Declaration of Helsinki: ethical norm in pursuit of common global goals.

The World Medical Association's Declaration of Helsinki is in the process of being revised. The following amendments are recommended to be incorporated in pursuit of the common goal of promoting health for all. 1. Data-driven research that facilitates broad informed consent and dynamic consent, assuring participant's rights, and the sharing of individual participant data (IPD) and research results to promote open science and generate social value. 2. Risk minimisation in a placebo-controlled study and post-trial access to the best-proven interventions for all who need them. 3. A future-oriented research framework for co-creation with all the relevant stakeholders.

Associated Anomalies and Outcome in Patients with Prenatal Diagnosis of Aortic Arch Anomalies as Aberrant Right Subclavian Artery, Right Aortic Arch and Double Aortic Arch.

We aimed to evaluate retrospectively associated anomalies and outcome in prenatal aortic arch anomalies (AAAs). We included ninety patients with aberrant right subclavian artery (ARSA), right aortic arch (RAA) with mirror image branching (RAA-mirror) or aberrant left subclavian artery (RAA-ALSA) and double aortic arch (DAA) between 2011 and 2020. In total, 19/90 (21.1%) had chromosomal anomalies, the highest rate being within the ARSA subgroup (17/46, 37%). All (13/13) of the RAA-mirror subgroup, 10/27 (37.0%) of RAA-ALSA, 13/46 (28.3%) of ARSA and 0/4 within the DAA subgroup had additional intracardiac anomaly. The rate of extracardiac anomalies was 30.7% in RAA-mirror, 28.3% in ARSA, 25.0% in DAA and 22.2% in the RAA-ALSA subgroup. A total of 42/90 (46.7%) had isolated AAAs: three (7.1%) with chromosomal anomalies, all trisomy 21 (3/26, 11.5%) within the ARSA subgroup. Out of 90, 19 (21.1%) were lost to follow-up (FU). Two (2.2%) intrauterine deaths occurred, and six (6.7%) with chromosomal anomalies terminated their pregnancy. In total, 63 (70.0%) were liveborn, 3/63 (4.8%) with severe comorbidity had compassionate care and 3/60 (5.0%) were lost to FU. The survival rate in the intention-to-treat cohort was 53/57 (93%). Forty-one (77.4%) presented with vascular ring/sling, two (4.9%) with RAA-ALSA developed symptoms and one (2.4%) needed an operation. We conclude that intervention due to vascular ring is rarely necessary. NIPT could be useful in isolated ARSA cases without higher a priori risk for trisomy 21 and after exclusion of other anomalies.

Monitoring of Women with Anti-Ro/SSA and Anti-La/SSB Antibodies in Germany-Status Quo and Intensified Monitoring Concepts.

Background: The fetuses of pregnant women affected by anti-Ro/anti-La antibodies are at risk of developing complete atrioventricular heart block (CAVB) and other potentially life-threatening cardiac affections. CAVB can develop in less than 24 h. Treatment with anti-inflammatory drugs and immunoglobulins (IVIG) can restore the normal rhythm if applied in the transition period. Routine weekly echocardiography, as often recommended, will rarely detect emergent AVB. The surveillance of these pregnancies is controversial. Home-monitoring using a hand-held Doppler is a promising new approach. Methods: To obtain an overview of the current practice in Germany, we developed a web-based survey sent by the DEGUM (German Society of Ultrasound in Medicine) to ultrasound specialists. With the intention to evaluate practicability of home-monitoring, we instructed at-risk pregnant women to use a hand-held Doppler in the vulnerable period between 18 and 26 weeks at our university center. Results: There are trends but no clear consensus on surveillance, prophylaxis, and treatment of anti-Ro/La positive pregnant between specialists in Germany. Currently most experts do not offer home-monitoring but have a positive attitude towards its prospective use. Intensified fetal monitoring using a hand-held Doppler is feasible for pregnant women at risk and does not lead to frequent and unnecessary contact with the center. Conclusion: Evidence-based guidelines are needed to optimize the care of anti-Ro/La-positive pregnant women. Individual risk stratification could help pregnancy care of women at risk and is welcmed by most experts. Hand-held doppler monitoring is accepted by patients and prenatal medicine specialists as an option for intensified monitoring and can be included in an algorithm for surveillance.

Comparison of the Results of Prenatal and Postnatal Echocardiography and Postnatal Cardiac MRI in Children with a Congenital Heart Defect.

OBJECTIVE: In fetuses with suspicion of congenital heart disease (CHD), assessment by segmental fetal echocardiography is of great importance. This study sought to examine the concordance of expert fetal echocardiography and postnatal MRI of the heart at a high-volume paediatric heart centre. METHODS: The data of two hundred forty-two fetuses have been gathered under the condition of full pre- and postnatal and the presence of a pre- and postnatal diagnosis of CHD. The haemodynamically leading diagnosis was determined for each test person and was then sorted into diagnostic groups. The diagnoses and diagnostic groups were used for the comparison of diagnostic accuracy in fetal echocardiography. RESULTS: All comparisons between the diagnostic methods for detection of congenital heart disease showed an "almost perfect" (Cohen's Kappa > 0.9) strength of agreement for the diagnostic groups. The diagnosis made by prenatal echocardiography showed a sensitivity of 90-100%, a specificity and a negative predictive value of 97-100%, and a positive predictive value of 85-100%. The diagnostic congruence resulted in an "almost perfect" strength of agreement for all evaluated diagnoses (transposition of great arteries, double outlet right ventricle, hypoplastic left heart, tetralogy of Fallot, atrioventricular septal defect). An agreement of Cohen's Kappa > 0.9 was achieved for all groups, with exception of the diagnosis of double outlet right ventricle (0.8) in prenatal echocardiography compared to postnatal echocardiography. This study came to the result of a sensitivity of 88-100%, a specificity and negative predictive value of 97-100%, and a positive predictive value of 84-100%. The performance of cardiac magnetic resonance imaging (MRI) as an additional measure to echocardiography had an added value in the description of the malposition of the great arteries when diagnosed with double outlet right ventricle and in the detailed description of the anatomy of the lung circulation. CONCLUSIONS: Prenatal echocardiography could be shown to be a reliable method for detection of congenital heart disease when regarding the slightly lower accuracy of diagnosis for double outlet right ventricle and right heart anomalies. Furthermore, the impact of examiner experience and the consideration of follow-up examinations for further improvement of diagnosis accuracy may not be underestimated. The main advantage of an additional MRI is the possibility to obtain a detailed anatomic description of the blood vessels of the lung and the outflow tract. The conduction of further studies that include false-negative and false-positive cases, and studies that are not set within the high-risk-group, as well as studies in a less specialized setting, would allow the completion and investigation of possible differences and discrepancies when comparing the results that have been obtained in this study.

Multicenter clinical experience with non-invasive cell-free DNA screening for monosomy X and related X-chromosome variants.

OBJECTIVE: We aimed to investigate how the presence of fetal anomalies and different X chromosome variants influences Cell-free DNA (cfDNA) screening results for monosomy X. METHODS: From a multicenter retrospective survey on 673 pregnancies with prenatally suspected or confirmed Turner syndrome, we analyzed the subgroup for which prenatal cfDNA screening and karyotype results were available. A cfDNA screening result was defined as true positive (TP) when confirmatory testing showed 45,X or an X-chromosome variant. RESULTS: We had cfDNA results, karyotype, and phenotype data for 55 pregnancies. cfDNA results were high risk for monosomy X in 48/55, of which 23 were TP and 25 were false positive (FP). 32/48 high-risk cfDNA cases did not show fetal anomalies. Of these, 7 were TP. All were X-chromosome variants. All 16 fetuses with high-risk cfDNA result and ultrasound anomalies were TP. Of fetuses with abnormalities, those with 45,X more often had fetal hydrops/cystic hygroma, whereas those with "variant" karyotypes had different anomalies. CONCLUSION: Both, 45,X or X-chromosome variants can be detected after a high-risk cfDNA result for monosomy X. When there are fetal anomalies, the result is more likely a TP. In the absence of fetal anomalies, it is most often an FP or X-chromosome variant.

Turner syndrome-omphalocele association: Incidence, karyotype, phenotype and fetal outcome.

OBJECTIVE: Omphalocele is known to be associated with genetic anomalies like trisomy 13, 18 and Beckwith-Wiedemann syndrome, but not with Turner syndrome (TS). Our aim was to assess the incidence of omphalocele in fetuses with TS, the phenotype of this association with other anomalies, their karyotype, and the fetal outcomes. METHOD: Retrospective multicenter study of fetuses with confirmed diagnosis of TS. Data were extracted from a detailed questionnaire sent to specialists in prenatal ultrasound. RESULTS: 680 fetuses with TS were included in this analysis. Incidence of small omphalocele in fetuses diagnosed ≥12 weeks was 3.1%. Including fetuses diagnosed before 12 weeks, it was 5.1%. 97.1% (34/35) of the affected fetuses had one or more associated anomalies including increased nuchal translucency (≥3 mm) and/or cystic hygroma (94.3%), hydrops/skin edema (71.1%), and cardiac anomalies (40%). The karyotype was 45,X in all fetuses. Fetal outcomes were poor with only 1 fetus born alive. CONCLUSION: TS with 45,X karyotype but not with X chromosome variants is associated with small omphalocele. Most of these fetuses have associated anomalies and a poor prognosis. Our data suggest an association of TS with omphalocele, which is evident from the first trimester.

Analysis of the Results of Sonographic Screening Examinations According to the Maternity Guidelines Before and After the Introduction of the Extended Basic Screening (IIb Screening) in Hesse.

AIM OF THE STUDY: The aim of the study is to examine the detection rates of malformations before and after the introduction of extended basic screening in Hesse by the Federal Joint Committee (Gemeinsamer Bundesausschuss, GQH) on July 1, 2013. METHOD: This is a retrospective, mainly exploratory data analysis of quality assurance data from the Office for Quality Assurance in Hesse (GQH). The data was collected in the period from January 1, 2010 to December 31, 2016 in the obstetric departments of the Hessian hospitals using documentation forms. The classification and evaluation of the diagnoses is based on ICD-10-GM-2019. RESULTS: At least one malformation is present in 0.7% of the cases. With a share of 30.0%, most of the congenital malformations are from the musculoskeletal system. 12.2% of the malformations come from the facial cleft, closely followed by malformations of the circulatory system with 11.3%. The highest prenatal detection rate (PDR) is found in congenital malformations of the nervous system at 56.8%. The lowest PDR is found in those of the genital organs with 2.1%. The PDR of cardiovascular malformations is 32.9%. Overall, a PDR of 25.2% is achieved. There was no change in the number of prenatal malformation diagnoses after the introduction of extended basic ultrasound. The distribution of malformation diagnoses not detected prenatally to the organ systems also has not changed after the introduction. CONCLUSION: The introduction of extended basic ultrasound did not bring the desired improvement with regard to the PDR in Hesse. Alternative approaches should be considered.

The Evolution and Developing Importance of Fetal Magnetic Resonance Imaging in the Diagnosis of Congenital Cardiac Anomalies: A Systematic Review.

Magnetic Resonance Imaging (MRI) is a reliable method, with a complementary role to Ultrasound (US) Echocardiography, that can be used to fully comprehend and precisely diagnose congenital cardiac malformations. Besides the anatomical study of the fetal cardiovascular system, it allows us to study the function of the fetal heart, remaining, at the same time, a safe adjunct to the classic fetal echocardiography. MRI also allows for the investigation of cardiac and placental diseases by providing information about hematocrit, oxygen saturation, and blood flow in fetal vessels. It is crucial for fetal medicine specialists and pediatric cardiologists to closely follow the advances of fetal cardiac MRI in order to provide the best possible care. In this review, we summarize the advance in techniques and their practical utility to date.

The Value of Delta Middle Cerebral Artery Peak Systolic Velocity for the Prediction of Twin Anemia-Polycythemia Sequence-Analysis of a Heterogenous Cohort of Monochorionic Twins.

Introduction: Twin anemia-polycythemia sequence (TAPS) is a complication in monochorionic-diamniotic (MCDA) twin pregnancies. This study analyzes whether the prenatal diagnosis using delta middle cerebral artery-peak systolic velocity (MCA-PSV) > 0.5 multiples of the median (MoM) (delta group) detects more TAPS cases than the guideline-based diagnosis using the MCA-PSV cut off levels of >1.5 and <1.0 MoM (cut-off group), in a heterogenous group of MCDA twins. Methods: A retrospective analysis of 348 live-born MCDA twin pregnancies from 2010 to 2021 with available information on MCA-PSV within one week before delivery and hemoglobin-values within 24 h postnatally were considered eligible. Results: Among postnatal confirmed twin pairs with TAPS, the cut-off group showed lower sensitivity than the delta group (33% vs. 82%). Specificity proved higher in the cut-off group with 97% than in the delta group at 86%. The risk that a TAPS is mistakenly not recognized prenatally is higher in the cut-off group than in the delta group (52% vs. 18%). Conclusions: Our data shows that delta MCA-PSV > 0.5 MoM detects more cases of TAPS, which would not have been diagnosed prenatally according to the current guidelines. In the collective examined in the present study, TAPS diagnostics using delta MCA-PSV proved to be a more robust method.

Is Fetal Hydrops in Turner Syndrome a Risk Factor for the Development of Maternal Mirror Syndrome?

Mirror syndrome is a rare and serious maternal condition associated with immune and non-immune fetal hydrops after 16 weeks of gestational age. Subjacent conditions associated with fetal hydrops may carry different risks for Mirror syndrome. Fetuses with Turner syndrome are frequently found to be hydropic on ultrasound. We designed a retrospective multicenter study to evaluate the risk for Mirror syndrome among pregnancies complicated with Turner syndrome and fetal hydrops. Data were extracted from a questionnaire sent to specialists in maternal fetal medicine in Germany. Out of 758 cases, 138 fulfilled our inclusion criteria and were included in the analysis. Of the included 138, 66 presented with persisting hydrops at or after 16 weeks. The frequency of placental hydrops/placentomegaly was rather low (8.1%). Of note, no Mirror syndrome was observed in our study cohort. We propose that the risk of this pregnancy complication varies according to the subjacent cause of fetal hydrops. In Turner syndrome, the risk for Mirror syndrome is lower than that reported in the literature. Our observations are relevant for clinical management and parental counseling.

The ethical responsibility to continue investigational treatments of research participants in situation of armed conflicts, economic sanctions or natural catastrophes.

This paper discusses the effects of armed conflict, economic sanctions, and natural catastrophes on ongoing clinical trials. We suggest that • stopping the accrual of new patients in clinical trials under such extreme conditions is acceptable. • research participants already receiving trial medication in such disruptive situations are to be considered highly vulnerable due to their medical dependency for ongoing treatment according to the approved clinical study protocol. • based on the present experience in Ukraine and Russia, we conclude that finishing ongoing trial treatments according to approved or amended protocols should be considered to be an ethical obligation of trial sponsors irrespective whether trial disruption is due to war, economic sanctions, or natural catastrophes. • it is important to devote more attention to the ethical challenges raised by such fundamentally disruptive situations to clinical trials generally in any region of the world.

Natural history of pulmonary atresia with intact ventricular septum (PAIVS) and critical pulmonary stenosis (CPS) and prediction of outcome.

OBJECTIVES: To analyse prenatal parameters predicting biventricular (BV) outcome in pulmonary atresia with intact ventricular septum/critical pulmonary stenosis (PAIVS/CPS). METHODS: We evaluated 82 foetuses from 01/08 to 10/18 in 3 centres in intervals 1 (< 24 weeks), 2 (24-30 weeks) and 3 (> 30 weeks). RESULTS: 61/82 (74.4%) were livebirths, 5 (8.2%) lost for follow-up, 3 (4.9%) had compassionate care leaving 53 (64.6% of the whole cohort and 86.9% of livebirths) with intention to treat. 9 died, 44/53 (83.0%) survived. 24/38 (63.2%) with information on postnatal outcome had BV outcome, 14 (36.8%) non-BV outcome (2 × 1.5 circulation). One with BV outcome had prenatal valvuloplasty. Best single parameter for BV outcome was tricuspid/mitral valve (TV/MV) ratio (AUC 0.93) in intervals 2 and 3 (AUC 0.92). Ventriculo-coronary-arterial communications (VCAC) were present in 11 (78.6%) in non-BV outcome group vs. 2 (8.3%) in BV outcome group (p < 0.001). Tricuspid insufficiency (TI)-Vmax > 2.5 m/s was present in BV outcome group in75.0% (18/24) vs. 14.3% (2/14) in non-BV outcome group. Including the most predictive markers (VCAC presence, TI- Vmax < 2.5 m/s, TV/MV ratio < cutoff) to a score, non-BV outcome was correctly predicted when > 1 criterion was fulfilled in all cases. After recently published criteria for foetal intervention, only 4/9 (44.4%) and 5/14 (35.7%) in our interval 2 + 3 with predicted non-BV outcome would have been candidates for intervention. Two (1 × intrauterine intervention) in interval 2, two in interval 3 reached BV outcome and one 1.5 circulation without intervention. CONCLUSION: TV/MV ratio as simple parameter has high predictive value. After our score, non-BV outcome was correctly predicted in all cases. Criteria for foetal intervention must further be evaluated.

Linking the Declarations of Helsinki and of Taipei: Critical Challenges of Future-Oriented Research Ethics.

Expansion of data-driven research in the 21st century has posed challenges in the evolution of the international agreed framework of research ethics. The World Medical Association (WMA)'s Declaration of Helsinki (DoH) has provided ethical principles for medical research involving humans since 1964, with the last update in 2013. To complement the DoH, WMA issued the Declaration of Taipei (DoT) in 2016 to provide additional principles for health databases and biobanks. However, the ethical principles for secondary use of data or material obtained in research remain unclear. With such a perspective, the Working Group on Ethics (WGE) of the International Federation of Associations of Pharmaceutical Physicians and Pharmaceutical Medicine (IFAPP) suggests a closer scientific linkage in the DoH to the (Declaration of Taipei) DoT focusing specifically on areas that will facilitate data-driven research, and to further strengthen the protection of research participants.

Development and Use of Gene Therapy Orphan Drugs-Ethical Needs for a Broader Cooperation Between the Pharmaceutical Industry and Society.

Gene therapy orphan medicinal products constitute a unique group of new drugs which in case of hereditary diseases are usually administered only once at an early age, in the hope to provide sufficient gene product to last for the entire life of the patients. The combination of an exceptionally large single payment and the life-long clinical follow-up needed for understanding the long-term benefits and safety of gene therapy, represent new types of scientific, financial, social and ethical challenges for the pharmaceutical industry, regulators and society. With special consideration of the uniqueness and importance of gene therapy, the authors propose a three points plan for a close cooperation between the pharmaceutical industry and society to develop orphan gene therapy. (1) In fully transparent health technology negotiations a close and long-lasting, contractually fixed cooperation should be established between the manufacturers and local health-care stakeholders for sharing the medical and scientific benefits, the financial risks as well as the burdens of the post-authorization clinical and regulatory development. (2) The parties should agree on a fair, locally affordable drug price without the usually very high premium price calculated to compensate for the low number of patients. In case of high manufacturing costs, the companies should offer prolonged, 15-20 years long payment by installment with risk-sharing, especially considering that the late outcome of the treatment is unknown. Society should assist scientifically and financially organizing a specific patient registry, treatment in specialized hospitals and adequate long-term follow-up of patients, the coordinated management of financial transactions related to the risk sharing program. (3) The post-authorization treatment and prolonged observation of additional new cases coordinated by society should provide real world data needed for the modern complex regulatory evaluation of gene therapy products by the competent authorities. We assume that fair sharing of the benefits and risks as well as a well-organized cooperation of society with the industry in collecting real world evidence might result in better drug evaluation and improved accessibility due to lower prices. The outlined concept might support gene therapy more efficiently than the presently requested outstandingly high prices.

Corrigendum: Linking the Declarations of Helsinki and of Taipei: Critical Challenges of Future-Oriented Research Ethics.

[This corrects the article DOI: 10.3389/fphar.2020.579714.].

The Shared Ethical Responsibility of Medically and Non-medically Qualified Experts in Human Drug Development Teams.

The complexity of developing and applying increasingly sophisticated new medicinal products has led to the participation of many non-medically qualified scientists in multi-disciplinary non-clinical and clinical drug development teams world-wide. In this introductory paper to the "IFAPP International Ethics Framework for Pharmaceutical Physicians and Medicines Development Scientists" it is argued that all members of such multidisciplinary teams must share the scientific and ethical responsibilities since they all influence directly or indirectly both the outcome of the various phases of the medicines development projects and the safety of the research subjects involved. The participating medical practitioner retains the overriding responsibility and the final decision to stop a trial if the well-being of the research subjects is seriously endangered. All the team members should follow the main ethical principles governing human research, the respect for autonomy, justice, beneficence and non-maleficence. Nevertheless, the weighing of these principles might be different under various conditions according to the specialty of the members.

Corrigendum: Core competencies for pharmaceutical physicians and drug development scientists.

[This corrects the article on p. 105 in vol. 4, PMID: 23986704.].

Core competencies for pharmaceutical physicians and drug development scientists.

Professional groups, such as IFAPP (International Federation of Pharmaceutical Physicians and Pharmaceutical Medicine), are expected to produce the defined core competencies to orient the discipline and the academic programs for the development of future competent professionals and to advance the profession. On the other hand, PharmaTrain, an Innovative Medicines Initiative project, has become the largest public-private partnership in biomedicine in the European Continent and aims to provide postgraduate courses that are designed to meet the needs of professionals working in medicines development. A working group was formed within IFAPP including representatives from PharmaTrain, academic institutions and national member associations, with special interest and experience on Quality Improvement through education. The objectives were: to define a set of core competencies for pharmaceutical physicians and drug development scientists, to be summarized in a Statement of Competence and to benchmark and align these identified core competencies with the Learning Outcomes (LO) of the PharmaTrain Base Course. The objectives were successfully achieved. Seven domains and 60 core competencies were identified and aligned accordingly. The effective implementation of training programs using the competencies or the PharmaTrain LO anywhere in the world may transform the drug development process to an efficient and integrated process for better and safer medicines. The PharmaTrain Base Course might provide the cognitive framework to achieve the desired Statement of Competence for Pharmaceutical Physicians and Drug Development Scientists worldwide.