Fetal Neurosonogaphy: Ultrasound and Magnetic Resonance Imaging in Competition.

Both in routine diagnostics and detailed, highly specialized workups, major advances have been observed in many areas of ultrasound due to an increase in expertise and improved technology in recent years. This is particularly true in the case of fetal neurosonography 1 2 3 4. Malformations of the CNS together with fetal heart defects are among the most common congenital anomalies. From the embryonic phase to the late third trimester, the CNS undergoes extensive development and maturation processes. The diagnosis of CNS anomalies is therefore primarily dependent on the time at which the examination is performed and the experience of the examiner. The introduction of transvaginal and 3 D ultrasound for evaluating fetal brain structures has made it possible to diagnose pathological findings of the CNS with increasing accuracy 5. The detection rates for CNS anomalies are up to 90 - 95 % depending on the finding 3 5. Today, detailed fetal neurosonography also includes differential diagnostic evaluation of the posterior cranial fossa, the corpus callosum (CC), and the gyri and therefore exceeds the primarily conspicuous, non-specific diagnosis of "ventricular dilation" often occurring as an accompanying symptom 6 7 The article "Prenatal Diagnosis of Corpus Callosum Anomalies" appearing in this issue shows an increase in the frequency of diagnosis and also shows that it is possible to differentiate between complete and partial corpus callosum agenesis and hypoplasia of the corpus callosum with differentiation between isolated and non-isolated cases is possible on ultrasound. In 4 of 44 cases in which both neurosonography and intrauterine MRI were performed, there was a discrepancy between the ultrasound diagnosis and the intrauterine MRI findings. In a comparison of the sonographic diagnoses and the MRI findings, additional pathologies were seen on MRI but not on ultrasound in only 3 of 44 cases. In a further case of CC hypoplasia, the sonographic diagnosis was superior to the MRI findings.Another study appearing in this issue study of CNS anomalies in fetuses with complex clubfoot also showed additionally diagnosed CNS anomalies in 4 cases on MRI. MRI yielded supplementary findings that were not visible on ultrasound in 6 cases. Although the number of cases is small, it was able to be shown, as in other studies, that a certain percentage of CNS anomalies is able to be evaluated on an additional or supplementary basis on MRI.Since intrauterine MRI has been becoming increasingly important in recent years, it is necessary to determine when MRI is indicated. There is general consensus in the literature that MRI is not a screening method for detecting fetal anomalies but should be viewed as a supplementary method to ultrasound 8 9 10. However, MRI application in pregnancy is increasing. Intrauterine MRI is most commonly used in the case of abnormal ultrasound findings regarding the CNS 11 12 13. This includes morphological evaluation of malformations and recently also of acquired hypoxic-ischemic diseases, bleeding and inflammation such as CMV infections. Thoracic and abdominal malformations are also indications for MRI for the evaluation of the lung volume in diaphragmatic defects and in the case of suspicion of esophageal atresia abnormal placentation. Further possible indications for the use of MRI include monochorial multiple pregnancies with a feto-fetal transfusion syndrome (for the evaluation of neurological development) and select cases with known diseases and syndromes 14. The majority of studies for comparing intrauterine MRI to sonographic diagnosis include a small number of cases with limited or no follow-up. Data regarding sensitivities, specificities, and positive predictive values is limited. Many studies simply calculate the difference in percentages on the basis of a small number of cases. The best available data is in regard to CNS anomalies. In one of the few meta-analyses including 34 studies and documented follow-up in 959 fetuses, intrauterine MRI was correct in 91 % of cases which was an increase of 16 % above that achieved by ultrasound 15. This means a significant diagnostic gain for specific issues. However, it must be taken into consideration that the analysis includes a period of 20 years and fetal neurosonography has made major progress in this time. The diagnostic gain would tend to be smaller today. In many studies the level of experience of the ultrasound examiners often remains unclear A possible bias is also that an examiner with less experience determines an indication for intrauterine MRI faster and more frequently and can thus gain more information compared to highly specialized, experienced ultrasound examiners in prenatal centers. Since advanced training in prenatal diagnosis is becoming increasingly difficult due to the transfer of centers to ambulatory practices, there is a certain risk that crash courses or brief internships in ultrasound will result in intrauterine MRI playing an additional role in fetal differential diagnosis and in the confirmation of findings. Because intrauterine MRI is stressful for pregnant women, indiscriminate indication for MRI cannot be recommended even if no fetal damage is to be expected provided that the appropriate safety measures are observed (examination duration of approx. 30 minutes and implementation of MRI after 18 weeks of gestation). After a properly performed ultrasound examination, little additional morphological information can be gained from MRI 16. However, in the case of an unclear sonographic finding or in the event of therapeutic consequences for the care of the fetus or for the birth, MRI is an excellent supplementary method to ultrasound. Concretely, this means ultrasound first. If the finding is not clear, intrauterine MRI can be used as an adjunct method. In this way the cost-benefit ratio can be optimized. The gains achieved by MRI compared to US depend on the quality of the examination and thus on the expertise of the examiner in both methods. The indications for fetal MRI should also follow defined standards based on a protocol adapted to the particular clinical issue 16.

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.

Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype.

Gene discovery using massively parallel sequencing has focused on phenotypes diagnosed postnatally such as well-characterized syndromes or intellectual disability, but is rarely reported for fetal disorders. We used family-based whole-exome sequencing in order to identify causal variants for a recurrent pattern of an undescribed lethal fetal congenital anomaly syndrome. The clinical signs included intrauterine growth restriction (IUGR), severe microcephaly, renal cystic dysplasia/agenesis and complex brain and genitourinary malformations. The phenotype was compatible with a ciliopathy, but not diagnostic of any known condition. We hypothesized biallelic disruption of a gene leading to a defect related to the primary cilium. We identified novel autosomal recessive truncating mutations in KIF14 that segregated with the phenotype. Mice with autosomal recessive mutations in the same gene have recently been shown to have a strikingly similar phenotype. Genotype-phenotype correlations indicate that the function of KIF14 in cell division and cytokinesis can be linked to a role in primary cilia, supported by previous cellular and model organism studies of proteins that interact with KIF14. We describe the first human phenotype, a novel lethal ciliary disorder, associated with biallelic inactivating mutations in KIF14. KIF14 may also be considered a candidate gene for allelic viable ciliary and/or microcephaly phenotypes.

Is a routine ultrasound in the third trimester justified? Additional fetal anomalies diagnosed after two previous unremarkable ultrasound examinations.

PURPOSE: The detection of fetal structural abnormalities is a routine part of antenatal care. Ultrasound examination policies vary among European countries. An additional ultrasound for fetal structural anomalies in the 3 rd trimester seems important for many reasons. Some abnormalities develop or first become apparent later in pregnancy. The aim of the study was to analyze the rate of previously undetected structural abnormalities in the 3 rd trimester. MATERIALS AND METHODS: 8074 fetuses were examined in this prospective study between 1998 and 2008. All received an examination at 11 - 14 weeks and 79 % (6378 / 8074) of these fetuses also received an ultrasound at 20 - 24 weeks. If both of the examinations did not detect structural abnormalities, the fetuses were included in the study group and received an ultrasound at 28 - 32 weeks (n = 5044). New structural abnormalities in the 3 rd trimester were analyzed. The outcome was available in 96 % of the cases. RESULTS: The overall incidence of fetal malformations was 3.6 % (n = 289), of which 40 % (116 / 289) were diagnosed at 11 - 14 weeks. The following 2nd trimester scan revealed 102 (35 %) new fetal malformations. An additional 44 (15 %) structural abnormalities were found in the 3 rd trimester. These were mainly abnormalities of the urogenital system (n = 18). There were also anomalies of the cardiovascular system (n = 9), the gastrointestinal system (n = 6) and the central nervous system (n = 4). One of the cases had a previously undiagnosed abnormal karyotype. CONCLUSION: The ultrasound examination in the 3 rd trimester is of additional benefit and can detect previously unknown structural abnormalities. These findings are relevant for perinatal management and postnatal follow-up.

Prenatal counseling--implications of the cultural background of pregnant women on information processing, emotional response and acceptance.

PURPOSE: Providing information about prenatal diagnosis (PND) that leads to an informed decision is ethically and psychologically challenging, especially in an intercultural context. The aim was to investigate cultural differences in information processing, test interpretation, evaluation of an established information leaflet, emotional response during screening and acceptance of PND. MATERIALS AND METHODS: This prospective study compared 30 pregnant Turkish immigrants with 30 women from Switzerland and countries within the European Union (EU). They completed a questionnaire prior to (T1) and after risk assessment between 11-14 weeks (T2) and after receiving the results (T3). The questionnaire focused on the perception of, experiences with and knowledge about the risk assessment and included the hospital anxiety and depression scale (HADS). χ(2) tests were used for dichotomous variables and Student's t-tests for scores on perception, experience, knowledge, depression and anxiety. Groups were compared over time by 2-factorial ANOVA. RESULTS: Regarding the 6 questions on knowledge, the rate of correct answers was between 32.2% and 62.5% at T1 and 35.1% and 75.0% at T2. The Turkish women's knowledge level was significantly lower. They rated the information leaflet as less helpful and found the counseling significantly more unsettling. The acceptance of PND was higher in Turkish women. CONCLUSION: Considering the information and knowledge deficits, informed consent was not given in every case, especially in Turkish women. Nevertheless, the acceptance of PND was good. Further studies will have to focus on counseling strategies that take into account the specific needs and expectations of pregnant women with different cultural backgrounds.

[Pregnant women's assessment and level of knowledge of prenatal counseling]. / Wie beurteilen Schwangere die pränatale Beratung und was wissen sie im Anschluss daran?

PURPOSE: Informed decision making and informed consent prior to any intervention are crucial in the ethically and psychologically complex field of prenatal diagnosis (PND). The aim of this study was to investigate whether and to what extent pregnant women understand the information provided by their physicians. MATERIALS AND METHODS: Fifty pregnant women in the first trimester answered a structured questionnaire after their first visit between 7 to 10 weeks of gestation that routinely includes basic prenatal counseling. A special focus was put on information transfer, knowledge about and understanding of prenatal tests, as well as previous experiences with PND. The results were analyzed with regard to differences due to background, educational level and previous experiences with PND. RESULTS: The maternal mean age was 31.1 years (SD 6.7). 38 patients (76 %) had at least one previous pregnancy and two thirds of them had experiences with PND. Their experience was mainly positive. About three quarters of the women stated that they had been informed about the test methods during the consultation and had understood the explanations. Uncertainty was reported in 12.2 % and 23.3 % of the women said they had further questions. The percentage of questions related to appropriate understanding that were answered correctly was only 44 % to 77.5 %. The percentage of correct answers was lower in women without experience with PND, with a lower educational level and born in countries outside the EU and Switzerland. CONCLUSION: Pregnant women are relatively well informed about prenatal tests. Their actual knowledge of the meaning of the tests, however, seems to be incomplete. Especially in the case of immigrants and women without previous experience with PND, it is therefore doubtful whether the preconditions for an informed consent are met. Further research needs to focus on more helpful information and individually adapted counseling concepts for decision making in PND.

[Recent advances in prenatal diagnostics]. / Neue Möglichkeiten in der pränatalen Diagnostik.

During the last years, technical improvements have increased the possibilities in prenatal ultrasound. During the eighties and nineties, fetal malformations were increasingly detected and specified. Since a few years, the measurement of the fetal nuchal translucency between 11 and 14 weeks of gestation has been implemented to calculate the individual risk, in combination with most recent biochemical markers. Today, the sonographic measurement of the nuchal translucency is regarded as a valuable screening tool for chromosomal anomalies in prenatal medicine. Beside standardized examinations, a profound information and counseling of the pregnant women should be emphasized. With the improvement of the specific maternal risk calculation, using the sonographic measurement of the nuchal translucency, the biochemical markers and the maternal age, unnecessary invasive examinations may be prevented and their overall number can significantly be reduced. The same trend is seen in the whole field of prenatal medicine, illustrated by the detection of the fetal rhesus D status from the maternal blood and the use of Doppler ultrasound in the management of fetal anemia.

Spontaneous fetal loss rates in a non-selected population.

The objective of this work was to determine the rate of spontaneous fetal loss up to 28 weeks of gestation in uncomplicated pregnancies of a low-risk population after sonographically identified intact intrauterine pregnancy during the first trimester. Transvaginal ultrasounds were given to 2,534 women at between six and 12 weeks of gestation. Inclusion criteria were a positive fetal cardiac activity and no antecedent signs of vaginal bleeding. Gestational age was confirmed by measurement of the crown-rump length and/or biparietal diameter (BIP). Patients were followed until delivery or up to a fetal loss. The mean fetal loss rate between 12 and 28 weeks was 3.86% (n = 99). Fetal loss increased with maternal age: fetal loss rate under 20 yr: 2.94% (OR 0.75; CI 0.23-2. 46), 20-24 yr: 3.20% (OR 0.77; CI 0.48-1.23), 25-29 yr: 3.39% (OR 0.77; CI 0.50-1.19), 30-34 yr: 3.89% (OR 1.01; CI 0.59-1.71), 35-39 yr: 7.82% (OR 2.13; CI 1.04-4.32), 40-45 y: 50% (OR 13.84; CI 6.67-28.72) and > 45 yr: 50% (OR 13.05; CI 1.96-86.71) respectively. The frequency of spontaneous fetal loss before 28 weeks gestation was assessed systematically in a low-risk population. There was a very clear correlation with advancing maternal age. These data now can be used as background loss rate information for evaluating the safety of invasive prenatal diagnosis, and they will be more valid for this purpose than the available data taken from selected cohorts of women, such as those from hospital clinics or from infertility programs.

Parental origin of the extra haploid chromosome set in triploidies diagnosed prenatally.

The parental origin of the additional chromosome complement in a total of 17 cases of triploidy was determined mainly using highly polymorphic microsatellites. Maternal origin of the triploidy was demonstrated in most cases. To the best of our knowledge, this is the first systematic evaluation of the parental origin of chromosome sets in fetuses who survived until a cytogenetic diagnosis was established. In contrast to previous investigations this study documented a predominance of maternal origin of the extra haploid set mainly due to longer survival time for digynic triploidies. The concept of 2 distinct fetal phenotypes in triploidy is clearly supported by this study.

Direct fetal administration of adenosine for the termination of incessant supraventricular tachycardia.

BACKGROUND: Adenosine terminates supraventricular reentry tachycardia safely and effectively in the pediatric age group. CASE: The recurrence of pretreated incessant tachycardia led to severe hydrops in a 28-week-old fetus. The tachycardia was terminated instantly with direct fetal administration of adenosine via the umbilical vein. Normal heart rate and rhythm were then preserved temporarily with digoxin and flecainide. CONCLUSION: Direct fetal adenosine administration might be helpful in the treatment of fetal reentry tachycardias if the sinus rhythm achieved quickly can be preserved by long-acting antiarrhythmic drugs. Such a combined therapeutic approach might be especially advantageous in hydropic fetuses.

Three dimensional volume measurement of the cervix during pregnancy compared to conventional 2D-sonography.

OBJECTIVE: To compare the three dimensional (3D) volume assessment of the cervix with the conventional two-dimensional cervical length measurement in a low and a high risk group for cervical incompetence. METHODS: In an observational study, we investigated a group A of low risk pregnancies (no preterm contractions, no vaginal bleeding or vaginal infections and no history of preterm delivery) and a group B of high risk pregnancies (preterm contractions or PROM). All patients underwent a transvaginal ultrasound investigation with a 7.5 MHz probe using a three-dimensional ultrasound system (Combison 530, Kretztechnik, Austria). After measuring the cervical length, the internal os and the funneling with the B-mode, 3D-volume was recorded twice by the same investigator using the same machine. Since 2D-length measurement of the cervix has been established to be predictive for spontaneous preterm delivery, we wanted to test whether 3D-volume assessment has a better discriminative power to differentiate a high-risk from a low-risk group. Therefore the 2D and 3D measurements (mm, resp. cm3) were compared between patient groups A and B using the two tailed Student t-test and Fisher's Exact test. RESULTS: In 2D cervical length measurement the mean cervical length in group A was significantly longer than in group B: 41.1 +/- 8.61 mm and 27.77 +/- 10.42 mm, P = 0.00000017. In 3D-sonography the mean cervical volume was larger in group A, but the difference compared to group B was not significant: 47.71 +/- 18.38 mm and 39.90 +/- 12.57 mm, P = 0.07. CONCLUSION: Contrary to our hypothesis cervical length measurement therefore was superior to cervical volume measurement assessed by 3D ultrasound for identifying women with increased risk of spontaneous preterm delivery. This may be due to the larger distribution of measurement values in the 3D group.

Charts for cervical length in singleton pregnancy.

OBJECTIVES: To construct charts for cervical length in a low risk population measured by transvaginal ultrasonography. METHODS: Pregnant women of an apparently normal population were seen in the ultrasound division of the University Women's Hospital Basel between 20 and 34 weeks of gestation and underwent once (one measurement per subject) a transvaginal ultrasound measurement of the cervix under standardized conditions. In order to establish normal values of the cervical length, finally only women who delivered spontaneously at term (>37 weeks of gestation) remained in the study. Exclusion criteria were preterm labor, multiple pregnancies, cerclage or surgical intervention prior to pregnancy. For statistical evaluation, regression analysis and calculation of 5th and 95th percentiles were performed. RESULTS: A total of 669 cervical measurements were recorded. The number of measurements differed from 22 measurements at 23 weeks of gestation to 86 at 31 weeks of gestation. Cervical length gradually and significantly decreased as the gestational age progressed (between 20 and 34 weeks of gestation). New charts with the 5th, 50th and 95th percentile are presented and compared with previously published data. CONCLUSIONS: Our charts for cervical length in a limited risk population can be used for observing patients at high risk of preterm delivery and for clearly identifying a significant deviation or decline in the percentile for these subjects.