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Study Question: Are non-visualized pregnancy losses (biochemical pregnancy loss and failed pregnancy of unknown location combined) in the reproductive history of women with unexplained recurrent miscarriage (RM) negatively associated with the chance of live birth in a subsequent pregnancy?, Summary Answer: Non-visualized pregnancy losses contribute negatively to the chance for live birth: each non-visualized pregnancy loss confers a relative risk (RR) for live birth of 0.90 (95% CI 0.83; 0.97), equivalent to the RR conferred by each additional clinical miscarriage., What Is Known Already: The number of clinical miscarriages prior to referral is an important determinant for live birth in women with RM, whereas the significance of non-visualized pregnancy losses is unknown., Study Design, Size, Duration: A retrospective cohort study comprising 587 women with RM seen in a tertiary RM unit 2000-2010. Data on the outcome of the first pregnancy after referral were analysed for 499 women., Participants/materials, Setting, Methods: The study was conducted in the RM Unit at Rigshospitalet, Copenhagen, Denmark. We included all women with unexplained RM, defined as ≥3 consecutive clinical miscarriages or non-visualized pregnancy losses following spontaneous conception or homologous insemination. The category 'non-visualized pregnancy losses' combines biochemical pregnancy loss (positive hCG, no ultrasound performed) and failed PUL (pregnancy of unknown location, positive hCG, but on ultrasound, no pregnancy location established). Demographics were collected, including BMI, age at first pregnancy after referral and outcome of pregnancies prior to referral. Using our own records and records from other Danish hospitals, we verified the outcome of the first pregnancy after referral. For each non-visualized pregnancy loss and miscarriage in the women's reproductive history, the RR for live birth in the first pregnancy after referral was determined by robust Poisson regression analysis, adjusting for risk factors for negative pregnancy outcome., Main Results and the Role of Chance: Non-visualized pregnancy losses constituted 37% of reported pregnancies prior to referral among women with RM. Each additional non-visualized pregnancy loss conferred an RR for live birth of 0.90 (95% CI 0.83; 0.97), which was not statistically significantly different from the corresponding RR of 0.87 (95% CI 0.80; 0.94) conferred by each clinical miscarriage. Among women with ≥2 clinical miscarriages, a reduced RR for live birth was also shown: 0.82 (95% CI 0.74; 0.92) for each clinical miscarriage and 0.89 (95% CI 0.80; 0.98) for each non-visualized pregnancy loss, respectively. Surgically treated ectopic pregnancies (EPs) were significantly more common for women with primary RM and no confirmed clinical miscarriages, compared with women with primary RM and ≥1 clinical miscarriage (22 versus 6%, difference 16% (95% CI 9.1%; 28.7%); RR for ectopic pregnancy was 4.0 (95% CI 1.92; 8.20)., Limitations, Reasons for Caution: RM was defined as ≥3 consecutive pregnancy losses before 12 weeks' gestation, and we included only women with unexplained RM after thorough evaluation. It is uncertain whether the findings apply to other definitions of RM and among women with known causes for their miscarriages., Wider Implications of the Findings: To our knowledge, this is the first comprehensive investigation of prior non-visualized pregnancy losses and their prognostic significance for live birth in a subsequent pregnancy in women with unexplained RM. We show that a prior non-visualized pregnancy loss has a negative prognostic impact on subsequent live birth and is thus clinically significant., Study Funding/competing Interest(s): None., Trial Registration Number: N/A.

The aim of the study was to investigate whether first trimester chorionic villous vascularisation is different in women who smoked cigarettes before and during pregnancy in comparison with women who did not smoke. Placentas of smoking (>10 cigarettes/day, n = 13) and non-smoking women (n = 13), scheduled for a legal termination of a viable first trimester pregnancy for social indications, were retrieved. Placental tissues of 3-5 mm³ were whole mount CD31 immunofluorescence stained. Images of the CD31 immunofluorescence and contour of the villi were captured using an Optical Projection Tomography scanner. An immersive BARCO virtual reality system was used to create an enlarged interactive 3-dimensional hologram of the reconstructed images. Automatic volume measurements were performed using a flexible and robust segmentation algorithm that is based on a region-growing approach in combination with a neighbourhood variation threshold. The villous volume, vascular volume and vascular density were measured for the total chorionic villous tree as well as for its central and peripheral parts. No differences in maternal age and gestational age were found between non-smoking and smoking women. No differences were found in the total, central and peripheral villous tree volume and vascular volume. The central (13.4% vs. 9.5%, p=0.03) and peripheral (8.4% vs. 6.4%, p=0.02) villous tree vascular densities were increased in the smoking women as compared with the non-smoking women. In conclusion, chorionic villous vascularisation is already altered in first trimester of pregnancy in women who smoked cigarettes before and during pregnancy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Aims: Studies of uterine natural killer (uNK) cells require reliable measurements of uNK cell density among diverse endometrial tissue. The aim of this study was to compare cell counting manually with two computer-aided methods based on a public domain software package, ImageJ., Methods and Results: Immunohistochemistry (IHC) of CD56(+) uNK cells was performed on endometrium from recurrent miscarriage patients. Numbers of stromal cells per high-power field (HPF) were counted by two observers using: (i) manual tally counter and graticule; (ii) ImageJ 'point picker' tool; and (iii) ImageJ 'particle analysis' tool. Coefficients of variation (CV) and Bland-Altman plots were used to evaluate interobserver differences. Evaluation of %uNK using ImageJ particle analysis for stromal cell counts and point picker tool for uNK counts was undertaken. Point picker and particle analysis were significantly better than manual counting [interobserver CVs mean (standard deviation) 6.1% (3.3%); 4.7% (3.9%), 8.2% (6.5%), respectively]. Mean inter- and intra-observer CVs for %uNK were 10.3% (6.6%), 8.5% (4.9%) and 6.8% (4.3%), respectively. Bland-Altman analysis revealed no systematic differences in cell counts with the number of cells in the image for each method., Conclusions: Compared to manual cell counting, computer-aided image analysis yields more reproducible results for the assessment of uNK cells density using IHC., (© 2011 Blackwell Publishing Limited.)

The objective was to determine whether chorionic villous vascularization is diminished in cases of early onset (<34 weeks) small for gestational age (SGA) and/or preeclampsia (PE). Placental morphometrical measurements were performed in 4 gestational-age-matched groups complicated by SGA, SGA with PE, PE, and spontaneous preterm delivery without SGA or PE as the reference group. Using a video image analysis system, in randomly selected intermediate and terminal villi, the stromal area and the following villous vascular parameters were manually traced and analyzed: number of total, centrally and peripherally localized vessels, vascular area, and vascular area density. No differences were observed in intermediate and terminal villous vascular area. Preeclampsia was associated with smaller terminal villous stromal area (reference 2299 μm2, SGA 2412 μm2, SGA + PE 2073 μm2, and PE 2164 μm2, P = .011), whereas SGA was associated with an increased terminal villous vascular area density (reference 26.1%, SGA 35.7%, SGA + PE 33.4%, and PE 32.0%, P = .029). Compared with preserved flow, lower terminal villous vascular area density was found in cases with absent or reversed end-diastolic (ARED) umbilical artery flow (39.3% vs. 30.3%, P = .013). These data demonstrate that villous vascularization was not influenced by PE, whereas in terminal villi an increased vascular area density was associated with SGA. Lower terminal villous vascular area density was associated with ARED flow in SGA pregnancies, indicating an increased risk of fetal compromise.

Purpose of Review: To evaluate the impact of early pregnancy complications involving placentation and early placental development on adverse obstetric outcome in ongoing and subsequent pregnancies., Recent Findings: We found an increased risk of adverse outcome (odds ratio >2.0) in ongoing pregnancies of preterm delivery (PTD), very preterm delivery (VPTD), placental abruption, small for gestational age (SGA), low birth weight (LBW) and very LBW (VLBW) after a threatened miscarriage episode; pregnancy-induced hypertension, preeclampsia, placental abruption, PTD, SGA and low 5-min Apgar score following the detection of an intrauterine haematoma; and VPTD, VLBW and perinatal death after a vanishing twin phenomenon. In subsequent pregnancies, the risk of perinatal death was increased (odds ratio >2.0) after a single miscarriage, the risk of VPTD after two or more miscarriages, the risk of placenta previa, premature preterm rupture of membranes, PTD, VPTD and LBW after recurrent miscarriage and the risk of VPTD after two or more terminations of pregnancy., Summary: Our analysis of the literature review indicates a link between early pregnancy complications involving the placenta and subsequent adverse obstetric and perinatal outcomes. Some of these associations are based on limited or small uncontrolled studies. Larger population-based prospective controlled studies have recently been published confirming most of these findings. This suggests that the early detection of these risk factors could improve the screening of women at high risk of specific obstetric complications in ongoing and subsequent pregnancies.

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.

Background: For normal fetal growth and development a well-developed chorionic villous vascularization is essential., Aim: The aim of this study is to investigate whether idiopathic second trimester fetal loss is associated with an underdeveloped chorionic villous vascularization., Methods: 38 placentas after late miscarriage, classified as idiopathic fetal loss (IFL, n=16) or as fetal loss due to intrauterine infection (IUI, n=22) were collected. After CD34 immunohistochemical staining the villous stromal area, number of villous vessels, vascular area and vascular area density (central, peripheral and total) were measured in randomly selected immature intermediate villi., Results: The mean gestational age was 19+4 weeks for the IFL group and 20+6 weeks for the IUI group. After controlling for gestational age, we found no differences in fetal weight, placental weight, villous stromal area, number of vessels and central vascular features. The mean peripheral vascular area and peripheral vascular area density were, after adjusting for gestational age, reduced in the IFL group., Conclusion: Idiopathic second trimester fetal loss is associated with a reduced peripheral chorionic villous vascularization. We hypothesize that in these cases, placentation is already disturbed in first trimester of pregnancy, leading to a reduced materno-fetal interface in second trimester, thus to early postplacental fetal hypoxia and fetal death., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

First trimester human villous vascularization is mainly studied by conventional two-dimensional (2D) microscopy. With this (2D) technique it is not possible to observe the spatial arrangement of the haemangioblastic cords and vessels, transition of cords into vessels and the transition of vasculogenesis to angiogenesis. The Confocal Laser Scanning Microscopy (CLSM) allows for a three-dimensional (3D) reconstruction of images of early pregnancy villous vascularization. These 3D reconstructions, however, are normally analyzed on a 2D medium, lacking depth perception. We performed a descriptive morphologic study, using an immersive Virtual Reality system to utilize the full third dimension completely. This innovative 3D technique visualizes 3D datasets as enlarged 3D holograms and provided detailed insight in the spatial arrangement of first trimester villous vascularization, the beginning of lumen formation within various junctions of haemangioblastic cords between 5 and 7 weeks gestational age and in the gradual transition of vasculogenesis to angiogenesis. This innovative immersive Virtual Reality system enables new perspectives for vascular research and will be implemented for future investigation.

The nomenclature used to describe findings during early pregnancy in The Netherlands needs to be revised. Various terms, like 'abortion' and 'miscarriage', are used to describe the same phenomenon, which is confusing for both patients and doctors. In addition, the meaning of some terms, like 'missed abortion', has changed over time. In accordance with the revision of the European nomenclature in the English language by the Special Interest Group for Early Pregnancy of the European Society for Human Reproduction and Embryology (ESHRE), a revision of the nomenclature in the Dutch language is needed as well. An unambiguous Dutch terminology pertaining to early pregnancy is recommended that corresponds to the English terminology; this includes the Dutch terms 'embryo' [embryo], 'foetus' [foetus], 'biochemische zwangerschap' [biochemical pregnancy], 'zwangerschap met onbekende lokalisatie' [pregnancy of unknown location], 'miskraam' [miscarriage], 'lege vruchtzak' [empty sac], 'gestopte hart-activiteit' [fetal loss], 'herhaalde miskraam' [recurrent miscarriage], 'extra-uteriene zwangerschap' [ectopic pregnancy], and 'trofoblast-ziekte' [gestational trophoblastic disease], because these are based on well-defined clinical and ultrasonographic concepts.