Clinical Aspects of HyFoSy as Tubal Patency Test in Subfertility Workup.

BACKGROUND: Tubal patency testing is an essential part of female subfertility evaluation. Traditionally, hysterosalpingography (HSG) was the first step to evaluate tubal patency. However, during the past decade Hysterosalpingo-Contrast Sonography (HyCoSy) was introduced in order to avoid radiation exposure and Hysterosalpingo-Foam Sonography (HyFoSy) has been developed as a safe and less painful alternative. OBJECTIVES AND RATIONALE: The aim of this narrative review is to provide an overview of the currently available HyFoSy literature and related clinical aspects. SEARCH METHODS: A literature search was conducted using PubMed and Embase from the introduction of HyFoSy to March 2019. Unfortunately, a meta-analysis was not possible due to a too small number of studies, being mutually incomparable for the various subjects of clinical aspects, even for the reliability as a test for tubal patency. OUTCOMES: Nine small studies concluded that the accuracy and effectiveness as a test for tubal patency of 2D- and 3D-HyFoSy are comparable or even better than HSG or HyCoSy. With or without using Doppler techniques, 3D-HyFoSy does not seem to offer benefits above real-time 2D-HyFoSy. Five studies reported on pain and discomfort during HyFoSy, concluding that HyFoSy is a well-tolerated, less painful procedure compared to HSG, without a need for the use of analgesics. There are suggestions about an increased pregnancy rate in the first three cycles after the procedure but in no studies pregnancy outcome after HyFoSy was compared with other or no intervention. WIDER IMPLICATIONS: HyFoSy is a promising and safe alternative for HSG with regard to accuracy and effectiveness. HyFoSy lacks radiation and iodine exposure and is a well-tolerated and less painful procedure than HSG, without the need for analgesics. However more research is needed to make clear statements regarding a therapeutic effect of HyFoSy.

Evaluation of First-Trimester Physiological Midgut Herniation Using Three-Dimensional Ultrasound.

INTRODUCTION: The aim of this study was to investigate the development of midgut herniation in vivo using three-dimensional (3D) ultrasonographic volume and distance measurements and to create reference data for physiological midgut herniation in ongoing pregnancies in a tertiary hospital population. MATERIALS AND METHODS: The transvaginal 3D ultrasound volumes of 112 women, seen weekly during the first trimester of pregnancy, were obtained and subsequently analysed in a virtual reality environment. The width of the umbilical cord insertion, the maximum diameter of the umbilical cord, and the volume of midgut herniation were measured from 6 until 13 weeks gestational age (GA). RESULTS: All parameters had a positive relation with GA, crown-rump length, and abdominal circumference. In approximately 1 of 10 volumes no midgut herniation could be observed at 9 and 10 weeks GA. In 5.0% of the fetuses the presence of midgut herniation could still be visualised at 12 weeks GA. CONCLUSION: Reference charts for several dimensions of physiological midgut herniation were created. In the future, our data might be used as a reference in the first trimester for comparison in case of a suspected pathological omphalocele.

First trimester physiological development of the fetal foot position using three-dimensional ultrasound in virtual reality.

AIM: In anatomic studies of the embryo, it has been established that during the development of the lower limb, several changes in foot position can be observed defined as a temporary 'physiological clubfoot'. The aim of this study was to develop and test a measurement tool for objective documentation of the first trimester foot position in vivo and made an attempt to create a chart for first trimester foot position. METHODS: We developed a virtual orthopedic protractor for measuring foot positioning using three-dimensional virtual reality visualization. Three-dimensional ultrasound volumes of 112 pregnancies of women examined during the first trimester were studied in a BARCO I-Space. The frontal angle (plantar flexion) and the lateral angle (adduction) between the leg and foot were measured from 8 until 13 weeks gestational age. RESULTS: We observed that the frontal angle steadily decreases, whereas the lateral angle first increases, resulting in transient physiological clubfeet position at 10- to 11-week gestation, followed by a decrease to a normal foot position. CONCLUSION: A transient clubfoot position is present during the normal development of the lower limbs, and it has been measured in vivo for the first time. This study emphasizes that a diagnosis of congenital clubfoot should not be made in the first trimester of pregnancy.

Human embryonic curvature studied with 3D ultrasound in ongoing pregnancies and miscarriages.

Embryonic growth is often impaired in miscarriages. It is postulated that derangements in embryonic growth result in abnormalities of the embryonic curvature. This study aims to create first trimester reference charts of the human embryonic curvature and investigate differences between ongoing pregnancies and miscarriages. Weekly ultrasonographic scans from ongoing pregnancies and miscarriages were used from the Rotterdam periconceptional cohort and a cohort of recurrent miscarriages. In 202 ongoing pregnancies and 33 miscarriages, first trimester crown rump length and total arch length were measured to assess the embryonic curvature. The results show that the total arch length increases and shows more variation with advanced gestation. The crown rump length/total arch length ratio shows a strong increase from 8+0 to 10+0 weeks and flattening thereafter. No significant difference was observed between the curvature of embryos of ongoing pregnancies and miscarriages. The majority of miscarried embryos could not be measured. Therefore, this technique is too limited to recommend the measurement of the embryonic curvature in clinical practice.

Accuracy of fetal sex determination in the first trimester of pregnancy using 3D virtual reality ultrasound.

PURPOSE: Early detection of fetal sex is becoming more popular. The aim of this study was to evaluate the accuracy of fetal sex determination in the first trimester, using 3D virtual reality. METHODS: Three-dimensional (3D) US volumes were obtained in 112 pregnancies between 9 and 13 weeks of gestational age. They were offline projected as a hologram in the BARCO I-Space and subsequently the genital tubercle angle was measured. Separately, the 3D US aspect of the genitalia was examined for having a male or female appearance. RESULTS: Although a significant difference in genital tubercle angles was found between male and female fetuses, it did not result in a reliable prediction of fetal gender. Correct sex prediction based on first trimester genital appearance was at best 56%. CONCLUSION: Our results indicate that accurate determination of the fetal sex in the first trimester of pregnancy is not possible, even using an advanced 3D US technique.

Macroscopic and microscopic morphology of first trimester miscarriage and subsequent pregnancy outcome - An exploratory study.

INTRODUCTION: Reduced chorionic villous vascularization is associated with first trimester miscarriage and second trimester fetal loss. Differences in villous vascularization have been observed in combination with complications in the third trimester of pregnancy. The aim of this study was to investigate whether abnormal morphology and reduced chorionic villous vascularization in first trimester miscarriages are associated with an increased risk on adverse outcome and/or pregnancy complications in subsequent pregnancy. Secondly, to assess the influence of these parameters on the length of the interpregnancy interval and infertility. METHODS: In a retrospective cohort study 134 consecutive women who underwent dilatation and curettage for a miscarriage were included. The degree of chorionic villous vascularization in miscarriage tissue was determined by a pathologist. Ultrasound details of these miscarriages and clinical data on the subsequent pregnancy of these women were obtained. RESULTS: Neither reduced vascularization nor early embryonic arrest in first trimester miscarriages are associated with an increased risk of a subsequent miscarriage or adverse obstetric and perinatal outcome of subsequent pregnancy. Abnormal morphology of the first trimester miscarriage did not influence the time to subsequent pregnancy. A shorter mean interpregnancy interval between miscarriages was observed after miscarriages with reduced chorionic villous vascularization (5.5 vs. 10.7 months; p = 0.051), showing a trend towards an association. DISCUSSION: Chorionic villous vascularization and morphology have no influence on subsequent pregnancy outcome. Therefore it remains unknown what aspects of miscarriage are causing the increased risk on subsequent miscarriage and complications in the third trimester of the subsequent pregnancy.

Design and validation of a 3D virtual reality desktop system for sonographic length and volume measurements in early pregnancy evaluation.

PURPOSE: To design and validate a desktop virtual reality (VR) system, for presentation and assessment of volumetric data, based on commercially off-the-shelf hardware as an alternative to a fully immersive CAVE-like I-Space VR system. METHODS: We designed a desktop VR system, using a three-dimensional (3D) monitor and a six degrees-of-freedom tracking system. A personal computer uses the V-Scope (Erasmus MC, Rotterdam, The Netherlands) volume-rendering application, developed for the I-Space, to create a hologram of volumetric data. Inter- and intraobserver reliability for crown-rump length and embryonic volume measurements are investigated using Bland-Altman plots and intraclass correlation coefficients. Time required for the measurements was recorded. RESULTS: Comparing the I-Space and the desktop VR system, the mean difference for crown-rump length is -0.34% (limits of agreement -2.58-1.89, ±2.24%) and for embryonic volume -0.92% (limits of agreement -6.97-5.13, ±6.05%). Intra- and interobserver intraclass correlation coefficients of the desktop VR system were all >0.99. Measurement times were longer on the desktop VR system compared with the I-Space, but the differences were not statistically significant. CONCLUSIONS: A user-friendly desktop VR system can be put together using commercially off-the-shelf hardware at an acceptable price. This system provides a valid and reliable method for embryonic length and volume measurements and can be used in clinical practice.

Safety aspects and side-effects of ExEm-gel and foam for uterine cavity distension and tubal patency testing.

A state-of-the-art overview of the safety and side-effects of ExEm-gel for uterine cavity distension and ExEm-foam for tubal patency testing is presented. A literature search was carried out using PubMed, textbooks, pharmaceutical databases and reports of toxicity tests. Information on clinical use in humans and experiments in animal models was collected and grouped according to the following components: glycerol, hydroxyethyl cellulose and purified water; subjects included toxicity test, influence on sperm cells, oocytes, blastocyst development, uterine cavity distension, tubal patency testing, pain and obstetric applications. No unknown side-effects of gel or foam, or unexpected concerns about safety, were reported. More information than expected was available on the absence of effects of the components on various human tissues. Although it is difficult to prove that the search is complete, and it is possible that side-effects remain unreported, the combination of glycerol, hydroxyethyl cellulose and purified water is considered to be safe for intrauterine application and tubal patency testing, indicating an optimal risk-benefit ratio in clinical use. The safest strategy, however, is to restrict clinical examinations with gel and foam to the pre-ovulatory phase of the menstrual cycle.

First-trimester hand measurements in euploid and aneuploid human fetuses using virtual reality.

OBJECTIVE: Although second-trimester and third-trimester reference curves for human fetal hand growth allow for identification of several genetic syndromes, little is known about first-trimester hand growth. We investigated first-trimester hand growth in euploid and aneuploid fetuses. METHOD: Between 9 and 12 weeks' gestational age (GA), wrist width, hand width, hand length, and hand index were measured in three-dimensional (3D) ultrasound datasets of 112 euploid and 65 aneuploid pregnancies. We constructed reference curves for these measurements in euploid pregnancies and calculated z-scores for measurements in aneuploid pregnancies. Reproducibility was established in a subset of 20 datasets. RESULTS: While wrist width, hand width, and hand length increased with gestational age, hand index decreased. Intraobserver and interobserver intraclass correlation coefficient values were >0.97. In trisomy 21 cases, wider wrists and hands were observed compared with euploid pregnancies (mean z-scores 1.06, SD 2.04, p < 0.001 and 1.16, SD 1.30, p < 0.001, respectively). Trisomy 18 cases showed narrower and shorter hands (mean z-scores -0.74, SD 1.20, p = 0.009 and -0.97, SD 0.86, p = 0.005, respectively). In trisomy 13 cases, no differences were observed. CONCLUSION: Reference values are available for first-trimester studies on human hand development. First-trimester hand measurements in trisomies 21 and 18 differ significantly from those in euploid pregnancies and may be useful for early identification of abnormal development.

Early pregnancy placental bed and fetal vascular volume measurements using 3-D virtual reality.

In this study, a new 3-D Virtual Reality (3D VR) technique for examining placental and uterine vasculature was investigated. The validity of placental bed vascular volume (PBVV) and fetal vascular volume (FVV) measurements was assessed and associations of PBVV and FVV with embryonic volume, crown-rump length, fetal birth weight and maternal parity were investigated. One hundred thirty-two patients were included in this study, and measurements were performed in 100 patients. Using V-Scope software, 100 3-D Power Doppler data sets of 100 pregnancies at 12 wk of gestation were analyzed with 3D VR in the I-Space Virtual Reality system. Volume measurements were performed with semi-automatic, pre-defined parameters. The inter-observer and intra-observer agreement was excellent with all intra-class correlation coefficients >0.93. PBVVs of multiparous women were significantly larger than the PBVVs of primiparous women (p = 0.008). In this study, no other associations were found. In conclusion, V-Scope offers a reproducible method for measuring PBVV and FVV at 12 wk of gestation, although we are unsure whether the volume measured represents the true volume of the vasculature. Maternal parity influences PBVV.

First-Trimester Detection of Surface Abnormalities: A Comparison of 2- and 3-Dimensional Ultrasound and 3-Dimensional Virtual Reality Ultrasound.

The aim was to determine the diagnostic performance of 3-dimensional virtual reality ultrasound (3D_VR_US) and conventional 2- and 3-dimensional ultrasound (2D/3D_US) for first-trimester detection of structural abnormalities. Forty-eight first trimester cases (gold standard available, 22 normal, 26 abnormal) were evaluated offline using both techniques by 5 experienced, blinded sonographers. In each case, we analyzed whether each organ category was correctly indicated as normal or abnormal and whether the specific diagnosis was correctly made. Sensitivity in terms of normal or abnormal was comparable for both techniques (P = .24). The general sensitivity for specific diagnoses was 62.6% using 3D_VR_US and 52.2% using 2D/3D_US (P = .075). The 3D_VR_US more often correctly diagnosed skeleton/limb malformations (36.7% vs 10%; P = .013). Mean evaluation time in 3D_VR_US was 4:24 minutes and in 2D/3D_US 2:53 minutes (P < .001). General diagnostic performance of 3D_VR_US and 2D/3D_US apparently is comparable. Malformations of skeleton and limbs are more often detected using 3D_VR_US. Evaluation time is longer in 3D_VR_US.

Diagnostic techniques and criteria for first-trimester conjoined twin documentation: a review of the literature illustrated by three recent cases.

OBJECTIVES: Conjoined twins are rare. High-quality imaging techniques are essential for proper first-trimester diagnosis. Technological development leads to new imaging techniques such as 3-dimensional virtual embryoscopy. The aim of this review was to explore imaging techniques used in the first-trimester diagnosis of conjoined twins and provide a systematic diagnostic table for making this diagnosis. DESIGN: A PubMed literature search was performed using the terms ultrasound, Doppler, MRI, and CT combined with first-trimester and conjoined twins. Three recent cases at our department are reviewed and examined additionally using 3-dimensional virtual embryoscopy. RESULTS: The different types of conjoined twins are summarized in a table for practical use during ultrasound examination. In evaluating conjoined twins, 2-dimensional ultrasound is the criterion standard. Three-dimensional and Doppler ultrasounds add anatomical and prognostic information. Virtual embryoscopy imaging reveals additional findings in our 3 cases not seen with routine 2-dimensionalultrasound examination. CONCLUSIONS: Each case of conjoined twins is unique and should be evaluated with the best possible imaging techniques. Three-dimensional and Doppler ultrasound should be added to the systematic diagnostic evaluation of conjoined twins. Virtual embryoscopy imaging may contribute to earlier, more appropriate counseling and management of these pregnancies.

An immunological basis for chronic histiocytic intervillositis in recurrent fetal loss.

PROBLEM: Chronic histiocytic intervillositis (CHIV) is a rare type of placental pathology that is associated with reproductive loss at all gestational ages. The aim of the study was to investigate the relationship between the severity of CHIV and the outcome of pregnancy and to compare the immune response between CHIV patients and controls to explore an immunological origin of CHIV. METHOD OF STUDY: Microscopic slides were reviewed and scored according to a previously published grading system in 30 pregnancies of 22 CHIV patients. Partner-specific mixed lymphocyte reactions, cytotoxic T-lymphocyte precursor frequencies (CTLpf), and anti-HLA antibodies were determined in four patients and seven controls. RESULTS: Higher CHIV scores are associated with worse pregnancy outcome. CHIV patients demonstrated a higher CTLpf against their partner compared to non-complicated pregnancies (P = 0.03). The CTLpf was extremely high in 75% of the patients. Antipaternal HLA antibodies were only present in 75% of the CHIV patients compared to none of the controls (P = 0.02). CONCLUSION: CHIV scores seem to be associated with the severity of adverse pregnancy outcome. High antipaternal cellular (T-cell) and humoral (B-cell) response to partner-specific CTLpf and the presence of anti-HLA antibodies directed to the partner suggest an immunologic origin of CHIV.

Human embryonic growth trajectories and associations with fetal growth and birthweight.

STUDY QUESTION: How do human embryonic growth trajectories evolve in the first trimester, and is first-trimester embryonic growth associated with fetal growth and birthweight (BW)? SUMMARY ANSWER: Human embryonic growth rates increase between 9 and 10 weeks of gestation and are associated with mid-pregnancy fetal growth and BW. WHAT IS KNOWN ALREADY: Fetal growth is associated with health and disease risks in later life. Until recently, prenatal care and research have been focused predominantly on fetal growth in the second and third trimesters of pregnancy. Longitudinal first-trimester data remain scarce. STUDY DESIGN, SIZE, DURATION: We recruited 201 pregnancies before 8 weeks of gestation in a prospective periconception cohort study conducted in a tertiary center. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed weekly 3D ultrasound scans from enrollment up to 13 weeks of gestation. To create embryonic growth trajectories, serial crown-rump length (CRL) measurements were performed using the V-Scope software in the BARCO I-Space. Mid-pregnancy fetal growth parameters and BW were obtained from medical records. Z-scores were calculated for CRL, mid-pregnancy estimated fetal weight (EFW) and BW. Associations between embryonic and fetal growth parameters were investigated using Pearson's correlation coefficients. MAIN RESULTS AND THE ROLE OF CHANCE: During the early first trimester (up to 9 weeks of gestation), we observed a constant absolute mean embryonic CRL growth rate of 0.99 mm/day (SD 0.10), while the relative growth rate decreased. Between 9 and 10 weeks of gestation, the absolute growth rate increased, and during late first trimester (from 10 weeks of gestation onward), we observed a constant mean relative growth rate of 4.1% (SD 0.006) per day. Overall, early and late first-trimester median CRL Z-scores were strongly correlated with mid-pregnancy EFW (r overall/early/late = 0.57/0.57/0.54, P < 0.001) but only overall and late CRL Z-scores were correlated with BW (r overall = 0.15, P = 0.04; r early = 0.10, P = 0.17; r late = 0.17, P = 0.02). LIMITATIONS, REASONS FOR CAUTION: This study was conducted in a tertiary hospital. Therefore, future studies in other populations are warranted to confirm our results. WIDER IMPLICATIONS OF THE FINDINGS: This study shows differences between early and late first-trimester embryonic growth coinciding with changes in intrauterine nourishment. The established associations between first-trimester embryonic growth and fetal size in mid-pregnancy and at birth emphasize that more research is warranted to establish the importance of these results for preconceptional and early pregnancy care.

Chorionic villous vascularization related to phenotype and genotype in first trimester miscarriages in a recurrent pregnancy loss cohort.

STUDY QUESTION: Is there an association between chorionic villous vascularization, ultrasound findings and corresponding chromosome results in early miscarriage specimens from a cohort of recurrent pregnancy loss patients? SUMMARY ANSWER: We did not find a significant difference in vascularization scores of chorionic villi between embryonic, yolk sac or empty sac miscarriages, or between euploid and noneuploid miscarriages. WHAT IS KNOWN ALREADY: At least half of first trimester miscarriages are due to embryopathogenesis associated with chromosome errors and/or major congenital anomalies, resulting in an empty sac, a yolk sac or an embryonic miscarriage. Absent and decreased chorionic villous vascularization is usually present in these pregnancies. STUDY DESIGN, SIZE, DURATION: For this retrospective study, 60 hematoxylin and eosin slides of miscarriage tissue of less than 10 weeks gestational age were collected from an academic institution. All patients were seen in consultation between July 2004 and October 2009. PARTICIPANTS, SETTING, METHODS: Chorionic villous vascularization was determined using a previously published classification. The results were validated and compared with the ultrasound findings and corresponding chromosome results. MAIN RESULTS AND THE ROLE OF CHANCE: There were 53 embryonic miscarriages, 5 yolk sac miscarriages and 2 empty sac miscarriages. Chromosome results were obtained in 59 of the 60 miscarriages; 37.3% were euploid and 62.7% were noneuploid. Validation of the vascularization score between observers was reasonable to good (Kappa 0.47-0.76), and 59% of the cases were classified as avascular. The vascularization score did not differ between euploid or noneuploid miscarriages, or between embryonic, yolk sac or empty sac miscarriages. Avascular villi were seen more frequently in miscarriages trisomic for chromosome 16, when compared with miscarriages with other trisomies (6 out of 7 versus 8 out of 22, P = 0.04). LIMITATIONS, REASONS FOR CAUTION: Unfortunately, the number of samples in the study was limited. WIDER IMPLICATIONS OF THE FINDINGS: Avascular villi may indicate abnormal early placentation as a part of embryopathogenesis. Further study is warranted to determine whether a genetic cause can be found to explain these results.

First experiences with hysterosalpingo-foam sonography (HyFoSy) for office tubal patency testing.

BACKGROUND: This study was conducted to describe the first experiences with hysterosalpingo-foam sonography (HyFoSy) as a first step routine office procedure for tubal patency testing. METHODS: A prospective observational cohort study was started in a university affiliated teaching hospital. In 2010, 73 patients with subfertility and a low risk of tubal pathology were examined. A non-toxic foam containing hydroxymethylcellulose and glycerol was applicated through a cervical applicator for contrast sonography (HyFoSy). Tubal patency was determined by transvaginal ultrasonographic demonstration of echogenic dispersion of foam in the Fallopian tube and/or the peritoneal cavity. Only in case patency could not be demonstrated, a hysterosalpingography (HSG) was performed as a control. RESULTS: In 67 out of 73 (92%) patients, a successful procedure was performed. In 57 out of 73 (78%) cases, there was no further need for a HSG. In five patients (5/73; 7%) tubal occlusion was confirmed by HSG and in five patients (5/73; 7%) there was discordance between HyFoSy and HSG. Of 73 patients, 14 (19%) conceived within a median of 3 months after the procedure. CONCLUSIONS: HyFoSy is a successful procedure to demonstrate tubal patency as a first step office procedure.