Fetal-neonatal neurology program development: Continuum of care during the first 1000 days

Abstract

Global estimates show that 10–20% of persons express developmental disability. During critical and sensitive periods of developmental neuroplasticity over the first 1000 days, adverse gene-environment interactions are likely to contribute to permanent life-long disabilities and early mortality. This article describes fetal-neonatal neurology (FNN) program development that integrates vertical and horizontal diagnostic perspectives. Trimester-specific conditions to the maternal-placental-fetal triad begin at conception, followed by pediatric patient care over the first two years of life to address changing phenotypic form and function. While fetal and neonatal neurology trainees prepare to offer person-centric healthcare, population-based considerations address obstacles to optimal health relevant to resource-rich and poor nations. Maternal and pediatric care practices over the first 1000 days underscore equitable health policy. Global initiatives apply geographic distance, biosocial dynamics, and cultural differences to developmental origins and life-course theories, to more effectively reduce disease burden over the life continuum.

Full text

REVIEW ARTICLE
Fetal-neonatal neurology program development: Continuum of
care during the first 1000 days
Sonika Agarwal
1
✉and Mark S. Scher
2
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2021
Global estimates show that 10–20% of persons express developmental disability. During critical and sensitive periods of
developmental neuroplasticity over the first 1000 days, adverse gene-environment interactions are likely to contribute to
permanent life-long disabilities and early mortality. This article describes fetal-neonatal neurology (FNN) program development that
integrates vertical and horizontal diagnostic perspectives. Trimester-specific conditions to the maternal-placental-fetal triad begin
at conception, followed by pediatric patient care over the first two years of life to address changing phenotypic form and function.
While fetal and neonatal neurology trainees prepare to offer person-centric healthcare, population-based considerations address
obstacles to optimal health relevant to resource-rich and poor nations. Maternal and pediatric care practices over the first 1000 days
underscore equitable health policy. Global initiatives apply geographic distance, biosocial dynamics, and cultural differences to
developmental origins and life-course theories, to more effectively reduce disease burden over the life continuum.
Journal of Perinatology (2022) 42:165–168; https://doi.org/10.1038/s41372-021-01282-5
INTRODUCTION
Developmental disabilities are reported in approximately 10–20% of
the population [1]. These are most likely underestimates based on
current inclusion criteria developed from suboptimal diagnostic
definitions. Under 36 months of age, approximately 9% of American
children have a reported developmental problem, with at least 17%
of children aged 3 through 17 years who have been identified with
one or more developmental disabilities [2,3]. Developmental
disabilities included in these studies specifically identified attention
deficit hyperactivity disorder, autism spectrum disorder, cerebral
palsy, visual impairment, hearing loss, learning disability, intellectual
disability, seizures, specific language disorders, and other develop-
mental delays not specified [2,3]. Lack of inclusion of the complete
DSM-5 classification of disorders under-estimate the incidence of
behavioral and mental health disorders that present either indepen-
dently or as co-morbid conditions. Disorders occurring during the first
1000 days have a greater risk for permanent life-long deficits after
developmental or destructive processes or both, given critical and
sensitive periods of developmental neuroplasticity. Disorders during
childhood and adolescence later are expressed, often with gene-
environment interactions previously active during the first 1000 days.
Common pathophysiological mechanisms start before conception to
impair the developing brain within the maternal-placental-fetal triad
across three trimesters into the neonatal period, sometimes below
detection by current diagnostic tools. Pediatric illnesses and
adversities contribute to clinical expressions at older ages, as more
complex brain connectivity represents more mature brain structure
and function susceptible to new or continued injuries.
GLOBAL BURDEN OF NEUROLOGICAL DISEASES IN EARLY LIFE
Disability adjusted life years (DALY) were devised to measure the
global burden of diseases (GBD), consisting of two components:
the years of life lost due to premature death (YLL) and the years
of life living in states of poor health or disability (YLD) [4]. In the
GBD for 2015 across all age groups, approximately 15% are
related to neurological conditions. By contrast, the neonatal
population accounts for over 40% of the DALYs resulting from
brain disorders primarily due to the trimester-specific effects of
prematurity and neonatal encephalopathy [5,6]. Over the years,
the total number of DALYs attributed to neurological disorders in
children has decreased, primarily related to a 57% reduction in
prematurity and a 23% reduction in hypoxic-ischemic encephalo-
pathy for the under 5-year age group [5,6]. This reduction has
been offset by the increased burden of survivors after neonatal
encephalopathy in the 5−14-year group [6]. These estimates are
dependent on the later expression of neurologic disorders in
more mature brains. There is a significant global and national
burden of neurologic disorders related to the first 1000 days that
impact life-course disease and disability. The concepts of the
continuum of maternal and pediatric health care from trimester-
specific time-periods through neonatal and childhood ages must
be emphasized as a formal subspecialty training program. Such
training is interdisciplinary among the fields of general pediatrics,
family medicine, obstetrics, neonatology, pediatric intensive care,
and pediatric subspecialties including pediatric neurology. The
first 1000-day perspective will later drive healthcare priorities into
adulthood.
Received: 16 September 2021 Revised: 10 November 2021 Accepted: 17 November 2021
Published online: 30 November 2021
1
Division of Neurology, Assistant Professor, University of Pennsylvania, Children’s Hospital of Philadelphia, 3500 Civic Center Blvd., Philadelphia, PA 19104, USA.
2
Emeritus Full
Professor of Pediatrics and Neurology, Rainbow Babies and Children’s Hospital/MacDonald Hospital for Women, University Hospitals Cleveland Medical Center, Case Western
Reserve University, School of Medicine, 11100 Euclid Avenue, Cleveland, OH 44106, USA. ✉email: agarwals2@chop. edu
www.nature.com/jp
Journal of Perinatology
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DEVELOPMENTAL ORIGINS OF NEUROLOGICAL DISEASES AND
THE RELEVANCE TO FETAL-NEONATAL NEUROLOGY
Developmental origins and life-course theories have framed the
academic research and educational discourse for decades across
specialties [7]. These concepts have led to revisions in teaching
curricula and research designs. A fetal-neonatal neurology (FNN)
program presents an interdisciplinary approach to gene-
environment (G x E) interactions that influence brain health or
disease beginning before conception, across three trimesters of
pregnancy and into postnatal life. Developmental plasticity across
all systems includes critical and sensitive time-periods early in life
that result in permanent changes in form and function of the
nervous system in relation to all other systems. [8,9]. Life-long
effects continue to change the expression of neurologic disorders
from diseases and adversities encountered during childhood and
adulthood [8,9]. Transgenerational effects perpetuate health or
disease for future offspring.
From the increased understanding of factors that impact the
developing brain have emerged genetic and pathway investiga-
tions that consider common mechanisms that potentially impair
prenatal brain development starting at conception and across
each trimester. Maternal immune activation alters embryonic and
early fetal brain development beginning at conception and during
the first trimester, even before placental function replaces reliance
on the yolk sac after 8 weeks post conception [10]. Effects from
maternal immune activation may continue as well as abnormal
trophoblastic development resulting in impaired angiogenesis
within developing placental vasculature during the second and
third trimesters [10]. This second disease model is collectively
referred to as the ischemic placental syndromes. Abnormal
maternal and fetal outcomes have been collectively referred to
as the ‘great obstetrical syndromes’, such as preterm labor,
prematurity, premature rupture of membranes, fetal demise,
preeclampsia, abruptio placentae, and intrauterine growth restric-
tion [11]. A recent international classification of placental
histopathological lesions has described four major categories
including malperfusion syndromes, inflammatory states, and
dysmaturation [12]. Clinical hospital and outpatient experiences
supported by didactic classroom instruction will better prepare
FNN trainees for career-long learning regarding these disease
mechanisms. Understanding trimester-specific G x E interactions
associated with disease processes such as maternal immune
activation and ischemic placental syndromes will enhance
strategies for timelier diagnoses and more effective neurother-
apeutic interventions.
The trainee can apply this trimester-specific knowledge-base of
the maternal-placental-fetal triad during the peripartum period
through labor and delivery. The use and limitations of fetal
surveillance testing are addressed, underscoring the need for the
development of more effective biomarkers that more accurately
distinguish fetal distress from brain injury, whether remote or
contemporaneous to sentinel or insidious events closer to birth.
FETAL-NEONATAL NEUROLOGY PROGRAM: ROLE OF AN
INTERDISCIPLINARY AND CONTINUUM APPROACH
There are complex neonatal phenotypes following delivery that
collectively are referred to as ‘the great neonatal neurological
syndromes’and include encephalopathy, encephalopathy of
prematurity, seizures, and stroke [7]. A neonate may express one
or multiple phenotypes. The ‘great obstetrical syndromes’and
‘great neonatal neurologic syndromes’share phenotypic features
following trimester-specific G x E interactions affecting the
maternal-placental-fetal triad. While the ‘great obstetrical syn-
dromes’classification defines diseases from the perspective of
ischemic placental syndromes, the ‘the great neonatal neurologi-
cal syndromes’represent peripartum and neonatal time-windows
when multi-systemic disorders are expressed during and after
placental functions have terminated and replaced by independent
neonatal systems functions. More immediate neurocritical care
interventions address the neonate’s suboptimal multi-systemic
responses to labor and delivery. Improved resuscitative proce-
dures better stabilize and support the critically ill neonate.
However, antepartum and peripartum factors collectively con-
tribute to long-term morbidities. Sequelae result despite ‘the great
neonatal neurological syndromes’or even without the need for
medical interventions.
A multi-authored article in 2016 provided an initial framework
towards training curriculum in this field and elaborates the clinical
and educational programmatic requirements [13]. Neonatal
neurocritical care programs (NNCCP) continue to expand world-
wide. More recent professional organizations such as the Newborn
Brain Society support clinical service, education, and research
efforts, with the present emphasis on postnatal interventions [14].
Neonatal neurocritical care would be more effective as one of
three components of a FNN program that assesses the maternal-
placental-fetal triad from conception until two years of life. More
details are available in a comprehensive review and as summar-
ized in an earlier briefer commentary to a multicenter proposal
[7,15].
The scientific basis of the FNN program development and
training is best achieved by integration of the vertical and
horizontal perspective of the maternal-placental-fetal triad to
better understand the interplay of the ‘the great obstetrical
syndromes’-‘the great neonatal neurological syndromes’pheno-
type and close collaborations of disciplines with a transgenera-
tional approach to care. This approach will help facilitate the life-
course perspective to study brain health and the early origins of
health and disease from fetal life to old age. This developmental
neuroscience perspective will also help guide collaborations for
innovative research, continuity of comprehensive care for
maternal, neonatal, and child health and establish a strong
foundation for learning and training. Such a transgenerational
approach also helps establish effective and long-lasting connec-
tions with the families which are crucial to the developmental
progress as we follow these neonates in the childhood years.
FETAL-NEONATAL NEUROLOGY PROGRAM CONCEPTS
The FNN program would offer a 12 preferably 24 month training
experience, merging clinical and research time within a structured
educational curriculum.
1. Antepartum Consultations: A trainee would rotate through
trimester-specific levels of maternal care by obstetrical and
high-risk maternal-fetal medicine services to acquire an
understanding of the uses and limits of fetal surveillance
procedures and the clinical pathways applied to women
requiring low to high-risk levels of prenatal care. Instruction
on preconception factors will include disease-specific
conditions including mental health disorders. Involvement
after a referral to a maternal fetal medicine service with
input from clinical genetics and pediatric multi-specialties
will be included. A system-based approach will offer critical
thinking regarding prenatal diagnosis using conventionally
available genetic and imaging modalities. Tutorials in the
use of abdominal sonography include fetal biometry and
Doppler flow studies. Interpretation of fetal magnetic
resonance imaging expanded to placental and organ-
specific imaging will depend on the institution’s capability
to support those services. Participation in multidisciplinary
conferences would complement individual consultations
under supervision. Trainees would be required to present
triad evaluations as well as offer didactic presentations of
related topics. If the host institution has an inpatient
maternity service for women with more acute medical
S. Agarwal and M.S. Scher
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Journal of Perinatology (2022) 42:165 – 168

complications requiring intensive care or general hospital
care, the trainee will participate in work rounds and patient
care discussions. Toxic stresses based on health-care
disparities from poverty, socioeconomic conditions, racial-
ethnic prejudice, and lifestyle choices will be factors to
consider.
2. Peripartum consultations: Trainees would accompany and
participate with obstetrical services for the woman closer to
the delivery date, while hospitalized for more acute medical
complications, as well as during the labor and delivery
period. Acquaintance with fetal surveillance procedures and
decision-making prior to birth will be important compo-
nents of these experiences.
3. Neonatal consultations: competencies in neonatal neuro-
critical care diagnosis include structured assessments of
history and examination techniques, participation in neona-
tal care with multisystem approach, and instruction in
neurodiagnostic tools including neurophysiology, neuroima-
ging, and neurogenetics. Besides the ‘the great neonatal
neurological syndromes’, involvement with other pediatric
subspecialties will include both bedside and neonatal clinical
conference participation. Binocular instruction with placental
pathologists of placental, umbilical cord, and uterine tissue
slices will re-enforce previously described gross examination
findings and emphasize clinical correlations.
4. Pediatric continuity consultations and follow up:The
trainee will take part in step-down unit rounds and participate
in family instruction before the neonate’s discharge. This will
include multidisciplinary conferences where all health profes-
sionals associated with the child’s care explain diagnostic and
prognostic information to families. Instruction from consultant
pediatric specialists, nurses, and therapy personnel are
essential components throughout this convalescent phase of
the program. Involvement in multi-disciplinary conferences
with the family will strengthen communication skills, particu-
larly involving the diagnosis and prognosis of the high-risk
survivor, consideration of neuro-palliative care, bioethical
considerations, and transitional plans for post-discharge care
[16,17]. Communication with the primary care physician
would be part of this experience to strengthen continuity of
care. Pediatric neurology consultations within the structured
environment of the follow-up neonatal program, during
outpatient clinical consultations, and during hospitalizations
for subsequent illnesses or complications will be performed.
Education in collaborative multidisciplinary rehabilitative care
for infants with neurodevelopmental challenges will be
provided within the concept of family-centered care with
attention to health disparities and challenges in the real world
[18]. For medically-fragile neonatal survivors who later require
pediatric intensive care, trainees will be rotated into those
units for experiences. All pediatric consultative experiences
will emphasize G x E interactions as the child expresses
epilepsies and developmental disorders during the first
1000 days. Critical consideration of appropriate exomic and
genomic testing will be discussed for each child, relevant to
the phenotypic presentation. Consultative instruction with
multiple pediatric specialists will further enrich the trainee’s
experiences regarding diagnosis, treatment options, and
prognosis for syndromic and non-syndromic multi-organ
conditions. Anticipation of neurologic sequelae during child-
hood and adolescence will include all forms of developmental
disorders, epilepsies, and mental health disorders according to
the DSM-5 classification. These experiences will be accom-
plished through continuity clinics as the patient matures
within the family, during the child’s educational experiences,
and with the transition to adulthood. Applicable develop-
mental assessment tools will be discussed in the context with
validation by later neuropsychometric testing. Continuity of
care into adulthood, particularly pertaining to individuals
challenged by special needs that impact neurologic health.
Didactic opportunities regarding adult neurology services will
acquaint the trainee to the relevance of the first 1000 days to
cognitive, behavioral, cerebrovascular, and neurodegenerative
disorders expressed across the lifespan. An appreciation of
life-course burden of the neurologic disease will stress health
disparities based on socio-economic determinants, highlight-
ing racial, ethnic, and sexual orientation.
FETAL-NEONATAL NEUROLOGY: A GLOBAL CALL FOR ACTION
A recent online survey sent to program directors of all ACGME-
accredited pediatric subspecialty programs in the US revealed a
widespread lack of formal training curricula in prenatal counseling
[19]. Nearly all program directors believed that prenatal consulta-
tion are relevant to their field but are under-utilized. The majority
of programs lack formal curricula in prenatal consultations.
Graduating trainees were perceived as inadequately prepared to
perform competent prenatal consultations, identifying significant
gaps in this area [19]. This also highlights the expanded role of the
FNN program adapted to trainees from other subspecialties. The
FNN trainee’s interactions with subspecialists in obstetrics and
maternal-fetal medicine, neonatology, genetics, and other pedia-
tric subspecialties will enhance the educational experiences for all
participants. Healthcare professionals including nurses and
therapists would also benefit from essential components of a
FNN program. Focused learning modules for computer scientists,
epidemiologists, engineers, social scientists, and mental health
providers would be offered.
The importance of early-life factors influencing later-life health
has been reinforced by birth cohorts research [20]. The scientific
disciplines of developmental origins of health and disease and life-
course challenges for the continuity of healthcare have incorpo-
rated birth cohort findings into national health care policies, as
well as international efforts. The Australian program applied the
position paper, linking the first 1000 days to brain health or
disease [21,22]. The Australian experience argued that there
would be a reduction in economic costs as one of the multiple
benefits for such as program.
ThemorerecentWHOMillenniumSustainableGoalswiththe
‘every newborn health action plan’(ENAP) illustrate interna-
tional efforts that recognize region-specific resource-rich or poor
status [23]. ENAP acknowledged the gaps in control of newborn
deaths and stillbirths and called for improved ‘access to, and
quality of, health care for women and newborns within the
continuum of care’[23]. The UN Secretary-General’sGlobal
Strategy for Women’sandChildren’s Health was launched at the
2010 UN Summit and identified key areas for achieving the WHO
goals [23,24]. Every Woman Every Child (EWEC) was launched at
thesametime—a global movement to enact the Global
Strategy’s roadmap, by mobilizing and intensifying national
and global stakeholders to address these gaps and improve
care. These global initiatives have highlighted the magnitude of
the problems related to women and children, especially during
the pregnancy and peripartum period, which is the core of a
well-designed FNN program. These global initiatives have also
built political momentum over the years and offer a conceptual
model to develop effective collaborations for the design of
educational curriculum for healthcare professionals to improve
transgenerational life-course health for families. For child
neurologists and other related subspecialties focusing on FNN
program development, it is imperative to take note of the global
momentum and apply these concepts to have a larger and long-
lasting impact on maternal, neonatal, and pediatric care.
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AUTHOR CONTRIBUTIONS
Dr. Agarwal conceptualized and designed the study, drafted the initial manuscript,
and reviewed and revised the manuscript. Dr. Scher conceptualized and designed the
study, and critically reviewed and revised the manuscript. All authors approved the
final manuscript as submitted and agree to be accountable for all aspects of
the work.
COMPETING INTERESTS
The authors declare no competing interests.
ADDITIONAL INFORMATION
Correspondence and requests for materials should be addressed to Sonika Agarwal.
Reprints and permission information is available at http://www.nature.com/
reprints
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims
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