Expert opinion on the use of transvaginal sonography for presurgical staging and classification of endometriosis.

Gynecological ultrasonography plays a central role in the management of endometriosis. The rapid technical development as well as the currently increasing evidence for non-invasive diagnostic methods require an updated compilation of recommendations for the use of ultrasound in the management of endometriosis. The present work aims to highlight the accuracy of sonography for diagnosing and classifying endometriosis and will formulate the present list of key messages and recommendations. This paper aims to demonstrate the accuracy of TVS in the diagnosis and classification of endometriosis and to discuss the clinical applications and consequences of TVS findings for indication, surgical planning and assessment of associated risk factors. (1) Sophisticated ultrasound is the primary imaging modality recommended for suspected endometriosis. The examination procedure should be performed according to the IDEA Consensus. (2) Surgical intervention to confirm the diagnosis alone is not recommended. A preoperative imaging procedure with TVS and/or MRI is strongly recommended. (3) Ultrasound examination does not allow the definitive exclusion of endometriosis. (4) The examination is primarily transvaginal and should always be combined with a speculum and a bimanual examination. (5) Additional transabdominal ultrasonography may enhance the accuracy of the examination in case of extra pelvic disease, extensive findings or limited transvaginal access. (6) Sonographic assessment of both kidneys is mandatory when deep endometriosis (DE) and endometrioma are suspected. (7) Endometriomas are well defined by sonographic criteria. When evaluating the ovaries, the use of IOTA criteria is recommended. (8) The description of sonographic findings of deep endometriosis should be systematically recorded and performed using IDEA terminology. (9) Adenomyosis uteri has sonographically well-defined criteria (MUSA) that allow for detection with high sensitivity and specificity. MRI is not superior to differentiated skilled ultrasonography. (10) Classification of the extent of findings should be done according to the #Enzian classification. The current data situation proves the best possible prediction of the intraoperative situs of endometriosis (exclusive peritoneum) for the non-invasive application of the #Enzian classification. (11) Transvaginal sonographic examination by an experienced examiner is not inferior to MRI diagnostics regarding sensitivity and specificity in the prediction of the extent of deep endometriosis. (12) The major advantage of non-invasive imaging and classification of endometriosis is the differentiated planning or possible avoidance of surgical interventions. The recommendations represent the opinion of experts in the field of non-invasive and invasive diagnostics as well as therapy of endometriosis. They were developed with the participation of the following national and international societies: DEGUM, ÖGUM, SGUM, SEF, AGEM/DGGG, and EEL.

Impact of preimplantation genetic testing for aneuploidies (PGT-A) on first trimester biochemical markers - PAPP-A (placenta-associated plasma protein) and free ß-hCG (human chorionic gonadotropin).

OBJECTIVE: The objective of the study was to study the effect of preimplantation genetic testing for aneuploidies (PGT-A) performed at blastocyst stage on the levels of first trimester biomarkers. METHODS: This is an observational, collaborative, retrospective study. Seven hundred and twenty-eight patients were included in the study. Patients were with singleton pregnancies resulting from either natural conception (NC), or assisted reproductive techniques (ARTs) with PGT-A and frozen embryo transfer (FET) (ART/PGT-A/FET) or after ART without PGT-A and fresh ET (ART/no PGT-A/fresh ET) or FET (ART/no PGT-A/FET), who had first trimester combined screening test between 11 and 14 gestational weeks. They were stratified into four groups: group A (ART/PGT-A/FET) - 143 patients; group B (ART/no PGT-A/FET) - 100 patients; group C (ART/no PGT-A/fresh ET) - 346 patients, and group D (NC) - 139 patients. RESULTS: Statistically significant differences among the examined groups were observed for maternal age, BMI, ethnicity, and parity. The median placenta-associated plasma protein (PAPP-A) was lowest in the group with ART/PGT-A/FET and the highest result was obtained in the group with ART/no PGT-A/FET. Statistically significant difference in the median PAPP-A levels was identified among the examined groups (p = .0186). When a subgroup analysis was performed, a statistically significant difference was observed in the median PAPP-A between ART/PGT-A/FET group versus ART/no PGT-A/FET group (p = .01) and NC versus ART/no PGT-A/FET (p = .01). A similar trend toward statistical significance was noted when comparing NC versus ART/no PGT-A/fresh ET (p = .06). Multivariate analysis elucidated that when age is present in the model, the effect of any method of conception or testing for aneuploidy disappears. The other factors (BMI, ethnicity, and parity) do not influence the levels of PAPP-A. The lowest median free human chorionic gonadotropin (ß-HCG) was recorded in the NC group and the highest result was identified in the group with IVF/PGT-A/FET. No statistically significant difference was observed in the median concentration levels of free ß-hCG among the compared groups (p = .5789) and when subgroup analysis was performed (p>.05). The normality of the distribution of variables was analyzed by the Kolmogorov-Smirnov test and the median PAPP-A and free ßhCG concentration difference by the Wilcoxon rank-sum test with nonparametric ANOVA. CONCLUSIONS: Testing for aneuploidy (PGT-A) and the decision to transfer either fresh or cryopreserved embryos (ET) appear not to affect the levels of first trimester biochemical markers. The findings of the present study should be a baseline for future studies and could be used to improve the antenatal screening counseling for women with ART pregnancies and PGT-A.

First-trimester risk assessment based on ultrasound and cell-free DNA vs combined screening: a randomized controlled trial.

OBJECTIVE: This was a randomized controlled trial to compare risk assessment by first-trimester combined screening (FTCS) with an approach that combines a detailed ultrasound examination at 11-13 weeks' gestation and cell-free DNA (cfDNA) analysis. METHODS: Pregnant women with a normal first-trimester ultrasound examination at 11-13 weeks' gestation (fetal nuchal translucency (NT) ≤ 3.5 mm and no fetal defects) were randomized into one of two groups. In the first group, risk of aneuploidy was assessed using FTCS based on the most recent UK Fetal Medicine Foundation algorithm. In the second group, risk assessment was based on ultrasound findings and cfDNA analysis. An additional tube of blood was collected for FTCS in case the cfDNA analysis was uninformative. Primary outcome was false-positive rate in screening for trisomy 21. A case was considered false positive if the karyotype was not trisomy 21 and if the risk for trisomy 21 was >1:100, irrespective of the method of risk calculation. Results were compared using 95% CIs using the Clopper-Pearson method. RESULTS: Between October 2015 and December 2016, 1518 women with singleton pregnancy underwent first-trimester screening. Thirty-one (2.0%) pregnancies were not eligible for randomization due to increased NT (> 3.5 mm) and/or fetal defect. After exclusion of women who declined randomization (n = 87) and cases of fetal death and loss to follow-up (n = 24), 688 pregnancies were randomized into the FTCS arm and 688 into the ultrasound + cfDNA analysis arm. There were no differences in maternal and gestational age, maternal weight and BMI, ethnicity, use of assisted reproduction and cigarette smoking between the two arms. In the ultrasound + cfDNA analysis arm, median risk for trisomy 21 was 1 in 10 000. None of the cases had a risk above 1: 100 (95% CI, 0.0-0.5%). In the FTCS arm, the median risk for trisomy 21 was 1 in 3787 and in 17 cases, the risk was higher than 1:100, which corresponds to 2.5% (95% CI, 1.5-3.9%) of the FTCS study-arm population. CONCLUSION: Our study has shown that first-trimester risk assessment for trisomy 21 that includes a detailed ultrasound examination as well as NT measurement and is followed by cfDNA testing is associated with a significant reduction in the false-positive rate compared with FTCS. This approach obviates the need for maternal serum free ß-human chorionic gonadotropin and pregnancy-associated plasma protein-A in screening for fetal aneuploidy. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Bronchopulmonary sequestration with massive pleural effusion: pleuroamniotic shunting vs intrafetal vascular laser ablation.

OBJECTIVE: To assess the incidence of complications among a relatively large cohort of fetuses with bronchopulmonary sequestration (BPS) and the success of two different intrauterine treatment modalities. METHODS: All cases with a prenatal diagnosis of BPS detected in a 10-year period (2002-2011) in two tertiary referral centers were reviewed retrospectively for intrauterine course and outcome. Up to May 2010 severe pleural effusions were treated with pleuroamniotic shunting. Thereafter, they were treated with ultrasound-guided laser coagulation of the feeding artery. RESULTS: A total of 41 fetuses with BPS were included in the study. In 29 (70.7%) there was no pleural effusion or hydrops and they were treated conservatively. In 19/29 (65.5%) there was partial or complete regression of the lesion during the course of pregnancy. All were born alive (median age at delivery, 38.3 (interquartile range (IQR), 34.0-39.6) weeks) and 16 (55.2%) required sequestrectomy. Intrauterine intervention was performed in all 12 (29.3%) fetuses with pleural effusion. Seven fetuses were treated with pleuroamniotic shunting. One fetus with severe hydrops died in utero. There was no complete regression in any case of BPS in this group. Six infants were born alive (median age, 37.2 (IQR, 30.3-37.4) weeks), of which five (83.3%) required sequestrectomy. Five fetuses were treated with laser ablation of the feeding vessel. In all cases of BPS there was regression after laser ablation. All infants were delivered at term (median age, 39.1 (IQR, 38.0-40.0) weeks). One (20.0%) neonate required sequestrectomy after birth. Following intrauterine shunt placement complete regression of the lesion was significantly less frequent (0/7 (0%) with shunt placement vs 4/5 (80%) with intrafetal laser treatment) and gestational age at birth was significantly lower, compared to treatment with intrafetal laser. Complete regression of the lesion was also significantly more frequent in the laser group compared to cases without intervention. CONCLUSION: In the absence of pleural effusion, the likelihood of spontaneous regression of BPS is high and the prognosis is therefore favorable. In cases with massive pleural effusion, treatment by laser ablation of the feeding vessel seems to be more effective than is pleuroamniotic shunting, with fewer complications. It might also reduce the need for postnatal surgery.

[Active surveillance of small-scale spatial cancer clusters: presentation of a new monitoring approach for the epidemiological Cancer Registry of Lower Saxony]. / Aktives Monitoring kleinräumiger Krebshäufungen : Vorstellung eines neuen Monitoringkonzeptes für das Epidemiologische Krebsregister Niedersachsen.

BACKGROUND: Cancer registries often receive inquiries on possible cancer clusters. In 2010, the Cancer Registry of Lower Saxony reported on a spatial leukemia accumulation in the community of Asse. As a result, the Cancer Registry was engaged in developing an approach for a regional cancer monitoring program by the federal government. The modular approach involves a two-stage process. First, all regional monitoring areas are under surveillance, and in the second phase, noticeable areas only are observed further. A positive confirmation test is regarded as an initial concern and may lead to further investigations. METHODS: The standardized incidence ratio (SIR) is used in the first stage. For confirmation, the Sequential Probability Ratio Test (SPRT) is applied in the second stage. All new observations are tested at a given time. The SPRT tests the null hypothesis (no increase) and an alternative hypothesis (increase) leading to three possible conclusions: warning, all-clear, or further surveillance necessary. RESULTS: A high false alarm rate due to clustering by chance is to be considered with multiple statistical testing. The number of false alarms depends on the number of tested areas, diagnoses, subgroup analyses, and time periods. Preliminary considerations comprise 400 spatial areas, three diagnosis groups, no subgroup analyses, and a biannual first-stage testing. Guidelines for the level of significance and for detecting an increase in incidence will be necessary for the assessment of the monitoring parameters. DISCUSSION: Before running the monitoring program, a number of questions have to handled politically; e.g., how many false alarms can be handled, the impact on the population involved, and existing risk communication structures.

First-trimester combined screening for trisomy 21 with different combinations of placental growth factor, free ß-human chorionic gonadotropin and pregnancy-associated plasma protein-A.

OBJECTIVE: To examine placental growth factor (PlGF) in euploid and trisomy 21 pregnancies at 11-13 weeks' gestation and to model the impact on first-trimester combined screening. METHODS: PlGF was measured in 509 (409 euploid and 100 trisomic) fetal serum samples derived from prospective first-trimester combined screening for trisomy 21 at 11-13 weeks' gestation. The serum samples were stored at -80°C, following the measurement of free ß-human chorionic gonadotropin (ß-hCG) and pregnancy-associated plasma protein-A (PAPP-A) levels, for median time spans of 0.9 and 4.1 years in the euploid and trisomy 21 pregnancies, respectively. The effect of additional PlGF measurement at the time of combined screening was investigated by simulating fetal nuchal translucency (NT) measurements and multiples of the median (MoM) values for PAPP-A, free ß-hCG and PlGF for 20,000 euploid and 20,000 trisomy 21 pregnancies. Patient-specific combined risks were calculated based on maternal age and fetal NT in addition to free ß-hCG, PAPP-A and PlGF, PAPP-A and PlGF or free ß-hCG and PlGF, and detection and false-positive rates were calculated. RESULTS: Median PlGF-MoM was 1.0 (95% confidence interval (CI), 0.96-1.04) in euploid fetuses and significantly lower, at 0.73 (95% CI, 0.70-0.76), in trisomy-21 fetuses (P < 0.0001). There was no significant dependency between PlGF-MoM and either gestational age at the time of blood sampling (r = 0.087, P = 0.392) or sample storage time (r = 0.028, P = 0.785). Modeled detection and false-positive rates for first-trimester combined screening (based on maternal and gestational age, fetal NT and maternal serum biochemistry) without PlGF were 85% and 2.7% for a fixed risk cut-off of 1:100. The addition of PlGF increased the detection rate to 87% and reduced the false-positive rate to 2.6%. Screening by maternal age and fetal NT in combination with PlGF and PAPP-A or in combination with PlGF and free ß-hCG provided detection rates of 82% and 79%, with false-positive rates of 2.7% and 3.0%, respectively. CONCLUSION: In pregnancies with trisomy 21 PlGF is reduced. The impact on the overall screening performance for trisomy 21 is low and does not justify the measurement of PlGF solely for trisomy 21 screening. However, as PlGF is measured with the aim of assessing the risk for pre-eclampsia, further improvement in screening for trisomy 21 can be considered as an added benefit.

Impact of bias in crown-rump length measurement at first-trimester screening for trisomy 21.

OBJECTIVE: To assess the repeatability of crown-rump length (CRL) measurement and examine the effect of its over- and underestimation on first-trimester combined screening. METHODS: Intra- and interoperator repeatability of CRL measurement at 11-13 weeks of gestation was assessed in 124 cases by two operators. Raw data were transformed into gestational age and intra- and interoperator repeatability was evaluated by within-operator standard deviation (SD) and the SD of differences in measurements between both operators. Modeling techniques were used to assess the impact of CRL measurement error on general population screening and on the operator-specific screening performance. The impact of errors in CRL measurement were investigated by simulating fetal nuchal translucency (NT) measurements and multiple of the median (MoM) values for pregnancy-associated plasma protein A (PAPP-A) and free ß-human chorionic gonadotropin (ß-hCG) for 500 000 euploid and 500 000 trisomy 21 pregnancies at 12 weeks and 9 weeks of gestation, and adding to or subtracting from each CRL value up to 10 mm and recalculating patient-specific risks. RESULTS: Within-operator SD of the CRL measurement was 1.27 days of gestation. The SD of the differences in CRL measurement between operators was 1.37 days of gestation. Both intra- and interoperator 95% limits of agreement were around ± 5 mm. In general population-based screening, a CRL measurement error SD of 5 mm accounts for an estimated 5% of the SD of log MoM PAPP-A and less than 1% of the SD of log MoM free ß-hCG. Modeling the effect of removing this measurement error on overall screening performance showed a minimal impact. For a risk cut-off of 1 in 100, the benefit in terms of overall screening performance would be an increase in detection rate of about 1% and a reduction in false-positive rate of less than 0.1%. With regard to the operator-specific screening performance, a consistent 5-mm underestimation of CRL reduces the detection rate from 84% to 79% and the false-positive rate from 2.4% to 1.2%. With a consistent 5-mm overestimation the rates would be 88% and 5.6%, respectively. CONCLUSION: The impact of the interoperator variability in CRL measurement on patient-specific risk needs to be taken into account when interpreting first-trimester screening results. A systematic under- or overestimation of CRL should be avoided.

[First-trimester screening for trisomies 18 and 13 with the combined use of the risk algorithms for trisomy 21, 18 and 13]. / Screening auf Trisomie 18 und Trisomie 13 durch das kombinierte Anwenden der Risiko-Algorithmen für Trisomie 21, 18 und 13.

PURPOSE: Assessment of first-trimester combined screening for trisomy 18 and 13 with the combined use of the risk algorithms for trisomy 21, 18 and 13. MATERIALS AND METHODS: First-trimester combined screening based on maternal and gestational age, fetal NT, PAPP-A and free ß-hCG was assessed in 39 ,004 pregnancies. Patient-specific risks for trisomy 21, 18, 13 were computed based on the current FMF London algorithm. RESULTS: The study population consisted of 38 ,751 singleton pregnancies including 39 cases with trisomy 18 or 13. In the aneuploid group, median delta NT was 0.72 mm, PAPP-A was 0.21 MoM and free ß-hCG was 0.33 MoM. Although only 41 % of the NT measurements of fetuses with trisomy 18 or 13 were above the 95th percentile, the detection rates for trisomy 18 or 13 were 82 % with the trisomy 18/13 algorithm and 56.4 % with the trisomy 21 algorithm. The respective false-positive rates were 0.7 % and 4.7 %. The combination of the trisomy 18/13 and the trisomy 21 algorithm with the same cut-offs led to a detection rate of 94.9 % at an overall false-positive rate of 5.0 %. CONCLUSION: Despite a substantial underestimation of the fetal NT, the combined use of the trisomy 18/13 and the trisomy 21 algorithm of the FMF London leads to a detection rate for trisomy 18/13 of about 95 % for a false-positive rate of 5.0 %.

Impact of the maternal age-related risk in first-trimester combined screening for trisomy 21.

OBJECTIVE: To examine the impact of the maternal age-related risk in first-trimester combined screening for trisomy 21. METHODS: Prospective assessment of risk for trisomy 21 by a combination of maternal age, fetal NT thickness and maternal serum PAPP-A and free ß-hCG at 11+0 to 13+6 weeks of gestation between April 2002 and February 2007. Screening for trisomy 21 by patient-specific risks based on the maternal and gestational age-related risk multiplied by a likelihood ratio for NT and for maternal serum biochemistry were compared with a screening policy that is only based on the combined likelihood ratio for fetal NT and maternal serum biochemistry. RESULTS: The study population consisted of 38,603 euploid pregnancies and 109 fetuses with trisomy 21. In screening for trisomy 21 by fetal NT and maternal serum biochemistry in combination with and without maternal age with a fixed false-positive rate of 3%, the detection rate was 82.6 and 79.8%, respectively. In the group of women with a maternal age of less than 30 years and between 30 and 35 years, there was no difference in the detection rate. For women with a maternal age of 35 years or older, the detection rate increased from 77.1% without maternal age to 94.3% with maternal age, respectively. CONCLUSION: The overall difference between first-trimester screening based on fetal NT and maternal serum biochemistry with and without maternal age is about 3%. In screening with a fixed cut-off, the maternal age-related risk keeps the false-positive rate low in younger women and increases the detection rate in older women.

[Cross-validation of the first trimester screening algorithm of the FMF London on 38,700 pregnancies in Germany]. / Cross-Validierung des Screening-Algorithmus der FMF London an 38,700 Ersttrimester-Untersuchungen in Deutschland.

PURPOSE: Validation of the performance of the new algorithm of the FMF London for screening for trisomy 21 using a combination of maternal age, fetal nuchal translucency (NT) and maternal serum free ß-hCG and PAPP-A. MATERIALS AND METHODS: Between 2002 and 2007, NT was measured prospectively in 39,004 pregnancies in the context of routinely performed first trimester screening in Germany. Individual trisomy 21 risks were calculated by a combination of NT, maternal age, free ß-hCG, and PAPP-A using the FMF algorithm in force at the time of investigation. In this study we recalculated the trisomy 21 risks applying the new algorithm of the FMF UK that includes the new mixture model for the NT measurement. RESULTS: 38,751 singleton pregnancies could be included in the study of which 109 (0.3 %) had a trisomy 21. Only 35 % of the NT measurements of euploids were above the median and 25 % of the NT measurements were below the 5th percentile of the FMF UK. For sonographers that were qualified according to level II or III of the German DEGUM system, the median NT of fetuses with trisomy 21 was 0.9 mm above the median of the FMF UK and only 0.5 mm above the median for all other sonographers. Despite the limited performance of the NT measurement, the overall detection rate for a trisomy 21 was 90.8 % when combining the NT with maternal age, PAPP-A and free ß-hCG. The overall false-positive rate for a trisomy 21 was 6.5 % at a cut-off value of 1:300. CONCLUSION: In this study we were able to show that the use of the new risk algorithm of the FMF UK leads to a trisomy 21 detection rate of about 90 % at a 5 % false-positive rate in a German collective despite a significant underestimation of the NT.