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.

Cell-free DNA screening for common autosomal trisomies using rolling-circle replication in twin pregnancies.

OBJECTIVE: To evaluate the performance of prenatal screening for common autosomal trisomies in twin pregnancies through the use of rolling-circle replication (RCR)-cfDNA as a first-tier test. METHOD: Prospective multicenter study. Women who underwent prenatal screening for trisomy (T) 21, 18 and 13 between January 2019 and March 2022 in twin pregnancies were included. Patients were included in two centers. The primary endpoint was the rate of no-call results in women who received prenatal screening for common autosomal trisomies by RCR-cfDNA at the first attempt, compared to that in prospectively collected samples from 16,382 singleton pregnancies. The secondary endpoints were the performance indices of the RCR-cfDNA. RESULTS: 862 twin pregnancies underwent screening for T21, T18 and T13 by RCR-cfDNA testing at 10-33 weeks' gestation. The RCR-cfDNA tests provided a no-call result from the first sample obtained from the patients in 107 (0.7%) singleton and 17 (2.0%) twin pregnancies. Multivariable regression analysis demonstrated that significant independent predictors of test failure were twin pregnancy and in vitro fertilization conception. All cases of T21 (n = 20/862; 2.3%), T18 (n = 4/862; 0.5%) and T13 (n = 1/862; 0.1%) were correctly detected by RCR-cfDNA (respectively, 20, 4 and 1 cases). Sensitivity was 100% (95% CI, 83.1%-100%), 100% (95% CI 39.8%-100%) and 100% (95% CI 2.5%-100%) for T21, T18 and T13, respectively, in twin pregnancies. CONCLUSION: The RCR-cfDNA test appears to have good accuracy with a low rate of no-call results in a cohort of twin pregnancies for the detection of the most frequent autosomal trisomies.

Pentaerythrityl tetranitrate improves the outcome of children born to mothers with compromised uterine perfusion-12-months follow-up and safety data of the double-blind randomized PETN trial.

BACKGROUND: This is a follow-up study to the pentaerythrityl tetranitrate randomized controlled multicenter trial that reports neonatal outcome data of newborns admitted to neonatal intensive care units and outcome data of the offspring at 12 months of age. OBJECTIVE: We present data on adverse events reported during the study to document the safety of pentaerythrityl tetranitrate treatment during pregnancy. To further evaluate the effects of pentaerythrityl tetranitrate on neonatal and long-term outcomes, we present follow up data from of 240 children at 12 months of age, including information on height, weight, head circumference, developmental milestones, and the presence of chronic disease and of 144 newborns admitted to the neonatal intensive care unit during the trial. STUDY DESIGN: The pentaerythrityl tetranitrate trial was a randomized, double-blind, placebo-controlled study designed to assess the efficacy and safety of the nitric oxide-donor pentaerythrityl tetranitrate in the prevention of fetal growth restriction and perinatal death in pregnancies complicated by abnormal placental perfusion. RESULTS: Results at 12 months demonstrated that significantly more children were age appropriately developed without impairments in the pentaerythrityl tetranitrate group (P=.018). In addition, the presence of chronic disease was lower in the pentaerythrityl tetranitrate group (P=.041). Outcome data of the 144 newborns admitted to the neonatal intensive care unit did not reveal differences between the treatment and placebo groups. There were no differences in the number or nature of reported adverse events between the study groups. CONCLUSION: The analysis shows that study children born in the pentaerythrityl tetranitrate cohort have a clear advantage compared with the placebo group at the age of 12 months, as evidenced by the increased incidence of normal development without the presence of chronic disease. Although safety has been proven, further follow-up studies are necessary to justify pentaerythrityl tetranitrate treatment during pregnancies complicated by impaired uterine perfusion.

Timing of antenatal corticosteroid administration in pregnancies with increased risk for premature birth: A retrospective cohort study.

OBJECTIVE: To investigate how often antenatal corticosteroids (ACS) were administered within the optimal time frame in women at risk of preterm birth (PTB) in relation to several diagnoses and risk factors. METHOD: The study was designed as a retrospective cohort trial, in which the data of all births taking place in 2016 in the German federal state of Rhineland-Palatinate were evaluated. Frequency analyses, subgroup analyses, and logistic regression were performed. RESULTS: Birth occurred within the ideal time frame (≥24 h, ≤7 days) in only 15.2% of all pregnant women who were treated with ACS because of an increased risk of PTB (N = 1544). The ideal time frame after ACS administration was reached in less than 25% of all cases in each subgroup, with little difference between the different diagnoses and risk factors for PTB (range 11.3%-22.2%). Patients with multiple pregnancy had a significantly higher chance for delivery within the ideal time frame. There was an odds ratio greater than 1 for a birth event within the ideal time frame in patients with preterm prelabor rupture of membranes, pre-eclampsia, oligohydramnios, amniotic infection syndrome, and in patients with multiple diagnoses. In most diagnoses, the average time between ACS administration and birth was significantly shorter compared with patients without the diagnosis or risk factor. CONCLUSION: In women at risk of PTB, the individual risk profile should first be identified before ACS management begins. The likelihood of achieving the ideal time frame additionally depends on the diagnosis.

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.

Toxoplasma gondii Infection in Pregnancy - Recommendations of the Working Group on Obstetrics and Prenatal Medicine (AGG - Section on Maternal Disorders).

Aim The AGG (Working Group for Obstetrics and Prenatal Diagnostics, Section Maternal Diseases) has issued these recommendations to improve the detection and management of Toxoplasma gondii infection in pregnancy. Methods Members of the Task Force developed the recommendations and statements presented here using recently published literature. The recommendations were adopted after a consensus process by members of the working group. Recommendations This article focuses on the epidemiology and pathophysiology of Toxoplasma gondii infection in pregnancy and includes recommendations for maternal and fetal diagnosis, transmission prophylaxis, therapy, prevention, screening, and peripartum management.

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.

Screen-positive rate in cell free DNA screening for trisomy 21.

OBJECTIVE: To assess whether the fetal fraction (FF) has an impact on the screen-positive rate (SPR) in cell-free DNA (cfDNA) screening for trisomy 21. METHODS: Retrospective analysis based on samples analyzed using the Harmony® Prenatal Test (Roche Inc). Due to the size of the data set, we focused on the SPR, which was stratified according to the maternal age, weight, gestational age, and FF distribution. RESULTS: The study cohort consisted of 364,881 patients, including 2614 with a high-risk-result. Median maternal and gestational ages were 34.6 years and 12.4 weeks. FF was dependent on maternal age, weight, and gestational age. SPR was 0.72% and it was independent of maternal weight but was dependent on maternal age. There was a positive but weak association between the FF and the SPR until the FF reached 20.0% (OR p = 1.021, p < 0.001, Nagelkerkes r2 = 0.001). This group included 357,800 pregnancies or 98.1% of the study population. In the group of pregnancies with a FF > 20%, the association was stronger (OR 1.099, p < 0.001, Nagelkerkes r2 = 0.042). CONCLUSION: The SPR in cfDNA screening for trisomy 21 was relatively constant up to a FF of about 20%.

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.

DEGUM Recommendations on Diagnostic Puncture in Prenatal Medicine. / Empfehlungen der DEGUM zu diagnostischen Punktionen in der Pränatalmedizin.

Diagnostic puncture (amniocentesis, chorionic villus sampling, and fetal blood sampling) is an essential part of prenatal diagnostics and the only established and sufficiently scientifically evaluated possibility of diagnosing genetic diseases from pregnancy-specific cells. The number of diagnostic punctures in Germany, as in other countries, has fallen significantly. This is largely due to the introduction of first-trimester screening with further detailed ultrasound examination of the fetus and the analysis of cf-DNA (cell-free DNA) from maternal blood (noninvasive prenatal test - NIPT). On the other hand, knowledge about the incidence and appearance of genetic diseases has increased. The development of modern molecular genetic techniques (microarray and exome analysis) makes a differentiated investigation of these diseases increasingly possible. The requirements for education and counseling regarding these complex correlations have thus increased. The studies performed in recent years make it clear that diagnostic puncture performed in expert centers is associated with a low risk of complications. In particular, the procedure-related miscarriage risk hardly differs from the background risk for spontaneous abortion. In 2013, the Section of Gynecology and Obstetrics of the German Society for Ultrasound in Medicine (DEGUM) published recommendations on diagnostic puncture in prenatal medicine 1. The developments described above and new findings in recent years make it necessary to revise and reformulate these recommendations. The aim of this review is to compile important and current facts regarding prenatal medical puncture (including technique, complications, genetic examinations). It is intended to provide basic, comprehensive, and up-to-date information on diagnostic puncture in prenatal medicine. It replaces the publication from 2013 1.

Screen-positive rate in cell-free DNA screening for microdeletion 22q11.2.

OBJECTIVE: To examine the impact of the fetal fraction (FF) on the screen-positive rate in screening for microdeletion 22q11.2. METHODS: This study is based on samples that were analyzed using the Harmony® Prenatal Test (Roche Inc). The study cohort comprised samples from women with singleton pregnancies who were at least 16 years old and at least at 11 weeks' gestation. Logistic regression analysis was used to determine significant covariates that carry an impact on the screen-positive rate. RESULTS: The study population consisted of 52,019 pregnancies, including 309 pregnancies with a high-risk result for microdeletion 22q11.2. Thus, the overall screen-positive rate was 0.59%. In the low-risk group, the FF was 10.1%, and in the high-risk group, it was 7.3%. Regression analysis indicated a strong correlation between the FF and the screen-positive rate. In the cases with an FF of <11.0%, the screen-positive rate was 0.92%, while it was 0.13% in the group with a higher FF. CONCLUSION: The screen-positive rate depends on the FF. In order to keep the rate low, we recommend restricting the analysis to samples with a FF of 11% and more.

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.

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.

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.