Seminars in Fetal and Neonatal Medicine

  • Optimal human and system performance during neonatal resuscitation
    Performance in the delivery of care to sick neonates in need of resuscitation has long been defined primarily in terms of the extent of the knowledge possessed and hands-on skill demonstrated by physicians and other healthcare professionals. This definition of performance in neonatal resuscitation is limited by its focus solely on the human beings delivering care and a perceived set of the requisite skills to do so. This manuscript will expand the definition of performance to include all of the skill sets that humans must use to resuscitate newborns as well as the often complex systems in which those humans operate while delivering that care.

  • Prophylactic and early targeted treatment of patent ductus arteriosus
    Treatment of a haemodynamically significant patent ductus arteriosus (PDA) in the very preterm infant has been an accepted approach for several decades. However, the rationale for closure of PDA has recently been challenged due to reports of success with conservative approaches and the lack of evidence for longer-term benefits from treatment. In this article, we address an approach to assess treatment of those babies most likely to benefit.

  • International perspective on management of a patent ductus arteriosus: Lessons learned
    Whereas association between a patent ductus arteriosus (PDA) and neonatal morbidities has been well described, consensus has not been reached on whether the relationship is causal, on benefit of (or lack of) treatment, on factors guiding the ‘need to treat’, and on treatment strategies. Trials to date have primarily focused on the narrow outcome of successful ductal closure. Evidence from several retrospective studies has suggested that management may be modified with increased use of conservative treatment.

  • Ductus arteriosus and fetal echocardiography: Implications for practice
    The ductus arteriosus (DA) is a crucial part of the fetal circulation, both in the normal fetus and in critical congenital heart disease (CHD). It allows shunting between the pulmonary and systemic circulations. In physiological prenatal conditions, the DA lets the majority of right ventricular output bypass the fluid-filled, high-resistance lungs. The DA can cause hemodynamic compromise in the fetus and neonate when constricted or absent (in isolation or in patients with CHD) and may lead to pre- or postnatal sequelae within other systems when forming part of a vascular ring.

  • Prenatal screening for fetal and obstetric complications: New opportunities and challenges
    This timely issue of Seminars in Fetal and Neonatal Medicine is devoted to prenatal screening for major contributors to perinatal morbidity and mortality, including preterm birth, fetal growth restriction, fetal genetic and chromosomal disorders, and structural birth defects. Rapidly evolving technologies are improving our ability to predict and diagnose pregnancy complications using non-invasive approaches, such as ultrasound and maternal blood analysis. This progress in prenatal screening has created new opportunities to provide women more information about the health of their unborn baby, and to offer interventions that may improve perinatal outcomes.

  • Genetics of the patent ductus arteriosus (PDA) and pharmacogenetics of PDA treatment
    Patent ductus arteriosus (PDA) is a frequent, complex, and difficult to treat clinical syndrome among preterm infants in the neonatal intensive care unit. In addition to known clinical risk factors, there are emerging data about genetic predisposition to PDA in both animal and human models. Clinical response and toxicity from drugs used to treat PDA are highly variable. Developmental and genetic aspects of pharmacokinetics and pharmacodynamics influence exposure and response to pharmacologic therapies.

  • Editorial
    This issue of Seminars provides in-depth analysis of the differences in vulnerability to seizures in the neonatal versus mature brain, seizures in term versus preterm neonates, and seizures related to acute brain injuries versus neonatal-onset epilepsies. Neonatal seizures are a common and consequential phenomenon. Seizures in newborn infants are most commonly due to acute acquired brain injuries [1]. Yet, the neonatal onset epilepsies account for approximately 10–15% of neonatal seizures [2]. Early differentiation of acute symptomatic seizures from neonatal-onset epilepsies is critical in order to guide diagnostic evaluations, treatments, and long-term management.

  • Amplitude-integrated electroencephalography for seizure detection in newborn infants
    The amplitude-integrated electroencephalogram (aEEG) is a filtered and compressed EEG trend that can be used for long-term monitoring of brain function in patients of all ages. aEEG is increasingly used in neonatal intensive care units since several studies have shown its utility in high-risk newborn infants. Main indications for aEEG monitoring include early evaluation of brain function after perinatal asphyxia and seizure detection. The aEEG is usually recorded from one or two channels derived from parietal, central, or frontal leads.

  • Designing a trial for neonatal seizure treatment
    Neonatal seizures are widely considered a neurological emergency with a need for prompt treatment, yet they are known to present a highly elusive target for bedside clinicians.Recent studies have suggested that the design of a neonatal seizure treatment trial will profoundly influence the sample size, which may readily increase to hundreds or even thousands as the achieved effect size diminishes to clinical irrelevance. The self-limiting and rapidly resolving nature of neonatal seizures diminishes the measurable treatment effect every hour after seizure onset and any effect may potentially be confused with spontaneous resolution, precluding the value of many observational studies.

  • Epileptogenesis in neonatal brain
    Epilepsy is a chronic neurological disorder affecting 65 million people worldwide. The etiologies of seizures can often be identified as genetic, metabolic, structural, immunologic or infectious, but in many cases the cause is unknown with the current diagnostic tools. Epileptogenesis is a process during which genetic or other acquired etiologies/insults lead to functional, structural, or network reorganization changes in the brain that may lead to the development of, or progression of, spontaneous seizures.

  • Acute symptomatic neonatal seizures in preterm neonates: etiologies and treatments
    Acute symptomatic neonatal seizures in preterm newborns are a relevant clinical challenge due to the presence of many knowledge gaps. Etiology-wise, acute symptomatic seizures have an age-specific epidemiology, with intraventricular hemorrhage and its complications representing the first cause in extremely and very preterm neonates, whereas other etiologies have similar occurrence rates as in full-term infants. Specific treatment strategies for the premature neonates are not yet available. Studies suggest a similarly low response rate with even more unfavorable prognosis than in full-term infants.

  • Ultrasound screening for complications in twin pregnancy
    In the decades since the introduction of ultrasound into routine obstetric practice, the advantages of ultrasound have moved beyond the simple ability to identify multiple pregnancies antenatally to the possibility of screening them for fetal anomalies, pre-eclampsia, preterm birth, and the complications specific to monochorionic pregnancies. Screening studies have often excluded twins because physiological differences impact on the validity and sensitivity of the screening tests in routine use in singletons, and therefore, the evidence of screening performance in multiple pregnancy lags behind the evidence from singleton pregnancies.

  • Outcomes after acute symptomatic seizures in neonates
    Acute symptomatic seizures are a common sign of neurological dysfunction and brain injury in neonates and occur in approximately one to three per 1000 live births. Seizures in neonates are usually a sign of underlying brain injury and, as such, are commonly associated with adverse outcomes. Neurological morbidities in survivors often co-occur; epilepsy, cerebral palsy, and intellectual disability often occur together in the most severely affected children. Risk factors for adverse outcome include prematurity, low Apgar scores, low pH on the first day of life, seizure onset 72 h after birth, abnormal neonatal neurological examination, abnormal neonatal electroencephalographic background, status epilepticus, and presence and pattern of brain injury (particularly deep gray or brainstem injury).

  • Acute symptomatic seizures in term neonates: Etiologies and treatments
    Acute symptomatic seizures caused by either diffuse or focal perinatal hypoxic–ischemic insults and intracranial hemorrhage in term newborns make up the large majority of all neonatal seizures. Acute seizures are one of the most common neurological disorders in term newborns who require admission to the neonatal intensive care unit. Despite elucidation of seizure pathogenesis in this population using animal models, treatment is limited by a lack of good evidence-based guidelines because of a paucity of rigorously conducted clinical trials or prospective studies in human newborns.

  • Neonatal epilepsies: Clinical management
    Whereas the majority of seizures in neonates are related to acute brain injury, a substantial minority are the first symptom of a neonatal-onset epilepsy, often linked to a pathogenic genetic variant. This defect may disrupt cortical development (e.g., lissencephaly, focal cortical dysplasia), lead to metabolic changes (e.g., pyridoxine-dependent epilepsy, sulfite oxidase deficiency) or lead to cortical dysfunction without metabolic or macroscopic structural changes (e.g., channelopathies, STXBP1).

  • Neonatal epilepsy genetics
    Neonatal epilepsy genetics is a rapidly expanding field with recent technological advances in genomics leading to an expanding list of genetic disorders associated with neonatal-onset epilepsy. The genetic causes of neonatal epilepsy can be grouped into the following categories: (i) malformations of cortical development, (ii) genetic–metabolic, (iii) genetic–vascular, (iv) genetic–syndromic, and (v) genetic–cellular. Clinically, epilepsy in the neonate shows phenotypic overlap with pathogenic variants in unrelated genes causing similar clinical presentation (locus heterogeneity) and variants in the same gene leading to a wide clinical spectrum ranging from benign familial neonatal seizures to more severe epileptic encephalopathies (variable expressivity).

  • Better organization of perinatal services along with protocolised approach to resuscitation and standardisation of neonatal intensive care has led to high rates of survival among neonates with life-threatening conditions like extreme prematurity, hypoxic ischaemic encephalopathy and congenital malformations. The quest to minimise secondary brain injury has led clinicians to place greater emphasis on neuro-physiology and is reflected in the incorporation of newer interventions like therapeutic hypothermia.

  • Electroencephalographic monitoring for seizure identification and prognosis in term neonates
    Seizures represent a manifestation of neurological disease in the neonatal period. Historically, neonatal seizures were identified by direct clinical observation. However, since most seizures are electroencephalographic (EEG)-only (subclinical, non-convulsive) and clinical manifestations may be subtle, many clinicians place increasing importance on EEG data including conventional EEG or amplitude-integrated EEG to identify seizures in neonates. Beyond seizure identification, the EEG is a robust source of information about brain function that can be useful for neurobehavioral prognostication in some neonates.

  • Beyond screening for chromosomal abnormalities: Advances in non-invasive diagnosis of single gene disorders and fetal exome sequencing
    Emerging genomic technologies, largely based around next generation sequencing (NGS), are offering new promise for safer prenatal genetic diagnosis. These innovative approaches will improve screening for fetal aneuploidy, allow definitive non-invasive prenatal diagnosis (NIPD) of single gene disorders at an early gestational stage without the need for invasive testing, and improve our ability to detect monogenic disorders as the aetiology of fetal abnormalities. This presents clinicians and scientists with novel challenges as well as opportunities.

  • Parental experiences after prenatal diagnosis of fetal abnormality
    For many pregnant women, prenatal testing is a routine component of contemporary pregnancy care. Receiving a prenatal diagnosis is frequently associated with intense feelings of shock and grief; the extent of which may be unrelated to the pregnancy gestation or the condition diagnosed. During this time of crisis, parents are often faced with important choices about their pregnancy. Levels of understanding and experiences of professional support throughout this time likely impact decisions that are made and how they are subsequently perceived.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.