Complication rate after termination of pregnancy for fetal defects.

OBJECTIVES: To assess the risk of complications in women undergoing termination of pregnancy (TOP) for fetal defects and to examine the impact of gestational age on the complication rate. METHODS: This was a retrospective study of women with a singleton pregnancy undergoing TOP at the University Hospital of Tübingen, Germany, between 2018 and 2021. TOP was performed by experienced operators according to the national protocol; dilatation and curettage (D&C) or evacuation (D&E) was used in the first and early second trimesters and induction was used later in pregnancy. The following were considered to be significant procedure-related complications: blood loss of more than 500 mL, uterine perforation, need for blood transfusion, allergic reaction, creation of a false passage (via falsa), systemic infection, readmission to hospital, any unplanned surgical procedure, such as repeat D&C/D&E or hysterectomy, and maternal death. RESULTS: The search of the hospital database identified 416 pregnancies that met the study criteria. Median maternal and gestational age at termination were 34.1 years and 17.4 weeks, respectively. In the first, second and third trimesters, respectively, 84 (20.2%), 278 (66.8%) and 54 (13.0%) pregnancies were terminated, for which D&C or D&E was used in 80 (95.2%), 21 (7.6%) and 0 (0.0%) cases. Seventy-seven (18.5%) women had at least one previous Cesarean section and 169 (40.6%) had at least one previous spontaneous delivery. Overall, 95 (22.8%) women had complications during or after TOP. A significantly higher complication rate was noted for terminations performed later in pregnancy. The median gestational age at termination was 16.6 weeks in women who did not experience complications and 20.7 weeks in those with complications (P < 0.001). The respective complication rates in the first, second and third trimesters were 6.0%, 27.0% and 27.8%. CONCLUSION: In women undergoing TOP for fetal defects, the risk of complications increases with advancing gestational age. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

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.

Outcome of pregnancies with recent primary cytomegalovirus infection in first trimester treated with hyperimmunoglobulin: observational study.

OBJECTIVE: To examine the efficacy of hyperimmunoglobulin (HIG) treatment in women with a recent primary cytomegalovirus (CMV) infection up to 14 weeks' gestation. METHODS: This is an ongoing observational study conducted at the prenatal medicine departments of the University Hospitals of Tübingen, Bonn, Cologne and Erlangen, Germany, as well as at the Laboratory Prof. Gisela Enders and Colleagues in Stuttgart, Germany and the Institute for Medical Virology at the University of Tübingen, Tübingen, Germany. Enrolment criteria were the presence of confirmed recent primary CMV infection in the first trimester and a gestational age at first HIG administration of ≤ 14 weeks. The following inclusion criteria indicated a recent primary infection: low anti-immunoglobulin (Ig)-G levels, low anti-CMV-IgG avidity in the presence of a positive CMV-IgM test and no positive reactivity or just seroconversion anti-gB2-IgG-reactivity. HIG administration was started as soon as possible within a few days after the first visit. HIG was administered intravenously at a dose of 200 IU/kg maternal body weight and repeated every 2 weeks until about 18 weeks' gestation. The primary outcome was maternal-fetal transmission at the time of amniocentesis. Multivariate logistic regression analysis was used to determine significant covariates that could predict maternal-fetal transmission. RESULTS: We included 149 pregnancies (153 fetuses) that completed the treatment. Median maternal age and weight were 32.0 years and 65.0 kg, respectively. Median gestational age at the time of first referral to one of the four centers was 9.4 weeks. Median anti-CMV-IgG level, anti-CMV-IgM index and CMV-IgG avidity were 5.7 U/mL, 2.5 and 22.3%, respectively. HIG treatment was started at a median gestational age of 10.6 weeks and ended at a median of 17.9 weeks. Within this time frame, HIG was administered on average four times in each patient. Amniocentesis was carried out at a median gestational age of 20.4 weeks. In 143 (93.5%) of the 153 cases, the fetus was not infected. Maternal-fetal transmission occurred in 10 cases (6.5% (95% CI, 3.2-11.7%)). On uni- and multivariate logistic regression analysis, the level of anti-IgM index was the only factor associated significantly with maternal-fetal transmission at amniocentesis. However, only four (40.0%) of the 10 cases with maternal-fetal transmission had an anti-IgM index above 11.4, which corresponds to the 95th centile of pregnancies without transmission. CONCLUSIONS: HIG is a treatment option to prevent maternal-fetal transmission in pregnancy with a primary CMV infection. However, HIG treatment seems to be beneficial primarily in women with a recent primary infection in the first trimester or during the periconceptional period, and when it is administered at a biweekly dose of 200 IU/kg. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Single and repeat cervical-length measurement in twin gestation with threatened preterm labor.

OBJECTIVE: To examine the effectiveness of single and repeat sonographic cervical-length (CL) measurement in predicting preterm delivery in symptomatic women with a twin pregnancy. METHODS: This was a retrospective study of women with a twin gestation who presented with painful and regular uterine contractions at 24 + 0 to 33 + 6 weeks' gestation at the perinatal unit of the University Hospital of Tübingen, Tübingen, Germany between 2012 and 2018. CL was measured on transvaginal ultrasound at the time of admission and a few days later after cessation of contractions. Treatment included administration of tocolytics (usually oral nifedipine), for no more than 48 h, and administration of steroids if CL was ≤ 25 mm. Patients were clustered into five groups according to the CL measurement obtained at first assessment: < 10.0 mm; between 10.0 and 14.9 mm; between 15.0 and 19.9 mm; between 20.0 and 24.9 mm; and ≥ 25.0 mm. For each group, we calculated the test performance of CL measurement for prediction of preterm delivery within the subsequent 7 days and before 34 weeks' gestation. Regression analysis was used to evaluate the test performance of the second CL measurement for predicting preterm delivery within 7 days after the second assessment. RESULTS: The study population consisted of 257 twin pregnancies, of which 80.2% were dichorionic diamniotic. Median maternal and gestational ages at the time of admission were 32.0 years and 29.9 weeks' gestation, respectively. Preterm birth within 7 days of admission occurred in 23 (8.9%) pregnancies, and 82 (31.9%) patients delivered prior to 34 weeks' gestation. Median CL for the entire study population was 17.0 mm. Delivery within 7 days after the first assessment occurred in 29.0%, 10.6%, 4.2%, 6.3% and 0% of women with CL < 10.0 mm, 10.0-14.9 mm, 15.0-19.9 mm, 20.0-24.9 mm and ≥ 25.0 mm, respectively. There was a weak, but significant, association between the CL measurement at the time of admission and the time interval between admission and delivery (interval = 27.9 + 0.58 × CL; P = 0.003, r = 0.184). CL was measured again after a median time interval of 3 (interquartile range (IQR), 2-5) days in 248 cases. Median second CL measurement was 17.0 (IQR, 11.5-22.0) mm. Delivery occurred within the subsequent 7 days after the second measurement in 25/248 (10.1%) cases. Binary regression analysis indicated that the first (odds ratio (OR), 0.895; P = 0.003) and second (OR, 0.908; P = 0.002) CL measurements, but not the difference between the two measurements (OR, 0.961; P = 0.361), were associated significantly with delivery within 7 days after the second measurement. Receiver-operating-characteristics (ROC)-curve analysis for the prediction of delivery within 7 days after the second assessment did not show a significant difference between the predictive performance of the first (area under ROC curve (AUC), 0.676 (95% CI, 0.559-0.793)) and the second (AUC, 0.661 (95% CI, 0.531-0.790)) measurement. CONCLUSION: Sonographic measurement of CL can be helpful in predicting preterm delivery within 7 days of presentation in symptomatic women with a twin gestation; however, the test performance is relatively weak. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

First-trimester ductus venosus velocity ratio as a marker of major cardiac defects.

OBJECTIVES: To examine ductus venosus (DV) flow in fetuses with and those without a cardiac defect and to evaluate different phases of DV flow in addition to the standard assessment of DV pulsatility index for veins (PIV) and the a-wave. METHODS: This was a retrospective study of singleton pregnancies that underwent first-trimester ultrasound screening, which included DV flow assessment, at the University of Tübingen (between 2010 and 2017) or the University of Cologne (between 2013 and 2016). The study population comprised normal fetuses and fetuses with major cardiac defects at a ratio of 10:1. For each fetus, the following parameters of the DV waveform were evaluated: qualitative assessment of the a-wave, PIV measurement and ratios of flow velocities during the S-wave (S) or D-wave (D) and the a-wave (a) or v-wave (v). Reproducibility of DV-PIV and DV flow ratios was evaluated in 30 fetuses in which the DV flow was assessed twice. RESULTS: Our study population included 480 anatomically normal fetuses and 48 with a cardiac defect. Median fetal nuchal translucency (NT) in the normal and in the affected group was 1.9 mm and 2.6 mm, respectively. In five (1.0%) of the normal and 18 (37.5%) of the affected cases, fetal NT thickness was above the 99th centile. In the normal group, the DV a-wave was reversed in 15 (3.1%) cases and the DV-PIV was above the 95th centile in 25 (5.2%). In the cases with cardiac defects, the a-wave was reversed and the DV-PIV measurement was above the 95th centile in 26 (54.2%). The reproducibility of measurement of the ratios of DV flow velocities was similar to that of the DV-PIV. Most cardiac defects were associated with an abnormal a/S or a/D ratio. If the cut-off for these two ratios was set at the 5th centile of the normal distribution, the detection rate of fetal cardiac anomalies would be 62.5%. This compares favorably with the DV-PIV, which detects 26 (54.2%) of the affected fetuses for the same threshold. CONCLUSION: In the first trimester, the a/S ratio has the potential to detect approximately 60% of congenital cardiac defects for a false-positive rate of 5%. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Prevention of maternal-fetal transmission of cytomegalovirus after primary maternal infection in the first trimester by biweekly hyperimmunoglobulin administration.

OBJECTIVE: To examine the efficacy of biweekly hyperimmunoglobulin (HIG) administration to prevent maternal-fetal transmission of cytomegalovirus (CMV) in women with primary first-trimester CMV infection. METHODS: This was a prospective observational study of women with confirmed primary CMV infection in the first trimester who had the first HIG administration at or before 14 weeks' gestation. All women had biweekly HIG treatment until 20 weeks' gestation at a dose of 200 IU/kg of maternal body weight. Each subject underwent amniocentesis at least 6 weeks after first presentation at about 20 weeks. Primary outcome was maternal-fetal transmission at the time of amniocentesis, and secondary outcome was the frequency of congenital CMV infection at birth. The results were compared with a historic cohort of women with first-trimester CMV infection who did not undergo HIG treatment and who had amniocentesis at about 20 weeks. RESULTS: Subjects were 40 pregnant women with a primary CMV infection, with a median gestational age at first presentation of 9.6 (range, 5.1-14.3) weeks. On average, HIG administration started at 11.1 weeks and continued until 16.6 weeks. Within this interval, HIG was administered between two and six times in each patient. While CMV immunoglobulin-G (IgG) monitoring showed periodic fluctuations during biweekly HIG administration cycles, high CMV-IgG avidity indices remained stable over the whole treatment period. Maternal-fetal transmission before amniocentesis occurred in only one of the 40 cases (2.5% (95% CI, 0-13.2%)). At delivery, two additional subjects were found to have had late-gestation transmission. Considering all three cases with maternal-fetal transmission, the transmission rate was 7.5% (95% CI, 1.6-20.4%) in our 40 cases. All infected neonates were asymptomatic at birth. The matched historical control group consisted of 108 pregnancies. Thirty-eight transmissions (35.2% (95% CI, 26.2-45.0%)) occurred in the control group, which was significantly higher (P < 0.0001) than the transmission rate in the HIG treatment group. CONCLUSION: After a primary maternal CMV infection in the first trimester, biweekly HIG administration at a dose of 200 IU/kg prevents maternal-fetal transmission up to 20 weeks' gestation. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

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.

Sphenofrontal distance in euploid and aneuploid fetuses.

OBJECTIVE: To examine the sphenofrontal distance (SFD) in a large series of aneuploid fetuses in the second and third trimesters and compare findings with those of a euploid population. METHODS: The database at our unit was searched to identify pregnancies with a diagnosis of trisomy 21, 18 or 13, triploidy or Turner syndrome after 15 weeks' gestation. Stored ultrasound images obtained between 19 and 22 weeks were reviewed. For the normal population, two euploid fetuses matched for gestational age were selected randomly for each aneuploid case. The SFD was measured from the anterior edge of the sphenoid bone to the lowest posterior edge of the frontal bone using on-screen calipers. The SFD measurement was parallel to the long axis of the maxilla. If the sphenoid bone did not extend superiorly enough for direct measurement of the SFD, a tangential line was drawn at the anterior wall of the sphenoid bone and extended cranially. In these cases, the distance between the extended line and the frontal bone was measured. One operator measured the SFD twice and was blinded to the results and karyotype. RESULTS: The study population consisted of 591 pregnancies: 394 euploid fetuses, 122 fetuses with trisomy 21, 45 with trisomy 18, 16 with trisomy 13, eight with Turner syndrome and six with triploidy. For both euploid and aneuploid groups, mean gestational age at examination was 22.8 (range: euploid, 15.0-40.7; aneuploid, 15.0-40.3) weeks. For euploid fetuses, mean SFD was 1.27 cm and measurements ranged from 0.53 cm to 2.56 cm. SFD was significantly dependent on gestational age (SFD = 0.138 + 0.005 × gestational age, P < 0.001, r = 0.802). Mean SFD was significantly smaller in each aneuploid group compared with the euploid population (trisomies 21, 18 and 13: all P < 0.001; triploidy: P = 0.026; Turner syndrome: P = 0.047). For 32 (26.2%), nine (20.0%) and six (37.5%) fetuses with trisomy 21, 18 and 13, respectively, SFD was < 5th percentile. Only one (12.5%) fetus with Turner syndrome and none with triploidy had SFD < 5th percentile. CONCLUSION: In aneuploid fetuses, the SFD is smaller than in their euploid counterparts. However, for a false-positive rate of 5%, the detection rate of trisomy 21 is only 26%. Therefore, using the method we have proposed, it is unlikely that this marker will play a major role in second- and third-trimester screening for aneuploidy. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

First-trimester screening for trisomies 18 and 13, triploidy and Turner syndrome by detailed early anomaly scan.

OBJECTIVE: To examine the performance of first-trimester ultrasound screening for trisomies 18 and 13, triploidy and Turner syndrome based on fetal nuchal translucency thickness (NT), additional fetal ultrasound markers including anatomy of the nasal bone (NB), blood flow across the tricuspid valve (TV) and through the ductus venosus (DV) and a detailed fetal anomaly scan at 11-13 weeks' gestation. METHODS: This was a retrospective case-matched study involving pregnant women at 11-13 weeks' gestation. The study population consisted of fetuses with trisomy 18, trisomy 13, triploidy or Turner syndrome. For each fetus with an abnormal karyotype, 50 randomly selected euploid fetuses were added to the study population. In all cases, the crown-rump length and NT were measured. In addition NB, TV flow and DV flow were examined. The summed risk for trisomies 21, 18 and 13 was computed based on: first, maternal age (MA); second, MA and fetal NT; third, MA, NT and one of the markers NB, TV flow or DV flow; fourth, MA, NT and all these markers combined; fifth, MA, NT and fetal anomalies; and, finally, MA, NT, all markers and fetal anomalies. RESULTS: The study population consisted of 4550 euploid and 91 aneuploid fetuses. Median NT was 1.8 mm in euploid fetuses and 4.8, 6.8, 1.8 and 10.0 mm in fetuses with trisomy 18, trisomy 13, triploidy and Turner syndrome, respectively. The NB, TV flow and DV flow were abnormal in 48 (1.1%), 34 (0.7%) and 99 (2.2%) euploid fetuses, respectively, and in 42 (46.2%), 31 (34.1%) and 62 (68.1%) aneuploid fetuses, respectively. At least one defect was found in 60 (1.3%) euploid and in 76 (83.5%) aneuploid fetuses. For a false-positive rate of 3%, the detection rate for screening based on MA and fetal NT was 75.8%. It increased to 84.6-86.8% when including one of the additional ultrasound markers and it was 90.1% when all three markers were included. When screening was based on MA, fetal NT and a detailed anomaly scan, the detection rate was 94.5% and increased to 95.6% with the addition of NB, TV flow and DV flow. CONCLUSION: A detailed anomaly scan at 11-13 weeks' gestation can identify about 95% of fetuses with trisomy 18, trisomy 13, triploidy and Turner syndrome. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Frontal space distance in facial clefts and retrognathia at 11-13 weeks' gestation.

OBJECTIVE: To examine the frontal space (FS) distance in first-trimester fetuses with bilateral, unilateral or median cleft lip and palate and in those with retrognathia. METHODS: This was a retrospective study using stored two-dimensional ultrasound images of fetal profiles that were recorded at the time of the nuchal translucency (NT) scan at three prenatal medical centers. Images of 300 normal fetuses and 53 fetuses with facial defects were obtained. To measure the FS distance, a line was drawn between the anterior edge of the mental protuberance of the mandible and anterior edge of the maxilla (MM line) and extended upwards in front of the forehead. The perpendicular distance (FS distance) between the MM line and the skin at the point of largest excursion of the fetal forehead was measured. In cases in which the MM line was located anteriorly to the forehead, the distance was measured in the same fashion but was multiplied by -1. Two operators measured the FS distance twice, independently of each other. FS distances were transformed into Z-scores based on the linear relationship with crown-rump length (CRL) in normal fetuses. The distribution of FS distances in fetuses with bilateral, unilateral or median cleft lip and palate and those with retrognathia were compared with that in the normal group using Student's t-test. RESULTS: A search of the centers' databases identified 53 abnormal cases including 20, nine and eight with a bilateral, unilateral and median cleft lip and palate, respectively, and 16 cases of retrognathia. In fetuses with bilateral, unilateral and median clefts and those with retrognathia, median delta NT was 1.00 mm, 0.37 mm, 4.00 mm and 0.26 mm, respectively. Among these affected groups, 12 (60.0%), six (66.7%), two (25.0%) and eight (50.0%) fetuses had an abnormal karyotype. In the normal population, FS distance was dependent on CRL measurement (FS = 6.62 - (0.08 × CRL); r = -0.539; P < 0.0001). In fetuses with a bilateral and median cleft and in those with retrognathia, FS distance was significantly different from that in the normal population (all P < 0.0001), however, the difference was not significant in fetuses with unilateral clefts (P = 0.103). The respective Z-scores of FS distance for fetuses with bilateral, unilateral and median clefts and retrognathia were -9.7 ± 2.0, -3.1 ± 5.1, 8.2 ± 3.4 and -7.3 ± 2.3. Measurements were ≥ 99(th) and ≤ 1(st) centiles in all but one (98.1%) case. CONCLUSION: The FS distance appears to be a helpful tool in the detection of facial clefts at 11-13 weeks' gestation. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Facial markers in second- and third-trimester fetuses with trisomy 18 or 13, triploidy or Turner syndrome.

OBJECTIVE: To examine the effectiveness of nasal bone (NB) evaluation (including NB length (NBL)), prenasal thickness (PT) measurement, the PT:NBL ratio and the prefrontal space ratio (PFSR) in the identification of fetuses with trisomy 18 or 13, triploidy or Turner syndrome. METHODS: This was a retrospective study using stored midsagittal two-dimensional images of the facial profile of fetuses with trisomy 18 or 13, triploidy or Turner syndrome in the second and third trimesters. For images of acceptable quality, measurements were obtained of NBL (where NB was present), PT, the PT:NBL ratio and PFSR, and these measurements were compared with previously published normal ranges. RESULTS: The search of databases identified 189 fetuses that met the study criteria: 132 (69.8%) with trisomy 18, 40 (21.2%) with trisomy 13, 10 (5.3%) with triploidy and seven (3.7%) with Turner syndrome. The NB was either absent or its measurement was below the 5(th) centile in 67 (50.8%), 20 (50.0%), five (50.0%) and two (28.6%) of the fetuses with trisomy 18, trisomy 13, triploidy and Turner syndrome, respectively. The PT measurement was above the 95(th) centile in 24 (18.2%), six (15.0%), one (10.0%) and one (14.3%) of the affected fetuses, respectively. The PFSR was abnormal in 72 (54.5%), 29 (72.5%), seven (70%) and four (57.1%) of the cases and the PT:NBL ratio was above the 95(th) centile or the nasal bone was absent in 72 (54.5%), 20 (50.0%), six (60.0%) and four (57.1%) cases, respectively. CONCLUSION: Although each of the facial markers considered provides some useful information in screening for trisomy 18, trisomy 13, triploidy and Turner syndrome, the performance of none of the markers appears to be as good as that in screening for trisomy 21.

Screening for chromosomal abnormalities by first trimester combined screening and noninvasive prenatal testing.

PURPOSE: To examine combined first trimester screening (FTS), noninvasive prenatal testing (NIPT) and a two-step policy that combines FTS and NIPT in screening for aneuploidy. MATERIALS AND METHODS: Retrospective study involving 21,052 pregnancies where FTS was performed at the Praxis Praenatal.de in Duesseldorf, Germany. In each case, the sum risk of trisomy 21, 18 and 13 was computed. We assumed that NIPT detects 99 %, 98 %, 90 % and 99 % of cases with trisomy 21, 18, 13 and sex chromosomal abnormalities and that the false-positive rate is 0.5 %. The following screening policies were examined: NIPT or FTS with sum risk cut-offs of 1 in 50 and 1 in 250 in all patients or a two-step-policy with FTS in all patients followed by NIPT in the intermediate sum risk group. For the intermediate risk group, sum risk cut-offs of 1 in 50 and 1 in 1000 and 1 in 150 and 1 in 500 were used. RESULTS: There were 127, 34, 13 and 15 pregnancies with trisomy 21, 18, 13 and sex chromosomal abnormalities. 23 fetuses had other chromosomal abnormalities with an increased risk for adverse outcome that are not detectable by NIPT. 20,840 pregnancies were classified as normal as ante- and postnatal examinations did not show any signs of clinically significant chromosomal abnormalities. FTS with a sum risk cut-off of 1 in 50 and 1 in 250 detects 81 % and 91 % for all aneuploidies. NIPT detects 88 % of the respective pregnancies. The 2-step approach with sum risk cut-offs of 1 in 50 and 1 in 1000 detects 94 % of all aneuploidies. With sum risk cut-offs of 1 in 150 and 1 in 500, the detection rate is 93 %. CONCLUSION: A 2-step policy with FTS for all patients and NIPT in the intermediate risk group results in the highest detection rate of all aneuploidies.

Optimal caliper placement: manual vs automated methods.

OBJECTIVE: To examine the inter- and intra-operator repeatability of manual placement of callipers in the assessment of basic biometric measurements and to compare the results to an automated calliper placement system. METHODS: Stored ultrasound images of 95 normal fetuses between 19 and 25 weeks' gestation were used. Five operators (two experts, one resident and two students) were asked to measure the BPD, OFD and FL two times manually and automatically. For each operator, intra-operator repeatability of the manual and automated measurements was assessed by within operator standard deviation. For the assessment of the interoperator repeatability, the mean of the four manual measurements by the two experts was used as the gold standard.The relative bias of the manual measurement of the three non-expert operators and the operator-independent automated measurement were compared with the gold standard measurement by means and 95% confidence interval. RESULTS: In 88.4% of the 95 cases, the automated measurement algorithm was able to obtain appropriate measurements of the BPD, OFD, AC and FL. Within operator standard deviations of the manual measurements ranged between 0.15 and 1.56, irrespective of the experience of the operator.Using the automated biometric measurement system, there was no difference between the measurements of each operator. As far as the inter-operator repeatability is concerned, the difference between the manual measurements of the two students, the resident, and the gold standard was between -0.10 and 2.53 mm. The automated measurements tended to be closer to the gold standard but did not reach statistical significance. CONCLUSION: In about 90% of the cases, it was possible to obtain basic biometric measurements with an automated system. The use of automated measurements resulted in a significant improvement of the intra-operator but not of the inter-operator repeatability, but measurements were not significantly closer to the gold standard of expert examiners.

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.

Prefrontal space ratio in second- and third-trimester screening for trisomy 21.

OBJECTIVE: To evaluate the prefrontal space ratio (PFSR) in second- and third-trimester euploid fetuses and fetuses with trisomy 21. METHODS: This was a retrospective study utilizing stored mid-sagittal two-dimensional images of second- and third-trimester fetal faces that were recorded during prenatal ultrasound examinations at the Department of Prenatal Medicine at the University of Tuebingen, Germany and at a private center for prenatal medicine in Nuremberg, Germany. For the normal range, 279 euploid pregnancies between 15 and 40 weeks' gestation were included. The results were compared with 91 cases with trisomy 21 between 15 and 40 weeks. For the ratio measurement, a line was drawn between the leading edge of the mandible and the maxilla (MM line) and extended in front of the forehead. The ratio of the distance between the leading edge of the skull and the leading edge of the skin (d1) to the distance between the skin and the point where the MM line was intercepted (d2) was calculated. The PFSR was determined by dividing d2 by d1. RESULTS: In the euploid and trisomy 21 groups, the median gestational age at the time of ultrasound examination was 21.1 (range, 15.0-40.0) and 21.4 (range, 15.0-40.3) weeks, respectively. Multiple regression analysis showed that PFSR was independent of maternal and gestational age. In the euploid group, the mean PFSR was 0.97 ± 0.29. In fetuses with trisomy 21, the mean PFSR was 0.2 ± 0.38 (P < 0.0001). The PFSR was below the 5(th) centile in 14 (5.0%) euploid fetuses and in 72 (79.1%) fetuses with trisomy 21. CONCLUSION: The PFSR is a simple and effective marker in second- and third-trimester screening for trisomy 21.

The cavum septi pellucidi in euploid and aneuploid fetuses.

OBJECTIVE: To examine whether the cavum septi pellucidi (CSP) is larger in second- and third-trimester fetuses with chromosomal abnormalities than in euploid fetuses. METHODS: This was a retrospective study utilizing stored two-dimensional images of second- and third-trimester fetuses between 18 and 40 weeks' gestation from three centers in Germany. The width of the CSP was measured by placing the calipers on the inner portion of its lateral borders. Two operators, both of whom were blinded to the fetal karyotype and to the measurements obtained by the other, measured the CSP width. The normal range in euploid fetuses was computed based on the biparietal diameter (BPD) by applying univariate regression analysis. The CSP width in euploid and aneuploid fetuses was transformed into Z-scores and compared using Student's t-test. Univariate regression analysis was used to determine the dependency of Z-score on head biometry. RESULTS: The study population consisted of 406 singleton pregnancies, 267 with euploid fetuses, 81 with trisomy 21, 50 with trisomy 18 and eight with trisomy 13. In the euploid group, the mean CSP width was 4.5 (range, 1.8-7.4) mm. Regression analysis showed a significant dependency of CSP width on BPD (CSP width = 0.658 + (0.064 × BPD), r = 0.781, P < 0.0001; both parameters in mm). The mean CSP width increased from 3.2 to 7.1 mm for BPD values of 40 to 100 mm, respectively. In the groups of fetuses with trisomy 21, 18 and 13, mean CSP width was 5.7 (range, 2.8-10.5), 7.9 (range, 3.5-12.8) and 5.8 (range, 4.0-9.0) mm, respectively. In 42.0% of the fetuses with trisomy 21, CSP width was above the 95(th) centile. In trisomy 18 and 13, CSP width was above the 95(th) centile in 92.0% and 37.5% of cases, respectively. CONCLUSION: A large CSP width should prompt a detailed ultrasound examination to further assess the risk for chromosomal abnormalities.

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.