogenic compounds. Our results suggest that the embryo itself is capable of detoxifying noxious compounds that are generated intracellularly or that cross the trophoblastic tissue. [ABSTRACT FROM AUTHOR]