Perinatal outcome after maternal primary cytomegalovirus infection in the first trimester: a practical update and counseling aid

Cytomegalovirus (CMV) is the most common cause of congenital infection with approximately 0.5% of pregnant women in developed countries seroconverting during pregnancy. In utero transmission occurs in about one third of women who develop primary infection in the first trimester, and these fetuses are at risk for adverse perinatal outcomes and long-term neurological complications. The great promise of a prenatal therapy to reduce fetal infection after maternal primary CMV infection has not been realized to date. The prediction of CMV sequelae is particularly challenging for clinicians because of the heterogeneity of the published literature, the wide spectrum of perinatal outcomes, the adjustment of fetal risk at each stage of assessment, and the variable quality of published data. Given the continued lack of a proven fetal therapy, it is timely to review the natural history of congenital CMV in the modern management era. We have analyzed the recent literature, integrated findings from multiple studies, and calculated stage-specific risks for adverse perinatal outcome to assist in counseling women with first trimester primary CMV infection. © 2014 John Wiley & Sons, Ltd.     

Computer-assisted surgical planning and intraoperative guidance in fetal surgery: a systematic review

Fetal surgery has become a clinical reality, with interventions for twin-to-twin transfusion syndrome (TTTS) and spina bifida demonstrated to improve outcome. Fetal imaging is evolving, with the use of 3D ultrasound and fetal MRI becoming more common in clinical practise. Medical imaging analysis is also changing, with technology being developed to assist surgeons by creating 3D virtual models that improve understanding of complex anatomy, and prove powerful tools in surgical planning and intraoperative guidance. We introduce the concept of computer-assisted surgical planning, and present the results of a systematic review of image reconstruction for fetal surgical planning that identified six articles using such technology. Indications from other specialities suggest a benefit of surgical planning and guidance to improve outcomes. There is therefore an urgent need to develop fetal-specific technology in order to improve fetal surgical outcome. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.     

Fetal therapy: practical ethical considerations

Progress in prenatal diagnosis can lead to the diagnosis of severe fetal abnormalities for which natural history anticipates a fatal outcome or the development of severe disability despite optimal postnatal care. Intrauterine therapy can be offered in these selected cases. Prenatal diagnosis is the only field of medicine in which termination is an option in the management of severe diseases. Fetal therapy has therefore developed as an alternative to fatalist expectant prenatal management as well as to termination of pregnancy (TOP). There are few standards of fetal care that have gone beyond the stage of equipoise and even fewer have been established based on appropriate studies comparing pre- and postnatal care. Several ethical questions are being raised as fetal surgery develops, including basic Hippocratic principles of patients' autonomy and doctors' duty of competence moving the boundaries between experimental surgery, therapeutic innovation and standard care. In addition, the technical success of a fetal intervention can only rarely fully predict the postnatal outcome. Managing uncertainty regarding long-term morbidity and the possibility for fetal therapy to change the risk of perinatal death into that of severe handicap remains a critical factor affecting women's choice for TOP as an alternative to fetal therapy. Copyright © 2011 John Wiley & Sons, Ltd.     

The value and limitations of using predetermined criteria in decision making for maternal-fetal interventions

Maternal-fetal interventions—such as prenatal fetal myelomeningocele (MMC) repair—are at the forefront of clinical innovation within maternal-fetal medicine, pediatric surgery, and neonatology. Many centers determine eligibility for innovative procedures using pre-determined inclusion and exclusion criteria based on seminal studies, for example, the “Management of Myelomeningocele Study” for prenatal MMC repair. What if a person's clinical presentation does not conform to predetermined criteria for maternal-fetal intervention? Does changing criteria on a case-by-case basis (i.e., ad hoc) constitute an innovation in practice and flexible personalized care or transgression of commonly held standards with potential negative consequences? We outline principle-based, bioethically justified answers to these questions using fetal MMC repair as an example. We pay special attention to the historical origins of inclusion and exclusion criteria, risks and benefits to the pregnant person and the fetus, and team dynamics. We include recommendations for maternal-fetal centers facing these questions.     

First trimester screening cannot predict adverse outcomes yet

The use of first trimester screening to detect aneuploidy has become an integral part of prenatal care. The application of similar screening algorithms to identify women at the highest risk for other adverse pregnancy outcomes in the first trimester could potentially have a major clinical impact. There has been much investigation into the ability to identify patients early in pregnancy at high risk for adverse pregnancy outcomes who may benefit from further surveillance and/or intervention. For this to be the case, however, as is true of any useful screening test, effective interventions need to be available. Unfortunately, for fetal growth restriction and stillbirth, no such interventions exist short of delivery. For preeclampsia, low dose aspirin has been demonstrated to be of benefit in specific subgroups. For preterm birth, although there are efficacious treatments, first trimester serum markers or cervical length measurements do not add significantly beyond historical or demographic factors, in prediction of preterm birth. Given the current evidence, first trimester screening, via serum or ultrasound markers, does not have sufficiently high enough positive predictive values for the development of preeclampsia, fetal growth restriction, preterm birth or stillbirth. In order to develop effective screening algorithms for adverse pregnancy outcomes in the first trimester, understanding the heterogeneous phenotype of these complications and the underlying pathophysiology is needed. © 2014 John Wiley & Sons, Ltd.     

Prenatal interventions for fetal lung lesions

The widespread availability of high resolution ultrasound equipment and almost universal routine anatomy scanning in all pregnant women in the developed world has lead to increased detection of abnormalities in the fetal thorax. Already in the 1980s, large pleural effusions and significant macrocystic lesions in the fetus were easily detected on ultrasound. However, smaller lung tumours were often missed. Nowadays, fetal medicine centres receive many referrals for evaluation of fetal lung lesions, of which the most common are congenital cystic adenomatoid malformation and bronchopulmonary sequestration. Almost invariably, both the parents and the referring physicians experience anxiety after detection of large lung masses in the fetus. However, the vast majority of the currently detected fetal lung lesions have an excellent prognosis without the need for prenatal intervention. In the small group of fetuses in which the prognosis is poor, almost exclusively those with concomitant fetal hydrops and cardiac failure, several options for fetal therapy exist, often with a more than 50% survival rate. Indications, techniques, complications and outcomes of these interventions will be described in this review. Copyright © 2011 John Wiley & Sons, Ltd.     

First trimester screening can predict adverse pregnancy outcomes

There has been an increasing drive over the last two decades to push the detection of women at risk of adverse pregnancy outcomes into the first trimester. This has led to a plethora of techniques, risk assessments and biomarkers, both fascinating and bewildering in its breadth. Despite the vast amount of knowledge available, it is often difficult to determine what is practicable and valuable for clinical practice. This is especially true as earlier diagnosis does not necessarily equate to improved outcomes for mother and child. We suggest that, at least for preeclampsia, fetal growth restriction, spontaneous preterm birth and gestational diabetes, there are effective first trimester tests available to identify the women at risk of subsequently developing complications. Unfortunately, there are no currently reliable first trimester tests available for identifying women at risk of stillbirth. It is likely that this field will continue to develop over time, and we hope that new and better strategies will continue to emerge to target these clinically important pathologies. © 2014 John Wiley & Sons, Ltd.     

Access to prenatal exome sequencing for fetal malformations: A qualitative landscape analysis in the US

Objective

There is increasing evidence supporting the clinical utility of next generation sequencing for identifying fetal genetic disorders. However, there are limited data on the demand for and accessibility of these tests, as well as payer coverage in the prenatal context. We sought to identify clinician perspectives on the utility of prenatal exome sequencing (ES) and on equitable access to genomic technologies for the care of pregnancies complicated by fetal structural anomalies.

Method

We conducted two focus group discussions and six interviews with a total of 13 clinicians (11 genetic counselors; 2 Maternal Fetal Medicine/Geneticists) from U.S. academic centers and community clinics.

Results

Participants strongly supported ES for prenatal diagnostic testing in pregnancies with fetal structural anomalies. Participants emphasized the value of prenatal ES as an opportunity for a continuum of care before, during, and after a pregnancy, not solely as informing decisions about abortions. Cost and coverage of the test was the main access barrier, and research was the main pathway to access ES in academic centers.

Conclusion

Further integrating the perspectives of additional key stakeholders are important for understanding clinical utility, developing policies and practices to address access barriers, and assuring equitable provision of prenatal diagnostic testing.     

Fetal therapies for cytomegalovirus: What we tell prospective parents

Congenital CMV is the most common congenital infection in the developed world. Infection results in congenital disease ranging from asymptomatic infection to severe neurodevelopmental impairment, and occasionally fetal or neonatal death. Fetal infection can occur through maternal-fetal transmission during primary maternal infection or maternal reactivation or re-infection. Awareness among maternal health care providers and parents is low. The prevention of maternal CMV infection currently relies on hygiene measures, with no effective CMV vaccine or prophylactic therapies. No licensed treatment options are available to prevent maternal-fetal transmission or fetal disease. Hyperimmunoglobulin and valaciclovir have been investigated for prevention of maternal-fetal transmission or fetal treatment, with some evidence supporting consideration of maternal administration of hyperimmunoglobulin or valaciclovir therapy in certain circumstances. This article outlines the clinical evidence regarding proven preventative behavioral measures and experimental hyperimmunoglobulin and valaciclovir therapies, that is structured around common questions asked by pregnant women about CMV infection. It is aimed to help maternity health care providers counsel prospective parents about congenital CMV disease and the preventative and therapeutic strategies currently available.     

Fetal surgery for cardiac lesions

Intrauterine dilation of critical fetal aortic stenosis (AS) and pulmonary stenosis or atresia has the potential to change the natural course of these congenital heart defects preventing progression to a single ventricle circulation. This article reviews the world experience in fetal cardiac interventions. In carefully selected cases, fetal cardiac surgery can reverse end-stage heart failure and can provide biventricular outcome postnatally in about two thirds of the cases with successful interventions. Copyright © 2011 John Wiley & Sons, Ltd.     

Pregestational diabetes in pregnancy: Complications,management, surveillance,and mechanisms of disease—A review

Diabetes is an increasingly common diagnosis among pregnant women. Pregestational diabetes is associated with an increase in many adverse pregnancy outcomes, which impact both on the woman and her fetus. The models of pregnancy care for women with diabetes are based largely on observational data or consensus opinion. Strategies for aneuploidy screening and monitoring for fetal well-being should be modified in women with diabetes. There is an increasing understanding of the mechanisms by which congenital anomalies and disorders of fetal growth occur, involving epigenetic modifications, changes in gene expression in critical developmental pathways, and oxidative stress. This knowledge may lead to pathways for improved care for these high-risk pregnancies.     

Postnatal management and long-term outcome for survivors with congenital diaphragmatic hernia

Significant advances in the postnatal management of patients with congenital diaphragmatic hernia (CDH) have resulted in a remarkable improvement in survival rates over the past two decades. The success of current postnatal management of CDH patients has rendered fetal intervention to be limited to the most severe cases, and the role for prenatal treatment of CDH patients remains unclear. The adoption of lung-preserving strategies including high-frequency oscillatory ventilation (HFOV) and extracorporeal membrane oxygenation (ECMO) have improved CDH outcomes especially in those patients with significant ventilatory or circulatory compromise. Survival rates of up to 90% are being reported in some high-volume centers. However, the increased survival in CDH patients has been accompanied by an increase in neurological, nutritional and musculoskeletal morbidity among the long-term survivors. This has resulted in the need to provide resources for the long-term follow-up and support of this patient population. In this article, the postnatal management strategies and primary and secondary outcomes of high-volume international pediatric surgical centers will be reviewed. Finally, the role of a multidisciplinary management team for the follow-up of long-term CDH survivors will be discussed. Copyright © 2008 John Wiley & Sons, Ltd.     

Fetoscopic myelomeningocoele closure: Is the scientific evidence enough to challenge the gold standard for prenatal surgery?

Since the completion of the Management of Myelomeningocoele Study, maternal-fetal surgery for spina bifida has become a valid option for expecting parents. More recently, multiple groups are exploring a minimally invasive approach and recent outcomes have addressed many of the initial concerns with this approach. Based on a previously published framework, we attempt to delineate the developmental stage of the surgical techniques. Furthermore, we discuss the barriers of performing randomized controlled trials comparing two surgical interventions and suggest that data collection through registries is an alternative method to gather high-grade evidence.     

Prenatal DNA Sequencing: Clinical,Counseling, and Diagnostic Laboratory Considerations

Clinical diagnostic laboratories are producing next-generation sequencing-based test results that are becoming increasingly incorporated into patient care. Whole genome and exome sequencing on fetal material derived from amniocytes, chorionic villi, or products of conception is starting to be offered clinically in specialized centers, but it has not yet become routine practice. The technical, interpretation, and ethical challenges are greatest in the area of prenatal medicine because the fetus has a limited health history, and the physical examination is only indirectly available via prenatal sonography. Here, we provide an overview of these challenges and highlight the clinical utility, reporting, and counseling issues associated with prenatal DNA sequencing. Future considerations are also discussed. © 2017 John Wiley & Sons, Ltd.     

Prenatal diagnosis,prediction of outcome and in utero therapy of isolated congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) can be associated with genetic or structural anomalies with poor prognosis. In isolated cases, survival is dependent on the degree of lung hypoplasia and liver position. Cases should be referred in utero to tertiary care centers familiar with this condition both for prediction of outcome as well as timed delivery. The best validated prognostic indicator is the lung area to head circumference ratio. Ultrasound is used to measure the lung area of the index case, which is then expressed as a proportion of what is expected normally (observed/expected LHR). When O/E LHR is < 25% survival chances are < 15%. Prenatal intervention, aiming to stimulate lung growth, can be achieved by temporary fetal endoscopic tracheal occlusion (FETO). A balloon is percutaneously inserted into the trachea at 26–28 weeks, and reversal of occlusion is planned at 34 weeks. Growing experience has demonstrated the feasibility and safety of the technique with a survival rate of about 50%. The lung response to, and outcome after FETO, is dependent on pre-existing lung size as well gestational age at birth. Early data show that FETO does not increase morbidity in survivors, when compared to historical controls. Several trials are currently under design. Copyright © 2008 John Wiley & Sons, Ltd.     

Isolated fetal hydrothorax with hydrops: a systematic review of prenatal treatment options

Objective To evaluate the effect of prenatal therapeutic interventions on perinatal outcome in pregnancies complicated by isolated fetal hydrothorax with hydrops. Methods A systematic review of the literature from January 1982 to January 2006 of perinatal outcome in pregnancies with isolated fetal hydrothorax with hydrops with any form of prenatal treatment was conducted. Results Forty-four articles met our selection criteria, reporting a total of 172 fetuses treated prenatally. Reported treatment options were single (n = 13) or serial thoracocentesis (n = 18), thoraco-amniotic shunt placement (n = 100) or a combination of thoracocentesis and shunting (n = 36). Four case-reports described pleurodesis with OK-432, (n = 3) and intrapleural injection of autologous blood (n = 2). Overall survival rate was 63%, ranging from 54% for single thoracocentesis to 80% in the 5 cases treated with pleurodesis, without statistically significant differences between the treatment modalities. Shunt-placement with or without prior thoracocentesis was most often described, with survival rates of 67 and 61% respectively. Discussion The available literature consists exclusively of case reports and case series. This systematic review suggests that with prenatal intervention, perinatal survival rates around 63% are possible. There is a need for prospective, adequately controlled studies with long-term follow-up to determine the best treatment and more reliable outcome data in pregnancies complicated by fetal hydrothorax with hydrops. Copyright © 2007 John Wiley & Sons, Ltd.     

SARS-CoV2 (COVID-19) infection: is fetal surgery in times of national disasters reasonable?

Even though the global COVID-19 pandemic may affect how medical care is delivered in general, most countries try to maintain steady access for women to routine pregnancy care, including fetal anomaly screening. This means that, also during this pandemic, fetal anomalies will be detected, and that discussions regarding invasive genetic testing and possibly fetal therapy will need to take place. For patients, concerns about Severe Acute Respiratory Syndrome-Corona Virus 2 will add to the anxiety caused by the diagnosis of a serious fetal anomaly. Yet, also for fetal medicine teams the situation gets more complex as they must weigh up the risks and benefits to the fetus as well as the mother, while managing a changing evidence base and logistic challenges in their healthcare system.     

The influence of prenatal diagnosis on postnatal outcome in patients with structural congenital heart disease

Examination of the fetal heart has become an established part of mid-trimester anomaly scanning. Along side this has emerged the ability to diagnose congenital heart disease in the fetus with accuracy. Despite this, the development of screening programmes to look for fetal cardiac disease has only been partially successful. Furthermore, when detected, there seems to be little survival advantage associated with prenatal diagnosis. Demonstrating such an advantage is complicated by the nature of fetal cardiac disease, which tends to be severe and is often associated with extra-cardiac abnormalities. More selective studies, mostly involving small numbers of cases, are now beginning to demonstrate both improved survival and reduced morbidity in prenatally diagnosed infants presenting to cardiac intensive care units compared to those with a postnatal diagnosis. Copyright © 2004 John Wiley & Sons, Ltd.     

In utero therapy for fetal thoracic abnormalities

Fetal thoracic lung anomalies are rare. The specific diagnosis can be made by utilizing ultrasound, magnetic resonance imaging (MRI), and Doppler studies. Perinatal surveillance is required for large lesions and mediastinal shift regardless of the pathological diagnosis. These can cause physiological changes in the cardiovascular system with resulting hydrops. In utero therapies are variable but with no large randomized trials to compare risks and benefits. In most cases of fetal lung lesions, continued observation with postnatal therapy is the outcome. When fetal hydrops is present or impending, in utero fetal therapy is required to try to reverse that pathological course associated with fetal or neonatal death. Maternal morbidity is increased with the development of MIRROR syndrome following the presence of long-standing fetal hydrops and possible surgical procedures. Copyright © 2008 John Wiley & Sons, Ltd.