Background In recent years it has become clear that fetal anomalies can already be detected at the end of the first trimester of pregnancy by two-dimensional (2D) ultrasound. This is why increasingly in developed countries the first trimester anomaly scan is being offered as part of standard care. We have developed a Virtual Reality (VR) approach to improve the diagnostic abilities of 2D ultrasound. Three-dimensional (3D) ultrasound datasets are used in VR assessment, enabling real depth perception and unique interaction. The aim of this study is to investigate whether first trimester 3D VR ultrasound is of additional value in terms of diagnostic accuracy for the detection of fetal anomalies. Health-related quality of life, cost-effectiveness and also the perspective of both patient and ultrasonographer on the 3D VR modality will be studied. Methods Women in the first trimester of a high risk pregnancy for a fetus with a congenital anomaly are eligible for inclusion. This is a randomized controlled trial with two intervention arms. The control group receives ‘care as usual’: a second trimester 2D advanced ultrasound examination. The intervention group will undergo an additional first trimester 2D and 3D VR ultrasound examination. Following each examination participants will fill in validated questionnaires evaluating their quality of life and healthcare related expenses. Participants’ and ultrasonographers’ perspectives on the 3D VR ultrasound will be surveyed. The primary outcome will be the detection of fetal anomalies. The additional first trimester 3D VR ultrasound examination will be compared to ‘care as usual’. Neonatal or histopathological examinations are considered the gold standard for the detection of congenital anomalies. To reach statistical significance and 80% power with a detection rate of 65% for second trimester ultrasound examination and 70% for the combined detection of first trimester 3D VR and second trimester ultrasound examination, a sample size of 2800 participants is needed. Discussion First trimester 3D VR detection of fetal anomalies may improve patients’ quality of life through reassurance or earlier identification of malformations. Results of this study will provide policymakers and healthcare professionals with the highest level of evidence for cost-effectiveness of first trimester ultrasound using a 3D VR approach. Trial registration Dutch Trial Registration number NTR6309, date of registration 26 January 2017.

SUMMARYVesicovaginal fistulas are a rare complication of hysterectomy. When conservative therapy fails, vaginal or abdominal repair is necessary. A robotic-assisted laparoscopic approach can be a useful tool to repair complex fistulas. A 50-year-old woman with a vesicovaginal fistula located at the top of the vagina, was treated with robotic-assisted laparoscopic repair. The fistula tissue was removed from the vaginal wall and bladder, and epiploic of the sigmoid was interposed in between. The total operation time was 104 min. The hospital stay was 3 days; no complications occurred. Cystography 6 weeks and 6 months postoperative confirmed a successful repair. A review of current literature is presented regarding the application of robotic assistance during this procedure. The presented case shows that robotic-assisted laparoscopic repair of a vesicovaginal fistula seems to be a feasible technique with promising results. BACKGROUND

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.

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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.