Seminars in Fetal and Neonatal Medicine

  • Screening for spontaneous preterm birth and resultant therapies to reduce neonatal morbidity and mortality: A review
    Despite considerable effort aimed at decreasing the incidence of spontaneous preterm birth, it remains the leading cause of perinatal morbidity and mortality. Screening strategies are imperfect. Approaches used to identify women considered by historical factors to be low risk for preterm delivery (generally considered to be women with singleton pregnancies without a history of a previous preterm birth) as well as those at high risk for preterm birth (those with a previous preterm birth, short cervix, or multiple gestation) continue to evolve.

  • First and second trimester screening for fetal structural anomalies
    Fetal structural anomalies are found in up to 3% of all pregnancies and ultrasound-based screening has been an integral part of routine prenatal care for decades. The prenatal detection of fetal anomalies allows for optimal perinatal management, providing expectant parents with opportunities for additional imaging, genetic testing, and the provision of information regarding prognosis and management options. Approximately one-half of all major structural anomalies can now be detected in the first trimester, including acrania/anencephaly, abdominal wall defects, holoprosencephaly and cystic hygromata.

  • Genetic counselling, patient education, and informed decision-making in the genomic era
    Genomic technologies are now being applied to reproductive genetic screening. Circulating cell-free DNA testing in pregnancy for fetal chromosomal abnormalities is becoming more widely used as a screening test, and expanded carrier screening for autosomal and X-linked recessive conditions for more than a hundred conditions is available to couples for testing before and during pregnancy. These are most typically available as a commercial test. The purpose of reproductive genetic screening is to facilitate autonomous reproductive choices.

  • Advances in fetal echocardiography
    The development of fetal echocardiography and success in prenatal cardiac screening programs over the past 30 years has been driven by technical innovation and influenced by the different approaches of the various specialties practicing it. Screening for congenital heart defects no longer focuses on examining a limited number of pregnant women thought to be at increased risk, but instead forms an integrated part of a high-quality anatomical ultrasound performed in the second trimester using the ‘five-transverse view’ protocol.

  • Screening for fetal growth restriction and placental insufficiency
    Fetal growth restriction (FGR) continues to be a leading cause of preventable stillbirth and poor neurodevelopmental outcomes in offspring, and furthermore is strongly associated with the obstetrical complications of iatrogenic preterm birth and pre-eclampsia. The terms small for gestational age (SGA) and FGR have, for too long, been considered equivalent and therefore used interchangeably. However, the delivery of improved clinical outcomes requires that clinicians effectively distinguish fetuses that are pathologically growth-restricted from those that are constitutively small.

  • Current and future antenatal management of isolated congenital diaphragmatic hernia
    Congenital diaphragmatic hernia is surgically correctable, yet the poor lung development determines mortality and morbidity. In isolated cases the outcome may be predicted prenatally by medical imaging. Cases with a poor prognosis could be treated before birth. However, prenatal modulation of lung development remains experimental. Fetoscopic endoluminal tracheal occlusion triggers lung growth and is currently being evaluated in a global clinical trial. Prenatal transplacental sildenafil administration may in due course be a therapeutic approach, reducing the occurrence of persistent pulmonary hypertension, either alone or in combination with fetal surgery.

  • Opportunities and difficulties for counseling at the margins of viability
    At the margins of viability, the interaction between physicians and families presents challenges but also opportunities for success. The counseling team often focuses on data: morbidity and mortality statistics and the course of a typical infant in the neonatal intensive care unit. Data that are generated on the population level can be difficult to align with the multiple facets of an individual infant’s trajectory. It is also information that can be difficult to present because of framing biases and the complexities of intuiting statistical information on a personal level.

  • Contemporary and diverse approaches to perinatal ethics
    For this issue of Seminars in Fetal and Neonatal Medicine, we were asked to bring together a series of articles exploring contemporary ethical issues faced by perinatal care providers – obstetric and pediatric – in diverse geographic and cultural settings. This challenged us to think beyond the long-standing but still vexing questions of what to do at the margins of gestational viability, and how to best advocate for women and their infants in low-resource settings. In laying out what we see to be some of the most important, and evolving ethical conundrums that we and our colleagues face, we learned that the approaches to these issues are as heterogeneous as the problems themselves.

  • Screening for fetal chromosomal and subchromosomal disorders
    Screening for fetal chromosomal disorders has evolved greatly over the last four decades. Initially, only maternal age-related risks of aneuploidy were provided to patients. This was followed by screening with maternal serum analytes and ultrasound markers, followed by the introduction and rapid uptake of maternal plasma cell-free DNA-based screening. Studies continue to demonstrate that cfDNA screening for common aneuploidies has impressive detection rates with low false-positive rates. The technology continues to push the boundaries of prenatal screening as it is now possible to screen for less common aneuploidies and subchromosomal disorders.

  • Twin–twin transfusion syndrome – What we have learned from clinical trials
    Monochorionic twin pregnancies are at increased risk for adverse outcome compared to dichorionic twin pregnancies and singletons. Monochorionic-specific complications include twin–twin transfusion syndrome (TTTS), twin anemia–polycythemia sequence, single intrauterine fetal demise and its consequences on the co-twin, and selective intrauterine growth restriction. Whereas the natural history of monochorionic-specific complications carries a high risk of fetal death or severe neurologic disability, a framework now exists, based on well-designed clinical trials, for optimal treatment of these entities.

  • Ethical considerations in the care of complicated twin pregnancies
    Twin gestations are increasing in prevalence worldwide, and are potentially subject to medical complications which present uniquely complex ethical and psychosocial challenges for the pregnant patient and obstetrician to navigate. In this article, we explore these issues as they relate to medical decision-making in cases of discordant growth and discordant anomalies in both monochorionic and dichorionic twin pregnancies, including those affected by twin–twin transfusion syndrome, with particular attention to scenarios in which the individual fetuses hold competing interests.

  • Rationing potentially inappropriate treatment in newborn intensive care in developed countries
    In newborn intensive care, parents sometimes request treatment that professionals regard as ‘futile’ or ‘potentially inappropriate’. One reason not to provide potentially inappropriate treatment is because it would be excessively costly relative to its benefit. Some public health systems around the world assess the cost-effectiveness of treatments and selectively fund those treatments that fall within a set threshold. This article explores the application of such thresholds to questions in newborn intensive care: (i) when a newborn infant’s chance of survival is too small; (ii) how long treatment should continue; (iii) when quality of life is too low; and (iv) when newborn infants are too premature for cost-effective intensive care.

  • Neonatal research ethics after SUPPORT
    The SUPPORT study (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments), sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development to evaluate different oxygen saturation targets for extremely premature babies, led to a national controversy that was surprisingly public, intense, and polarizing. This article describes the study design, the study outcomes, and the key issues. I conclude that the controversy was based on two different views of the clinical investigator.

  • Improving neonatal care with the help of veteran resource parents: An overview of current practices
    Over the past decade, veteran parents who have lived a neonatal intensive care unit (NICU) experience have become increasingly involved as ‘resource parents’ to provide peer-to-peer support to “new” NICU parents. These parents can provide a unique form of support to new parents. They can also assume other roles in clinical care, research, administration and/or teaching, but those roles are rarely described in the literature. This article reviews many of the activities performed by resource parents in neonatology.

  • Ethical implications of the use of decision aids for antenatal counseling at the limits of gestational viability
    Shared decision-making is a recent priority in neonatology. However, its implementation is at an early stage. Decision aids are tools designed to assist in shared decision-making. They help patients competently participate in making healthcare decisions. There are limited studies in neonatology on the formal use of decision aids as used in adult medicine. Decision aids are relatively new, even in adult medicine where they were pioneered; therefore, there is a lack of systematic oversight to their development and use.

  • Ethical considerations in prenatal testing: Genomic testing and medical uncertainty
    Prenatal diagnostic testing has recently progressed from karyotype to routinely available chromosomal microarray, and the potential for fetal whole exome sequencing, both through invasive diagnostic testing and, in some cases, non-invasive prenatal testing. These tests bring beneficence through providing a higher diagnostic yield, often with lower risks of miscarriage than previously available testing, but also raise the question of harms related to an increase in uncertain and unknown results. Some parents-to-be report a desire to learn as much information as possible prenatally, and there may be beneficence in providing them with this information.

  • Fetal intervention: Improving evidence and expanding applications
    This issue of Seminars in Fetal and Neonatal Medicine addresses both established and still-developing interventional therapies for a broad range of fetal and pediatric disorders. Fetal treatment is no longer restricted to desperately ill fetuses that will perish before birth. Open fetal surgery is now applied to both lethal and non-lethal fetal disorders in an expanding number of centers. Fetoscopic procedures offer the hope of improved maternal outcomes and are being performed for a number of established and more controversial applications.

  • Fetal surgery for myelomeningocele: After the Management of Myelomeningocele Study (MOMS)
    Myelomeningocele (MMC) is the most frequently occurring congenital abnormality of the central nervous system and leads to significant physical disabilities. Historically treatment involved postnatal closure with management of the associated sequelae including ventricular shunting. The mechanism of neurologic damage that begins with abnormal neurulation followed by continued injury over the course of gestation made MMC a plausible candidate for in-utero surgical repair. Animal and early human studies demonstrated the feasibility of fetal closure.

  • Ethical issues in global health engagement
    With an increasing number of clinicians participating in global health work, such engagement is now more than ever in need of critical ethical scrutiny. Exemplary initiatives in research, academics and publication, and other special considerations, provide potential approaches for overcoming ethical challenges in global health work. These methods demonstrate that successful global health work includes a commitment to foundational ethical principles such as trust, honesty, open communication and transparency, sustainability, capacity building, and appreciation for multiple perspectives – principles that surpass the traditional considerations of clinical practice.

  • The ethics of maternal–fetal surgery
    Maternal–fetal surgery is performed on two patients, the pregnant patient and the fetal patient. Ethics is therefore an essential dimension of maternal–fetal surgery. From its beginnings in only a few centers, various procedures have become available in highly specialized centers in developed countries. Innovation and research have played an indispensable role in the development of maternal–fetal surgery and will continue to do so. In this article we present ethically justified criteria, based on the ethical concept of the fetus as a patient, for clinical innovation and research of maternal–fetal surgery and for the professionally responsible transition from innovation and research into clinical practice.

  • The use and misuse of moral distress in neonatology
    The neonatal intensive care unit is recognized as a stressful environment; the nature of caring for sick babies with uncertain outcomes and the need to make difficult decisions results in a work place where moral distress is prevalent. According to the prevailing definition, moral distress occurs when the provider believes that what is “done” is not the right course of action, with an element of constraint: the provider has no choice but to act this way. This can lead to adverse outcomes, including burnout and a change of career.

  • Shunt-based interventions: Why, how, and when to place a shunt
    The broad categories of surgical fetal therapy can be separated into either open surgical techniques or minimally invasive endoscopic/ultrasound-guided techniques that require only puncture of the uterus with single or multiple small ports. Benefits of fetoscopic or ultrasound-guided fetal intervention include decreased uterine irritability, decreased incidence of preterm labor, and avoidance of risks associated with hysterotomy and commitment to cesarean delivery for future pregnancies. Fetal abnormalities potentially amenable to ultrasound-guided drainage techniques include thoracic fluid-filled lesions and lower urinary tract obstruction.

  • How to value patient values: Cesarean sections for the periviable fetus, and home births
    Respect for patient autonomy involves providing sufficient information to patients to allow them to make informed decisions, and then honoring their requests unless they are unethical or futile. At times, the factors that patients consider may not be purely biologic ones but rather will include “spiritual” factors (a sense of control in a home birth). When patients balance biologic risks against spiritual gain, physicians may not be comfortable giving deference to patients’ choice. In order to explicate this issue we explore two clinical scenarios: home birth, and cesarean section for a periviable fetus; and we consider futility and limits on affirmative autonomy.

  • Values-based shared decision-making in the antenatal period
    Despite advances in life-saving technology for critically ill neonates, challenges continue to arise for infants delivered with extreme prematurity, congenital anomalies, and genetic conditions that exceed the limits of currently available interventions. In these situations, parents are forced to make cognitively and emotionally difficult decisions, in discussion with a neonatologist, regarding how aggressively to provide supportive measures at the time of delivery and at what point burdens of therapy outweigh benefits.

  • Ethics and palliative care in the perinatal world
    The perinatal world is unique in its dutiful consideration of two patients along the lines of decision-making and clinical management – the fetus and the pregnant woman. The potentiality of the fetus-newborn is intertwined with the absolute considerations for the woman as autonomous patient. From prenatal diagnostics, which may be quite extensive, to potential interventions prenatally, postnatal resuscitation, and neonatal management, the fetus and newborn may be anticipated to survive with or without special needs and technology, to have a questionable or guarded prognosis, or to live only minutes to hours.

  • The boundaries of fetal cardiac intervention: Expand or tighten?
    Fetal cardiac intervention (FCI) is a relatively new and continually evolving field, and, for select cardiac defects, offers the potential to alter the progression of the disease and improve outcomes. It is a procedure that requires a collaborative effort between maternal–fetal medicine, interventional cardiology and fetal echo/ultrasound specialists, as well as fetal and maternal anesthesiologists, nursing specialists, and social workers. This article reviews the most recently reported data and advances in FCI.

  • Carrier screening for single gene disorders
    Screening for genetic disorders began in 1963 with the initiation of newborn screening for phenylketonuria. Advances in molecular technology have made both newborn screening for newborns affected with serious disorders, and carrier screening of individuals at risk for offspring with genetic disorders, more complex and more widely available. Carrier screening today can be performed secondary to family history-based screening, ethnic-based screening, and expanded carrier screening (ECS). ECS is panel-based screening, which analyzes carrier status for hundreds of genetic disorders irrespective of patient race or ethnicity.

  • Fetal stem cell and gene therapy
    Advances in our understanding of stem cells, gene editing, prenatal imaging and fetal interventions have opened up new opportunities for the treatment of congenital diseases either through in-utero stem cell transplantation or in-utero gene therapy. Improvements in ultrasound-guided access to the fetal vasculature have also enhanced the safety and efficacy of cell delivery. The fetal environment offers accessible stem cell niches, localized cell populations with large proliferative potential, and an immune system that is able to acquire donor-specific tolerance.

  • Responsible surgical innovation and research in maternal–fetal surgery
    The field of maternal–fetal intervention is rapidly evolving with new technologies and innovations. This raises complex ethical and medico-legal challenges related to what constitutes innovative treatment versus human experimentation, with or without the umbrella of “medical research.” There exists a gray zone between these black and white classifications, but there are also clear guidelines that should be responsibly negotiated when making the essential transition between an innovative treatment and a validated therapy.

  • An EXTrauterine environment for neonatal development: EXTENDING fetal physiology beyond the womb
    Extreme prematurity is a major cause of neonatal mortality and morbidity, and remains an unsolved clinical challenge. The development of an artificial womb, an extrauterine system recreating the intrauterine environment, would support ongoing growth and organ maturation of the extreme preterm fetus and would have the potential to substantially improve survival and reduce morbidity. Previous efforts toward the development of such a system have demonstrated the ability to maintain the isolated fetus for short periods of support, but have failed to achieve the long-term stability required for clinical application.

  • Selective intrauterine growth restriction in monochorionic diamniotic twin pregnancies
    Selective intrauterine growth restriction (sIUGR) affects 10–15% of all monochorionic pregnancies. Early severe forms are associated with intrauterine demise or neurological adverse outcome for both twins. The characteristics of umbilical artery (UA) Doppler in the IUGR fetus determine three clinical types: (I) normal UA Doppler and associated with good prognosis; (II) persistently absent/reverse UA end-diastolic flow and associated with early deterioration of the IUGR twin and very preterm delivery; (III) intermittently absent/reverse end-diastolic flow in the UA, and associated with unexpected fetal demise or neurological injury in one or both twins.

  • Placenta-directed gene therapy for fetal growth restriction
    Fetal growth restriction (FGR) is a serious pregnancy complication affecting ∼8% of all pregnancies. There is no treatment to increase fetal growth in the uterus. Gene therapy presents a promising treatment strategy for FGR, with the use of adenoviral vectors encoding for proteins such as vascular endothelial growth factor (VEGF) and insulin-like growth factor demonstrating improvements in fetal growth, placental function, and neonatal outcome in preclinical studies. Safety assessments suggest no adverse risk to the mother or fetus for VEGF maternal gene therapy; a clinical trial is in development.