Peter Kozlowski

Prenatal Sonographic Findings in Trisomy 22 Five Case Reports and Review of the Literature

The purpose of this study was to survey prenatal sonographic findings and their frequencies in fetuses with complete trisomy 22 and to identify potential sonographic markers of this aneuploidy.

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.

Fetal Renal Insufficiency Following Trastuzumab Treatment for Breast Cancer in Pregnancy: Case Report und Review of the Current Literature

Some drugs are known for their fetal nephrotoxicity and should be avoided during pregnancy. We report on a pregnant woman suffering from breast cancer who received a weekly neoadjuvant trastuzumab (Herceptin®) therapy from 15 weeks of gestation onward, in addition to a 3-weekly carboplatin/docetaxel chemotherapy. Fetal renal insufficiency with anhydramnios and missing visualization of the fetal bladder developed at 21 weeks. After discontinuation of trastuzumab and repeated instillation of amniotic fluid, the amount of amniotic fluid remained stable after 24 weeks of gestation. After caesarean section at 34 weeks because of fetal growth restriction, the renal function of the neonate was normal postnatally. In accordance with the current literature, our case shows a reversible adverse effect of trastuzumab on the fetal renal function and confirms the current recommendation that trastuzumab in pregnancy should be avoided. In pregnancies exposed to trastuzumab, treatment should be discontinued and the fetus should be closely monitored, with particular attention to the amniotic fluid and the fetal bladder volume, as these reflect fetal renal function.

Quality Requirements for the early Fetal Ultrasound Assessment at 11-13(+6) Weeks of Gestation (DEGUM Levels II and III)

The early fetal ultrasound assessment at 11 - 13(+6) weeks of gestation remains the cornerstone of care despite the progress in diagnosing fetal chromosomal defects using cell-free fetal DNA (cffDNA) from the maternal circulation. The measurement of nuchal translucency (NT) allows the risk calculation for the fetal trisomies 21, 18 and 13 but also gives information on those fetal chromosomal defects which are at present unable to be detected using cffDNA. Nuchal translucency is the only auditable parameter at 11 - 13(+6) weeks and gives thus information on the quality of the first trimester anomaly scan. In addition it gives indirect information on the risks for fetal defects and for cardiac anomalies. Also the chances for a healthy live baby can be estimated. As experience with first trimester anomaly scanning increases, and the resolution of the ultrasound equipment has increased substantially, more and more details of the fetal anatomy become accessible at the first trimester scan. Therefore fetal anatomical defects and complex anomalies have become amenable to examination in the first trimester. This guideline describes compulsory and optional parameters for investigation at the first trimester scan and outlines a structured method of examining a first trimester fetus at 11 - 13(+6) weeks of gestation.

Impact of maternal obesity and maternal overweight on the detection rate of fetal heart defects and the image quality of prenatal echocardiography.

PURPOSE The purpose of this study was to compare the prenatal detection of four congenital heart defects (CHDs) and the image quality of five corresponding ultrasound planes among obese, overweight and normal-weight women. MATERIALS AND METHODS This was a retrospective cohort study of 54,846 pregnancies undergoing fetal echocardiography between 18 and 37 weeks of gestation in the years from 2000 to 2007. The women were categorized according to pre-pregnancy body mass index (BMI) as normal-weight (BMI < 25), overweight (BMI 25 - 29.9) and obese (BMI ≥ 30). Image quality and prenatal detection of atrioventricular septal defect (AVSD), double outlet right ventricle (DORV), tetralogy of fallot (TOF) and dextro transposition of the great arteries (D-TGA) were evaluated in the BMI strata. RESULTS 108 cases with one of the considered CHDs were identified. The prevalence was significantly higher (relative risk = 2.04) in overweight or obese women (57/19,404 vs. 51/35,442, p < 0.0002) than in normal-weight women. In total 86.1% of CHDs were correctly identified prenatally (93/108, CI: 79.6%-92.6%), 84.3% (43/51) in the normal weight group, 88.6% (39/44) in the overweight group and 84.6% (11/13) in the obese group. The rate of insufficient ultrasound images increased from 6.4% in normal-weight patients to 17.4% in obese women within the 108 CHD cases. CONCLUSION The prenatal detection of fetal AVSD, DORV, TOF and D-TGA was also satisfactory in overweight and obese patients, but image quality substantially decreases with an increasing maternal BMI. If there is a BMI-associated difference in the detection rate, it probably will not exceed 20%.

Fetal Gastroschisis: A Comparison of Second vs. Third-Trimester Bowel Dilatation for Predicting Bowel Atresia and Neonatal Outcomes

PURPOSE To compare various gestational ages and thresholds for diagnosing bowel dilatation in fetuses with gastroschisis and to evaluate the prognostic value of bowel dilatation for predicting postnatal bowel atresia and neonatal outcomes. MATERIALS AND METHODS This was a retrospective observational study conducted from March 1997 to September 2009 that included 78 pregnancies with fetal gastroschisis. The predictive value of prenatal bowel dilatation for neonatal bowel atresia and postnatal complications was investigated in three subgroups: those with bowel dilatations ≥ 10 mm at a gestational age < 27 + 0 weeks, ≥ 10 mm at a gestational age < 30 + 0 weeks and ≥ 18 mm at a gestational age ≥ 30 weeks. RESULTS Prenatally, 6 %, 81 % and 13 % of the bowel malformations were identified in the first, second and third trimesters, respectively. There were three stillbirths and three neonatal deaths, and the mean gestational age at delivery was 35.4 weeks (range 31 + 4 to 41 + 6). Bowel atresia was significantly correlated with prenatal bowel dilatation in all three subgroups. Bowel dilatations of ≥ 10 mm before 30 + 0 gestational weeks achieved the best performance in predicting bowel atresia, with a sensitivity of 89 % (8 / 9) and a specificity of 79 % (30 / 38). A prenatal bowel diameter ≥ 10 mm through 30 completed weeks was also the best predictor of a prolonged neonatal hospital stay ≥ 8 weeks (sensitivity = 61.1, 11 / 18, p = 0.002). CONCLUSION Fetuses with isolated gastroschisis successfully underwent postnatal surgery in most cases (93.2 %), except for one termination, one intrauterine death and 3 cases of neonatal death. A fetal bowel dilatation > 10 mm before 30 + 0 weeks had the highest predictive value for postnatal bowel complications.

Cranial and cerebral signs in the diagnosis of spina bifida between 18 and 22 weeks of gestation: a German multicentre study

The aim of this article is to study secondary cranial signs in fetuses with spina bifida in a precisely defined screening period between 18 + 0 and 22 + 0 weeks of gestation.

Predicting SGA neonates using first-trimester screening: influence of previous pregnancy's birthweight and PAPP-A MoM.

Abstract Objective: Investigating the proportions of anamnestic and biochemical variables of the previous and current pregnancies for the prediction of small for gestational age (SGA) neonates in the current pregnancy. Methods: In this observational retrospective study, 45 029 pregnancies were examined, including 3862 patients with more than one pregnancy. Odds ratios for SGA using anamnestic parameters and pregnancy-associated plasma protein A (PAPP-A) values from all pregnancies were estimated by using a logistic regression model. Results: There were 2552 (5.7%) SGA neonates. Two threshold PAPP-A values were identified at 0.15 MoM and 0.33 MoM with probabilities for SGA of 23% and 17%, respectively. A previous SGA < 10th centile and a current PAPP-A MoM value < 5th centile result in odds ratios of 4.8 (95% CI: 3.5–6.5) and 3.0 (95% CI: 1.8–5.0), respectively. The parameters’ combined odds ratio is 14.1 (95% CI: 3.9–50.3) with a number needed to screen of ten for one SGA neonate at a detection rate of 37%. Conclusion: Information on previous pregnancies affected by SGA and a current pregnancy’s low PAPP-A value are reliable predictors for a SGA delivery. First-trimester biochemical analysis should be maintained to detect women at risk for delivering a SGA neonate.

DEGUM, ÖGUM, SGUM and FMF Germany Recommendations for the Implementation of First-Trimester Screening, Detailed Ultrasound, Cell-Free DNA Screening and Diagnostic Procedures

First-trimester screening between 11 + 0 and 13 + 6 weeks with qualified prenatal counseling, detailed ultrasound, biochemical markers and maternal factors has become the basis for decisions about further examinations. It detects numerous structural and genetic anomalies. The inclusion of uterine artery Doppler and PlGF screens for preeclampsia and fetal growth restriction. Low-dose aspirin significantly reduces the prevalence of severe preterm eclampsia. Cut-off values define groups of high, intermediate and low probability. Prenatal counseling uses detection and false-positive rates to work out the individual need profile and the corresponding decision: no further diagnosis/screening - cell-free DNA screening - diagnostic procedure and genetic analysis. In pre-test counseling it must be recognized that the prevalence of trisomy 21, 18 or 13 is low in younger women, as in submicroscopic anomalies in every maternal age. Even with high specificities, the positive predictive values of screening tests for rare anomalies are low. In the general population trisomies and sex chromosome aneuploidies account for approximately 70 % of anomalies recognizable by conventional genetic analysis. Screen positive results of cfDNA tests have to be proven by diagnostic procedure and genetic diagnosis. In cases of inconclusive results a higher rate of genetic anomalies is detected. Procedure-related fetal loss rates after chorionic biopsy and amniocentesis performed by experts are lower than 1 to 2 in 1000. Counseling should include the possible detection of submicroscopic anomalies by comparative genomic hybridization (array-CGH). At present, existing studies about screening for microdeletions and duplications do not provide reliable data to calculate sensitivities, false-positive rates and positive predictive values.

Aktuelle Entwicklungen im vorgeburtlichen Screening auf chromosomale Störungen / Recent developments in antenatal screening for chromosomal abnormalities

Zusammenfassung Das klassische Ersttrimesterscreening (ETS) liefert eine durch unabhängige prospektive Studien validierte Nachweisrate für ein fetales Down-Syndrom von 86–90% bei einer falsch-positiv Rate von 5%. Durch eine Kombination von Erst- und Zweittrimestermarkern (Integrated Screening) kann eine Verbesserung der Nachweisrate auf 94–96% erreicht werden, wenn das Gesamttestergebnis erst nach Vorliegen der Zweittrimesterwerte mitgeteilt wird. Die frühe Diagnostik des klassischen Ersttrimesterscreenings und die bessere Testgenauigkeit des Integrierten Screenings können durch ein sequentielles Screening kombiniert werden, bei dem man in Fällen mittlerer Risiken eine zusätzliche Zweittrimesterbiochemie durchführt. Patientinnen mit hohen Risiken im Ersttrimesterscreening würde direkt eine invasive Diagnostik empfohlen, Patientinnen mit sehr niedrigen Risiken benötigten keine weitere Untersuchung. Genaue Zahlen für einen Risikogrenzwert ab dem eine Zweittrimesterbiochemie empfohlen wird und prospektive Studien zu diesem sequentiellen Screening liegen jedoch noch nicht vor. Sind über die Risikoangabe für eine fetale Trisomie 21 hinaus weitere Informationen zum Gesundheitszustand des Kindes gewünscht, ist ein erweitertes Ultraschallscreening im ersten Trimenon eine gute Alternative. Quantitative Aussagen zur Screeningperformance des erweiterten Ultraschallscreenings für ein fetales Down-Syndrom sind zurzeit noch nicht möglich. Abstract Various prospective studies have shown a detection rate of 86%–90% for fetal Down syndrome with a positive screening rate of 5% in classic first-trimester screening. A combination of first- and second-trimester markers (integrated screening) allows improvement in the detection rate to 94%–96% if the result is kept until the second-trimester results are available. The early results of first-trimester screening and the better test performance of integrated screening are combined to determine the need for sequential screening, so that additional secondtrimester biochemical testing is only performed in cases of intermediate risk. Patients at high risk after first-trimester screening can be offered invasive diagnostic testing, whereas patients at very low risk do not need further testing. Prospective studies evaluating a definite risk cutoff on which to base recommendation of second-trimester testing have not been published. If further information on the health of the fetus beyond the risk for fetal aneuploidies is requested, extended first-trimester ultrasound is an appropriate alternative. It is currently unclear to what extent screening performance for Down syndrome is improved by additional first-trimester ultrasound markers.