Bi-allelic loss-of-function variants in KIF21A cause severe fetal akinesia with arthrogryposis multiplex.

BACKGROUND: Fetal akinesia (FA) results in variable clinical presentations and has been associated with more than 166 different disease loci. However, the underlying molecular cause remains unclear in many individuals. We aimed to further define the set of genes involved. METHODS: We performed in-depth clinical characterisation and exome sequencing on a cohort of 23 FA index cases sharing arthrogryposis as a common feature. RESULTS: We identified likely pathogenic or pathogenic variants in 12 different established disease genes explaining the disease phenotype in 13 index cases and report 12 novel variants. In the unsolved families, a search for recessive-type variants affecting the same gene was performed; and in five affected fetuses of two unrelated families, a homozygous loss-of-function variant in the kinesin family member 21A gene (KIF21A) was found. CONCLUSION: Our study underlines the broad locus heterogeneity of FA with well-established and atypical genotype-phenotype associations. We describe KIF21A as a new factor implicated in the pathogenesis of severe neurogenic FA sequence with arthrogryposis of multiple joints, pulmonary hypoplasia and facial dysmorphisms. This hypothesis is further corroborated by a recent report on overlapping phenotypes observed in Kif21a null piglets.

Obesity in prenatal medicine: a game changer?

Obesity is recognized by the World Health Organization (WHO) as a disease in its own right. Moreover, obesity is an increasingly concerning public health issue across the world and its prevalence is rising amongst women of reproductive age. The fertility of over-weight and obese women is reduced and they experience a higher rate of miscarriage. In pregnant women obesity not only increases the risk of antenatal complications, such as preeclampsia and gestational diabetes, but also fetal abnormalities, and consequently the overall feto-maternal mortality. Ultrasound is one of the most valuable methods to predict and evaluate pregnancy complications. However, in overweight and obese pregnant women, the ultrasound examination is met with several challenges, mainly due to an impaired acoustic window. Overall obesity in pregnancy poses special challenges and constraints to the antenatal care and increases the rate of pregnancy complications, as well as complications later in life for the mother and child.

Prenatal parvovirus B19 infection.

Parvovirus B19 (B19V) causes erythema infectiosum, a.k.a., fifth disease. This disease primarily affects children. It is generally self-limiting and subsides after 1-2 weeks. In pregnancy, the virus can cross the placenta and result in a fetal infection. This may lead to severe fetal anemia, hydrops fetalis, a miscarriage, or intrauterine fetal death. The risk of long-term sequelae also appears to be increased. About one-third of pregnant women are not immune to B19V and, therefore, are at risk to contract a primary infection. The seroconversion rate during pregnancy is generally around 1-2%. During a primary infection, maternal-fetal transplacental transmission of B19V occurs in about 30-50% of the cases and the risk of fetal infection increases with advancing gestational age. The risk of severe fetal anemia or hydrops is around 3-4% overall and is around 6-7% if the primary infection occurs before 20 weeks' gestation. Fetal monitoring in women with a primary B19V infection includes regular ultrasound examinations looking for evidence of hydrops fetalis and Doppler measurements of the middle cerebral artery peak velocity. Fetal blood sampling is performed if a significant anemia is suspected and, if such is found, an intrauterine blood transfusion is needed. This article provides an overview of the epidemiology, pathogenesis, clinical manifestations, diagnostic methods, and management of B19V infection during pregnancy.

Fetal eye ultrasound: Normal anatomy, abnormal findings, and clinical impact. / Ultraschall des fetalen Auges: Normale Anatomie, abnorme Befunde und klinische Bedeutung.

Until now, ultrasound examination of the fetal eyes has not played an important role in prenatal diagnosis. National and international guidelines are generally confined to documentation of the presence of the orbits and the lenses. However, in recent years, with the advent of high-resolution ultrasound technology and increasing knowledge of prenatal medicine and genetics, careful examination of the fetal eye has enabled the detection of many ocular malformations before birth. This article provides an overview of the anatomy related to the development of the fetal eye and covers the following conditions: hypertelorism, hypotelorism, exophthalmos, microphthalmos, coloboma, cataract, persistent hyperplastic primary vitreous, retinal detachment, dacryocystocele, and septooptic dysplasia, etc. It is designed to illustrate the spectrum of ocular malformations and their appearance on prenatal ultrasound and to discuss their clinical impact and association with various syndromes.

Firsttrimester Diagnosis and Therapy @ 11-13+6 Weeks of Gestation - Part 1. / Ersttrimester Diagnostik und Therapie @ 11­13+6 Schwangerschaftswochen ­ Teil 1.

This extensive AWMF 085-002 S2e-guideline "First Trimester Diagnosis and Therapy @ 11-13+6 Weeks of Gestation" has systematically analyzed high-quality studies and publications and the existing evidence (evidence tables) and produced recommendations (level of recommendation, level of evidence, strength of consensus).This guideline deals with the following topics in the context of the 11-13+6 weeks scan: the legal basis, screening for anatomical malformations, screening for chromosomal defects, quality assessment and audit, screening for preeclampsia and FGR, screening for preterm birth, screening for abnormally invasive placenta (AIP) and placenta accreta spectrum (PAS), screening for velamentous cord insertion and vasa praevia, screening for diabetes mellitus and LGA.Screening for complications of pregnancy can best be carried out @ 11-13+6 weeks of gestation. The issues of how to identify malformations, chromosomal abnormalities and certain disorders of placentation (high blood pressure and proteinuria, intrauterine growth retardation) have been solved. The problem of how to identify placenta percreta and vasa previa has been partially solved. What is still unsolved is how to identify disorders of glucose metabolism and preterm birth.In the first trimester, solutions to some of these problems are available: parents can be given extensive counselling and the risk that a pregnancy complication will manifest at a later stage can be delayed and reduced. This means that screening is critically important as it helps in decision-making about the best way to manage pregnancy complications (prevention and intervals between follow-up examinations).If no treatment is available and if a termination of pregnancy is considered, the intervention can be carried out with far lower complications compared to the second trimester of pregnancy. In most cases, further examinations are not required and the parents can be reassured. A repeat examination at around week 20 of gestation to complete the screening for malformations is recommended. NOTE:: The guideline will be published simultaneously in the official journals of both professional societies (i.e. Ultraschall in der Medizin/European Journal of Ultrasound for the DEGUM and Geburtshilfe und Frauenheilkunde for the DGGG).

Firsttrimester Diagnosis and Therapy @ 11-13+6 Weeks of Gestation - Part 2. / Ersttrimester Diagnostik und Therapie @ 11­13+6 Schwangerschaftswochen ­ Teil 2.

This extensive AWMF 085-002 S2e-guideline "First Trimester Diagnosis and Therapy @ 11-13+6 Weeks of Gestation" has systematically analyzed high-quality studies and publications and the existing evidence (evidence tables) and produced recommendations (level of recommendation, level of evidence, strength of consensus).This guideline deals with the following topics in the context of the 11-13+6 weeks scan: the legal basis, screening for anatomical malformations, screening for chromosomal defects, quality assessment and audit, screening for preeclampsia and FGR, screening for preterm birth, screening for abnormally invasive placenta (AIP) and placenta accreta spectrum (PAS), screening for velamentous cord insertion and vasa praevia, screening for diabetes mellitus and LGA.Screening for complications of pregnancy can best be carried out @ 11-13+6 weeks of gestation. The issues of how to identify malformations, chromosomal abnormalities and certain disorders of placentation (high blood pressure and proteinuria, intrauterine growth retardation) have been solved. The problem of how to identify placenta percreta and vasa previa has been partially solved. What is still unsolved is how to identify disorders of glucose metabolism and preterm birth.In the first trimester, solutions to some of these problems are available: parents can be given extensive counselling and the risk that a pregnancy complication will manifest at a later stage can be delayed and reduced. This means that screening is critically important as it helps in decision-making about the best way to manage pregnancy complications (prevention and intervals between follow-up examinations).If no treatment is available and if a termination of pregnancy is considered, the intervention can be carried out with far lower complications compared to the second trimester of pregnancy. In most cases, further examinations are not required and the parents can be reassured. A repeat examination at around week 20 of gestation to complete the screening for malformations is recommended. NOTE: The guideline will be published simultaneously in the official journals of both professional societies (i.e. Ultraschall in der Medizin/European Journal of Ultrasound for the DEGUM and Geburtshilfe und Frauenheilkunde for the DGGG).

Fetal Assessment in Pregnancy (Indication and Methodology for Fetal Monitoring in a low-risk Population). Guideline of the DGGG, DEGUM, OEGGG and SGGG (S3-Level, AWMF Registry No. 015/089, February 2023). / Fetale Überwachung in der Schwangerschaft (Indikation und Methodik zur fetalen Zustandsdiagnostik im Low-Risk-Kollektiv). Leitlinie der DGGG, DEGUM, OEGGG und SGGG (S3-Level, AWMF-Registernummer 015/089, Februar 2023).

PURPOSE: The aim of this guideline was to find evidence on whether carrying out Doppler examinations and CTGs in low-risk cohorts of pregnant women improves outcomes. METHODS: First, a systematic search for guidelines was carried out. Identified guidelines were evaluated using the DELPHI instrument of the AWMF. Three guidelines were found to be suitable to evaluate CTG. Two DEGUM best practice guidelines were judged suitable to describe the methods. All studies on this issue were additionally analyzed using 8 PICO questions. A structured consensus of the participating professional societies was achieved using a nominal group process and a structured consensus conference moderated by an independent moderator. RECOMMENDATIONS: No antepartum Doppler sonography examinations should be carried out in low-risk cohorts in the context of antenatal care. No antepartum CTG should be carried out in low-risk cohorts. NOTE: The guideline will be published simultaneously in the official journals of both professional societies (i. e., Geburtshilfe und Frauenheilkunde for the DGGG and Ultraschall in der Medizin/European Journal of Ultrasound for the DEGUM).

Effect of pentaerythritol tetranitrate (PETN) on the development of fetal growth restriction in pregnancies with impaired uteroplacental perfusion at midgestation-a randomized trial.

BACKGROUND: Fetal growth restriction is strongly associated with impaired placentation and abnormal uteroplacental blood flow. Nitric oxide donors such as pentaerythritol tetranitrate are strong vasodilators and protect the endothelium. Recently, we demonstrated in a randomized controlled pilot study a 38% relative risk reduction for the development of fetal growth restriction or perinatal death following administration of pentaerythritol tetranitrate to pregnant women at risk, identified by impaired uterine perfusion at midgestation. Results of this monocenter study prompted the hypothesis that pentaerythritol tetranitrate might have an effect in pregnancies with compromised placental function as a secondary prophylaxis. OBJECTIVE: This study aimed to test the hypothesis that the nitric oxide donor pentaerythritol tetranitrate reduces fetal growth restriction and perinatal death in pregnant women with impaired placental perfusion at midgestation in a multicenter trial. STUDY DESIGN: In this multicenter, randomized, double-blind, placebo-controlled trial, 2 parallel groups of pregnant women presenting with a mean uterine artery pulsatility index >95th percentile at 19+0 to 22+6 weeks of gestation were randomized to 50-mg Pentalong or placebo twice daily. Participants were assigned to high- or low-risk groups according to their medical history before randomization was performed block-wise with a fixed block length stratified by center and risk group. The primary efficacy endpoint was the composite outcome of perinatal death or development of fetal growth restriction. Secondary endpoints were neonatal and maternal outcome parameters. RESULTS: Between August 2017 and March 2020, 317 participants were included in the study and 307 were analyzed. The cumulative incidence of the primary outcome was 41.1% in the pentaerythritol tetranitrate group and 45.5% in the placebo group (unadjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; adjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; P=.43). Secondary outcomes such as preterm birth (unadjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; adjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; P=.01) and pregnancy-induced hypertension (unadjusted relative risk, 0.65; 95% confidence interval, 0.46-0.93; adjusted relative risk, 0.65; 95% confidence interval, 0.46-0.92; P=0.01) were reduced. CONCLUSION: Our study failed to show an impact of pentaerythritol tetranitrate on the development of fetal growth restriction and perinatal death in pregnant women with impaired uterine perfusion at midgestation. Pentaerythritol tetranitrate significantly reduced secondary outcome parameters such as the incidence of preterm birth and pregnancy-induced hypertension in these pregnancies.

Prenatal testing for Imprinting Disorders: A clinical perspective.

Imprinting Disorders (ImpDis) are a group of congenital conditions caused by aberrant imprinting resulting in disturbed expression of parentally imprinted genes. ImpDis are rarely associated with major malformations, but pre- and/or postnatal growth and nutrition are often affected. In some ImpDis, behavioral, developmental, metabolic and neurological symptoms might present in the perinatal context or later in life, and in single ImpDis, there is a higher risk of tumors in childhood. Prognosis depends in part on the molecular cause of each ImpDis, but due to high clinical variability and (epi)genetic mosaicism, predicting the clinical outcome of a pregnancy solely based on the underlying molecular disturbance is difficult. Therefore, interdisciplinary care and treatment approaches play an important role in the management and decision making of affected pregnancies, especially taking into account fetal imaging in addition to genetic findings. Prenatal findings influence perinatal management, and thereby improve the prognosis of ImpDis associated with severe but sometimes transient clinical complications in the neonatal period. Therefore, prenatal diagnosis can be crucial for appropriate management not only to the pregnancy itself but might also have a life-long effect.

How to do a 3D uterus ultrasound?

Three-dimensional (3D) ultrasound is an invaluable tool in the detection and evaluation of many uterine anomalies and improves upon the traditional approach of two-dimensional (2D) ultrasonography. We aim to describe an easy way of assessing the uterine coronal plane using the basic three-dimensional ultrasound in everyday gynecological practice.

How to do a second trimester anomaly scan.

A systematic evaluation of the fetal anatomy as part of the second trimester ultrasound examination in pregnancy is useful in detecting pregnancy complications, fetal abnormalities, and genetic diseases. We aim to illustrate the basic and detailed second trimester scan, according to current international and national guidelines, as well as to our own every-day practice in the Department for Prenatal Diagnosis at the University of Tübingen, Germany.

Importance of a detailed anomaly scan after a cfDNA test indicating fetal trisomy 21, 18 or 13.

OBJECTIVE: To investigate the effect of the presence or absence of fetal anomalies and soft markers diagnosed by ultrasound on positive predictive value (PPV) 21, 18 and 13 in pregnancies with a high-risk cfDNA result. METHODS: Retrospective study including singleton pregnancies with high-risk NIPT results for common trisomies followed by invasive testing. The cases were grouped by gestational age at the time of invasive testing and by the presence or absence of fetal abnormalities or soft markers. The ultrasound was considered abnormal if at least one major defect or a soft marker was detected. RESULTS: A total of 173 women were included. Median maternal and gestational age was 37.7 years and 14.0 weeks, respectively. CfDNA test result showed high-risk for trisomy 21 and trisomy 18 or 13 in 119 and 54 cases, respectively. The "pre-ultrasound" PPV for trisomy 21 and for trisomy 18 or 13 were 98.3% and 68.4%, respectively. In case of a high-risk result for trisomy 21 and no fetal anomalies, the PPV was 86.7% while it was 100% if there were anomalies or markers present. In the case of a high-risk result for trisomy 18 or 13, the PPV was 9.5% if the ultrasound examination was normal and 100% if the ultrasound examination was abnormal. CONCLUSION: This study suggests that a detailed ultrasound examination performed after a cfDNA result that is high-risk for one of the common autosomal trisomies adds significantly to establishing an individualized risk assessment. This is particularly true in cases with a high-risk result for trisomies 18 or 13.

Uterine allograft removal by total laparoscopic hysterectomy after successful cesarean delivery in a living-donor uterus recipient with uterovaginal agenesis (MRKHS).

PURPOSE: To limit the burden of long-term immunosuppression (IS) after uterus transplantation (UTx), removal of the uterine allograft is indicated after maximum two pregnancies. Hitherto this has required graft hysterectomy by laparotomy. Our objective was to demonstrate, as a proof of concept, the feasibility of less traumatic transplantectomy by total laparoscopic hysterectomy (TLH). PATIENT: A 37-year-old woman with uterovaginal agenesis due to Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) who had undergone neovaginoplasty at age 19 years prior to living-donor (LD) UTx in 10/2019 at age 35 years gave birth to a healthy boy by primary cesarean section in 06/2021. During pregnancy, she developed impaired renal function, with bilateral hydronephrosis, necessitating early allograft removal in 09/2021 to prevent chronic kidney disease, particularly during a potential second pregnancy. METHODS: Transplantectomy by TLH essentially followed standard TLH procedures. We paid meticulous attention to removing as much donor tissue as possible to prevent postoperative complications from residual donor tissue after stopping IS, as well as long-term vascular damage. RESULTS: TLH was performed successfully without the need to convert to open surgery. Surgical time was 90 min with minimal blood loss. No major complications occurred intra- or postoperatively and during the subsequent 9-month follow-up period. Kidney function normalized. CONCLUSIONS: To our knowledge, we report the first successful TLH-based removal of a uterine allograft in a primipara after LD UTx, thus demonstrating the feasibility of TLH in uterus recipients with MRKHS.

Fetal Profile Markers for the Detection of Robin Sequence in Fetuses with Retrognathia.

OBJECTIVE: To determine whether the prefrontal space ratio (PSFR), inferior facial (IFA) and maxilla-nasion-mandible angle (MNM), and the fetal profile line (FPL) are helpful in identifying fetuses with Robin sequence (RS) in cases with isolated retrognathia, and thus better predict the likelihood of immediate need for postnatal respiratory support. METHODS: This was a retrospective matched case-control study of fetuses/infants with isolated retrognathia with or without RS receiving pre- and postnatal treatment at the University Hospital of Tübingen, Germany between 2008 and 2020. The PFSR, IFA, MNM, and FPL were measured in affected and normal fetuses according to standardized protocols. Cases were stratified into isolated retrognathia and RS. RESULTS: 21 (n=7 isolated retrognathia, n=14 RS) affected fetuses and 252 normal fetuses were included. Their median gestational age at ultrasound examination was 23.6 and 24.1 weeks, respectively. In fetuses with isolated retrognathia and RS, the PSFR, IFA, and FPL were significantly different from the normal population. At a false-positive rate of 5%, the detection rate was 76.2% for the PFSR, 85.7% for the IFA, and 90.5% for both parameters combined. However, all parameters failed to distinguish between isolated retrognathia and RS. CONCLUSION: PSFR and IFA are simple markers for identifying retrognathia prenatally. However, they are not helpful for the detection of RS in fetuses with isolated retrognathia. Therefore, delivery should take place in a center experienced with RS and potentially life-threatening airway obstruction immediately after birth.

Basic Gynecologic Ultrasound Examination (Level I): DEGUM, ÖGUM, and SGUM Recommendations. / Qualitätsanforderungen an gynäkologische Ultraschall-Untersuchungen der DEGUM-Stufe I: Empfehlungen der DEGUM, ÖGUM und SGUM.

Ultrasound has become an essential diagnostic tool in gynecology, and every practicing gynecologist must be able to differentiate normal from pathologic findings, such as benign or malignant pelvic masses, adnexal torsion, pelvic inflammation disease, endometriosis, ectopic pregnancies, and congenital uterine malformations at least on a basic level. A standardized approach to the correct settings of the ultrasound system, the indications for gynecologic ultrasound investigations, and the sonographic appearance of normal anatomy and common pathologic findings in the standard planes are important prerequisites for safe and confident clinical management of gynecologic patients. Based on current publications and different national and international guidelines, updated DEGUM, ÖGUM, and SGUM recommendations for the performance of basic gynecologic ultrasound examinations were established.

A single center experience of prenatal parent-fetus trio exome sequencing for pregnancies with congenital anomalies.

OBJECTIVES: To examine the diagnostic yield of trio exome sequencing in fetuses with multiple structural defects with no pathogenic findings in cytogenetic and microarray analyses. METHODS: We recruited 51 fetuses with two or more defects, non-immune fetal hydrops or fetal akinesia deformation syndrome|or fetal akinesia deformation sequence (FADS). Trio exome sequencing was performed on DNA from chorionic villi samples and parental blood. Detection of genomic variation and prioritization of clinically relevant variants was performed according to in-house standard operating procedures. RESULTS: Median maternal and gestational age was 32.0 years and 21.0 weeks, respectively. Forty-three (84.3%) fetuses had two or more affected organ systems. The remaining fetuses had isolated fetal hydrops or FADS. In total, the exome analysis established the genetic cause for the clinical abnormalities in 22 (43.1%, 95% CI 29.4%-57.8%) pregnancies. CONCLUSIONS: In fetuses with multiple defects, hydrops or FADS and normal standard genetic results, trio exome sequencing has the potential to identify genetic anomalies in more than 40% of cases.

Prenatal sonographic findings in confirmed cases of Wolf-Hirschhorn syndrome.

BACKGROUND: Wolf-Hirschhorn syndrome (WHS) is a common genetic condition and prenatal diagnosis is difficult due to heterogeneous expression of this syndrome and rather non-specific ultrasound findings. Objective of this study was to examine the prenatal ultrasound findings in fetuses with Wolf-Hirschhorn syndrome (WHS). METHODS: Retrospective assessment of 18 pregnancies that were seen at three tertiary referral centers (Universities of Bonn, Tuebingen and Nuernberg / Germany). Findings of prenatal ultrasound examinations, genetic results and outcome were compared. Additionally, findings of our study were compared to previous small case series from the literature and then compared to data on postnatal frequencies and abnormalities in affected patients. RESULTS: Median gestational age at the time of examination was 23 + 1 weeks' (range: 13 + 4 to 29 + 1 weeks') with female-to-male ratio of > 2.5:1. Most frequent ultrasound findings were facial abnormalities, symmetric IUGR and microcephaly that presented in 94.4, 83.3 and 72.2% of cases, respectively. The combination of microcephaly and hypoplastic nasal bone was a particularly characteristic finding. Growth retardation presented in all fetuses > 20 weeks, but not below. Other frequent abnormalities included cardiac anomalies in 50 and single umbilical artery (SUA) in 44.4% of fetuses. CONCLUSION: WHS should be considered in the presence of symmetric IUGR together with microcephaly, hypoplastic nasal bone and facial abnormalities on prenatal ultrasound. Genetic testing by chromosomal microarray analysis (CMA) is strongly recommended in this context.

Evaluation of Adnexal Masses: The IOTA Concept.

Ovarian lesions have a wide range of sonomorphological features with numerous different underlying benign and malignant histologies. Based on the studies conducted by the International Ovarian Tumor Analysis (IOTA) group, ovarian masses can currently be reliably characterized by ultrasound. In the following article, we explain how to use the IOTA terms and definitions and we provide insight into how to safely triage patients with an ovarian mass.

Quality Requirements for gynecological ultrasound examinations of DEGUM level II - Recommendations of the Sections/Working Groups Gynecology and Obstetrics of DEGUM, ÖGUM and SGUM. / Qualitätsanforderungen an die gynäkologischen Ultraschalluntersuchungen der DEGUM Stufe II ­ Empfehlungen der Sektionen/Arbeitskreise Gynäkologie und Geburtshilfe der DEGUM, ÖGUM und SGUM.

Gynecological sonography is the central and most frequently used technical examination method used by gynecologists. Its focus is on the clarification of masses of the uterus and the adnexa, fertility diagnosis, clarification of bleeding disorders and chronic and acute pelvic problems, pelvic floor and incontinence diagnosis as well as the differential diagnosis of disturbed early pregnancy. The indication for diagnostic and therapeutic interventions, preoperative planning and postoperative controls are largely based on the findings of gynecological sonography. These examinations are particularly dependent on the experience of the examiner.Based on the proven multi-stage concept of obstetric diagnostics, gynecological sonography should primarily be performed by an experienced and specialized examiner in patients for whom the initial gynecological examinations have not yet led to a sufficient assessment of the findings. So that the expert status required for this has an objective basis, the Gynecology and Obstetrics Section of DEGUM in cooperation with ÖGUM and SGUM implemented the option of acquiring DEGUM Level II for gynecological sonography. The effectiveness of the care in the multi-level concept depends on the quality of the ultrasound examination at level I. Quality requirements for the basic examination and the differentiation between the basic and further examination have therefore already been defined by DEGUM/ÖGUM. The present work is intended to set out quality requirements for gynecological sonography of DEGUM level II and for the correspondingly certified gynecologists.Common pathologies from gynecological sonography and requirements for imaging and documentation are described.

Universal Cell Free DNA or Contingent Screening for Trisomy 21: Does It Make a Difference? A Comparative Study with Real Data.

OBJECTIVE: The aim of the objective was to compare the detection rate for trisomy 21 of universal cell free DNA (cfDNA) screening with contingent screening. METHODS: Retrospective study was carried out at 3 German centers. The study included euploid and trisomy 21 pregnancies where cfDNA and first trimester (FT) screening assessment was carried out. The FT risk for trisomy 21 was computed based on combined screening and stratified into the following classes: high risk ≥1:10, intermediate risk 1:11-1,000, low risk ≤1,001. For universal cfDNA screening, the cfDNA test results were examined. For the contingent screening model, the result of the cfDNA test was taken into account in case of an intermediate FT risk. Different strategies combining maternal age, nuchal translucency, nasal bone, beta-hCG, and PAPP-A were evaluated. Screen positivity was defined as either a high risk after FT screening or a cfDNA test indicating a high-risk result. An inconclusive cfDNA test was also considered as screen positive. RESULTS: The search of the database identified 2,255 euploid and 163 affected pregnancies. All affected fetuses were identified by universal cfDNA screening. 1.3% of the euploid fetuses were classified as screen positive due to final inconclusive cfDNA test result. The detection and false-positive rate of a contingent approach that is based on combined screening and cfDNA screening in the intermediate group would be 98.4% and 0.7%, respectively. With this approach, cfDNA screening would be necessary in only about 27% of all pregnancies. CONCLUSION: This study demonstrates that a contingent approach provides similar detection rates for trisomy 21 as universal cfDNA screening, by a reduction of 73% the number of cfDNA tests.