• Sign Up

Developmental Delay


Developmental Delay

Article Author:
Israr Khan
Article Editor:
Bennett Leventhal
Updated:
9/19/2020 12:46:15 PM
For CME on this topic:
Developmental Delay CME
PubMed Link:
Developmental Delay

Introduction

Human development refers to the physical, cognitive, and psychosocial changes occurring throughout the lifespan. Many developmental lines progress sequentially and independently over time while also interacting with each other.  Examples of the many developmental lines include:

  • Physiologic development and homeostasis
  • Structural and anatomic development
  • Motor development – both fine and gross motor
  • Development of language (the full spectrum of communications skills, including gesture and speech)
  • Cognitive development
  • Personality Development
  • Social development
  • Psychological development
  • Sexual development
  • Development of adaptive skill (Activities of daily living (ADL)

The development of the fetal brain starts during the first trimester, more specifically in the fourth week of gestation, and continues throughout pregnancy with very rapid growth in early childhood but continuing actively through adolescence and into the middle of the third decade of life with ongoing development throughout the lifespan.[1][2]

Delay in development is generally determined with a child does not attain developmental milestones as compared to peers from the same population. Statistical terms are often used to classify the degree of delay into mild (functional age (FA) <33% below chronological age (CA), moderate (FA 34% to 66% of CA), and severe (FA <66% of CA).[3][4] "Developmental delay" is a general descriptor of a broad phenotype that must then be specified by carefully determining one or more elements linked with the area of disrupted development. Developmental delay is not a diagnosis by itself rather a categorical, illustrative term used in the clinic.[5] Further, the terms often used to specify a developmental delay may vary by country or area of practice.  For example, the term "mental retardation is no longer in use with "learning disability" being used in the UK and Intellectual Disability being used in the US to define a group of individuals with a significant delay defined by "performance equal or greater than two standard deviations below the mean on age-appropriate standardized norm-referenced testing" (IQ or intelligent quotient testing). There are three types of developmental delay based on the number of domains involved: 1) Isolated developmental delay (involving single domain); 2. Multiple Developmental Delays — 2 or more domains or developmental lines affected; and, 3) Global developmental delay (GDD) —significant delay in most developmental domains.[1][3] Other entities with abnormal developmental models are:

Intellectual disability (ID) — is a developmental disability that mainly affects cognitive functioning. As per American Association on Intellectual and Developmental Disabilities (ID) guidelines, it is characterized by significant lifelong developmental deficits in areas that are responsible for learning, problem-solving, adaptive skills development, and independence, generally with onset prior to age 18 years of age.[3][6]

Developmental disorders — are a very large group of syndromes in which the typical sequences or patterns of development are disrupted with delays in developmental steps and/or deviations in development processes.[3] Despite the American Academy of Pediatrics policy on early screening, a significant number of developmental disorders remain undiagnosed and untreated.[7]

Etiology

The etiology of developmental delay is multifactorial. The etiology for the vast majority of developmental delay is idiopathic.  When known, etiology may include genetic, environmental, and/or psychosocial factors.

Genetic: There is no known genetic substrate for developmental delay, per se.  However, developmental patterns are often familial, including late walking and talking.  Nonetheless, these developmental delays can also represent risks for syndromes or developmental disorders.  There is a considerable variation in the genetics of developmental disorders, ranging from copy number variants (CNV's), insertions, deletions, and duplications. While most are rare variants, some represent common variants. The most common, known genetic factor for ID is Fragile X syndrome, a trinucleotide repeat disorder (CGG) targeting the Fragile Mental Retardation 1(FMR1) gene located on X-chromosome. Fragile X appears to confer risk for ASD, as well. Imprinting can also be seen as is the case of Prader-Willi and Angelman syndrome, which vary with paternal (Prader-Willi) and maternal (Angelman) loss of function on chromosome 15q. Both developmental delay and physical phenotypes can be associated with other disorders in which there are extra chromosomes or pieces of chromosomes, for example, Down syndrome (trisomy 21), Edward syndrome(trisomy 18) & Patau syndrome (trisomy 13).[8][9][10][11] Other X-linked disorders include Coffin-Lowry syndrome predominantly in male and Rett syndrome in females.[6] 

Environmental: A wide number of environmental factors can lead to developmental delays and subsequent developmental disorders.  These factors can affect development at a single of multiple points in the developmental process. 

Antenatal:

  • Heritable disorders — for example (e.g.) Fragile X syndrome, Down syndrome, or chromosomal microdeletion and duplications.
  • Early maternal infections, (e.g., rubella, cytomegalovirus (CMV), toxoplasmosis
  • Late maternal infections, (e.g., varicella, HIV, malaria, etc.)
  • Primigravida
  • Short inter-pregnancy interval
  • Teen pregnancy
  • Vascular — comprises of hemorrhage and occlusion
  • Prescribed medications — include antiepileptic drugs (AEDs), cytotoxic
  • Teratogens/toxins — include smoking, alcohol, opioids, etc.
  • Poverty

Perinatal:

  • Intrauterine growth restriction (IUGR), prematurity, periventricular leukomalacia
  • Hypoxic-ischemic encephalopathy (HIE), perinatal asphyxia
  • Metabolic — Hypoglycemia, bilirubin-related neurotoxicity, etc.
  • Poverty

Postnatal:

  • Metabolic disorders like hypoglycemia, hyponatremia, or hypovolemia
  • Inborn errors of metabolism - PKU
  • Teratogens/toxins — such as lead, arsenic, mercury, etc.
  • Trauma — head trauma
  • Infections (e.g., neonatal meningitis, encephalitis)
  • Maternal stress — such as depression, anxiety, etc.
  • Maltreatment, intimate partner, and/or domestic violence
  • Poverty
  • Malnutrition — especially multivitamins and minerals deficiency, such as iron, folate, Vitamin D, calcium, etc.[1][3][12]

Epidemiology

Globally, in 2016, approximately 52.9 million children reportedly had identifiable developmental problems delay. Since 95% of the population resides in low and middle-income countries (LMICs), there is an increased risk for developmental delays and disorder.[13] Although the exact prevalence of developmental delay is unknown, according to the World Health Organization (WHO), 10% of the population in each country population has a disability of one or another kind.[14] In the United States, roughly 15% of children have been reported to have at least one developmental problem.[15] In England, the prevalence of ID in children under age five and adults' population is 2.7% and 2.17%, respectively. The GDD incidence rate is 1% to 3% in school-age children or younger.[6] Autism prevalence is approximately 2.5%.[16] 

The prevalence of delay in development involving respective domains among children (which is based on data reported in children getting services in 2007 by USPSTF on their respective website) is given below:[15]

  • Cognitive (1% to 1.5%)
  • Learning disability (8%)
  • Speech and language (2% to 19%)
  • Any delay (15%)

According to Drakenstein Child Health Study (DCHS) conducted in Western Cape, South Africa, the risk of low developmental performance in the high-risk environment was high among boys. Likewise, several other studies have also reported a slightly increased incidence in males, possibly due to genetic variability on the X-chromosome.[6][12]

Pathophysiology

Except for specific syndromes that include developmental delay, the vast majority of developmental delay is idiopathic.  Although the exact underlying pathophysiology is unknown, several mechanisms have been proposed by epidemiologic studies that lead to some sort of developmental delay and/or disabilities. Since some forms of developmental delay may run in families, genes have been assumed to play a significant role in developmental delay. 

A multitude of genes and mechanisms for genetic transmission have been proposed.  While for some causes of developmental delay such as Fragile X or Down syndrome have known genetic etiologies, for most others, it is unclear. Even for well-characterized disorders like autism spectrum disorder, there are over 100 risk alleles. Perinatal complications, profound deprivation, and poverty, among other environmental stressors, can play a role in causing developmental delays, but special causal links remain elusive.

The hypothalamic-pituitary axis (HPA) is responsible for the normal regulation of stress response in progenies. Psychosocial stressors during pregnancy, maternal immune activation (MIA), and modification of HPA may significantly affect fetal brain development, but there are no specific cause and effect relationships for most disorders. Boyce and his colleagues offered the concept of differential susceptibility. This suggests that risk for developmental anomalies is increased by a variety of factors that create a biological vulnerability to environmental stressors but are only expressed when the environmental stresses occur. Furthermore, even vulnerable children can do well if environmental circumstances are highly favorable and foster resilience.[17][18]

History and Physical

A comprehensive history and thorough physical examination are essential elements of the examination of children with developmental delays. Additional information can also be gathered by a play interaction with the child us age-appropriate toys (e.g., toy cars, blocks, crayons, and paper) as well as watching the child move around the clinic. Additionally, home videos may prove to be useful.[1]

History

  • Collect comprehensive data on the entirety of the child's development from conception to the current age.
  • Collect a detailed family history of at least first, second, and third-degree relatives. Construction of a pedigree chart is often helpful.
  • Prepare a detailed narrative of the presentation and course of the relevant developmental delays.
  • Obtain and review prenatal, perinatal/birth, and postnatal records when they are available.
  • Check the neonatal history for adverse events, including HIE, jaundice, hypotonia, hypothyroidism, congenital abnormalitiesChart each of the developmental lines by listing each critical developmental milestone, including sitting, crawling, walking, talking, social interaction, language, learning, etc.
  • Obtain an immunization history
  • Obtain a nutritional history — (i.e., feeding and eating habits).
  • Collect a detailed medical history, including hospitalization, surgeries, accidents, injuries, medications, etc.
  • Collect data on social and academic performance in school[6][19]

Physical Examination

  • Growth parameters — such as occipitofrontal circumference, weight, height, and BMI.
  • General physical examination involving head-to-toe assessment.
  • Detailed neurologic exam, including hearing and vision evaluation.
  • Examination for dysmorphology.[3][6][19]

Evaluation

Assessment of developmental delays often requires the work of a team with experts in general and specific areas.  This should start with primary care providers followed by pediatric subspecialists such as neurologists, child and adolescent psychiatrists, developmental and behavioral pediatricians, and other pediatric subspecialists as indicated. Besides, the skills from other disciplines may be necessary, for example, psychology, genetics, speech and language pathology, occupational therapy, physical therapy, nutritionists, etc. The United States Preventive Services Taskforce (USPSTF) offers specific recommendations for speech and language delays and autism but does not explicitly cover other developmental delays. Clinicians, particularly primary care providers, must have a sound understanding of developmental milestones and patterns, as well as up-to-date knowledge about screening tests and their strengths & limitations, to ensure proper screening for a referral if the clinical suspicion of developmental screening is high.[1][15][20] 

During each well-child encounter, a PCP should encourage parents to express their concerns about their child's behavior or developmental milestones.[3] Furthermore, since developmental delay can be due to normal variations or can be an indicator of a developmental disorder such as sensory or cognitive impairment, cerebral palsy, or autism, thorough evaluation and follow up is warranted. Therefore, in addition to direct physical examination and observation, the use of validated screening instruments at every well-child visit can aid in the early detection of problematic developmental delays. Developmental screening should take place in response to parental concerns or clinicians' observations as well as during every well-child visit at 9, 18, and 30 months of age. An autism-specific screening test is recommended at 18 and 24 months. Among many general developmental screening instruments, The Ages and Stages Questionnaire, Third Edition (ASQ-3), and the Parents' Evaluation of Developmental Status (PEDS) are commonly used parent-report tools for use during well-child encounters. Hamilton et al. 2016, cited by Vitrikas, reported the sensitivity and specificity of PEDS questionnaires for all ages 75% and 74%, respectively. Although the sensitivity and specificity for ASQ-3 vary among different age groups; however, overall sensitivity is 85%, and specificity is 86%.[15][21][22][23]

Laboratory Workup

Laboratory evaluations of children with developmental delays should be done judiciously.  There should be careful attention to resource utilization and the risk-benefit analysis for each test.  Since most causes of developmental delay are idiopathic, it is rare to obtain significant or pathognomonic findings in laboratory testing.  Therefore, aside from routine healthcare assessments, testing should only be completed if there is a specific indication.

Blood: Routine complete blood count (CBC), electrolytes, and lead screening are appropriate for most children, along with a lipid panel. If indicated, additional testing may include a metabolic chemistry panel(CMP), iron,  calcium, phosphate, creatinine kinase (CK) enzyme. Additionally, uric acid level, thyroid function tests, lactic acid, very-long-chain fatty acids (VLFA), transferrin, lead, copper, ceruloplasmin level, ammonia, and acylcarnitine levels.

Urine: A routine urinalysis is appropriate but additional studies may be added to include organic acids, amino acids, oligosaccharides, sialic acids, glycosaminoglycans, urea, urine purine, and pyrimidines, etc.

Cerebrospinal fluid (CSF): CSF analysis is rarely appropriate for developmental assessment delay.  If there is a specific indication for a lumbar puncture, it can be considered.  The particular indication will largely determine appropriate assessments of the spinal fluid, which may include glucose, lactic acid, glycine, pyruvate, etc.

Other tests need to be done to rule out TORCH (Toxoplasma, Others (HBV, HIV), Rubella, CMV, and Herpesvirus) infections.

Genetic: In general, genetic testing is not indicated for developmental delay unless there is a specific indication or evidence of a discrete syndrome.  If further genetic testing is indicated, this should begin with a chromosomal microarray (CMA). Since the most commonly known genetic cause of intellectual delay is Fragile X, FraX screening may be appropriate. As per Moeschler et al., CMA is required for Fragile X syndrome. The detection of significant copy number variants and approximated diagnostic yield of microarray tests are 15-20% and 12%, respectively. If further genetic testing is indicated, referral to a geneticist is indicated. Consideration of a whole exome scan (WES) or whole-genome scan will determine the clinical syndromes being considered.[6][11][15]

Additional Assessments

Magnetic resonance imaging (MRI) brain — In the absence of discrete family history, specific injury, or focal neurological finding, MRI is rarely indicated in the routine assessment of children with developmental delay.  This is because children under the age of 7 or 8 will have difficulty being still, and so movement artifacts will make interpretation of the scans difficult to impossible. Examinations can be completed using anesthesia, but, in most cases, the risk of anesthesia outweighs the potential benefit of the MRI scan. MRI is used to evaluate for microcephaly, macrocephaly, seizures, abnormal neurologic signs and symptoms, and hydrocephalus. One prospective and observational study compared the MRI findings of eighty-one (n=81) pediatric patients. Among them, 68% of cases showed abnormal MRI findings compared to 32%  normal MRI results. The abnormal 68% MRI results demonstrated by traumatic/ neurovascular diseases (31%), congenital & developmental (17%), neoplastic (2.5%), metabolic & degenerative (10%), and non-specific (7.5%).

Electroencephalography (EEG) — In the absence of discrete family history, specific injury, or focal neurological finding, EEG studies are rarely indicated in the routine assessment of children with developmental delay.  EEG may be useful if there is a clear history of regression and/or directly observed seizure activity.[3][6][24]

To summarize, children with developmental delays are usually identified as a result of parental concern, school/daycare observation, or during the course of routine care in primary care settings. When there is information from parents and/or teachers, the primary care provider should take it seriously and carefully assess the developmental delay and its possible causes.

Treatment / Management

The management of developmental delay is a team effort that includes primary care providers as well as pediatric subspecialists such as neurologists, child and adolescent psychiatrists, developmental and behavioral pediatricians, and other pediatric subspecialists as indicated. Also, the skills from other disciplines may be necessary, for example, psychology, genetics, speech and language pathology, occupational therapy, physical therapy, nutritionists, etc. In short, treatment strategies are usually multi-modal.

Treatment strategies require that the lead member of the team, often the primary care provider, establishes a therapeutic partnership with the pediatric care team, educating and providing parents/families with necessary information about the developmental delay and any evidence of an evolving syndrome, including the course of the disorder, diagnosis, prognosis, and complications. Additionally, psychosocial support and parental counseling/guidance are essential elements of care. Information should be provided at the level consistent with the ability of the parents to understand as this will enhance acceptance and adherence to care plans.[6] 

For some families, social work support services may be necessary for coordination and transportation services, regular home visits, and other services essential to complete evaluations.[15] If there is significant clinical concern that the developmental delay represents an evolving clinical syndrome and the parents appear to not understand or be in denial, then follow-up appointments with the primary care provider during the developmental evaluation will be helpful.[3] Other recommendations for early interventions and referrals are given below:

  1. Early childhood education
  2. Early intervention programs
  3. Early and periodic screening, diagnostic, and treatment (EPSDT)
  4. Parenting problems – consider referral for parent training. This might include parent-child interaction therapy (PCIT) consisting of two phases, such as parent-directed interaction (PDI) and child-directed interaction (CDI). Additionally, parents may need help in providing their children with appropriately stimulating environments at home, school, and daycare. Many children with developmental delays are eligible for community-based services. Primary care providers should be familiar with these services, eligibility, and how to make referrals.  Among many, these include:
  5. Behavior Problems – consider referral to child and adolescent psychiatrist and/or behavior therapist (BCBA board-certified behavior analyst)
  6. Social skills problems – consider referral for social skills training (individual and group_
  7. Auditory impairment – consider referral to audiology (15)
  8. Visual impairment – consider referral to ophthalmology.
  9. Gross or fine motor delay— consider referral to physical therapy and/or occupational therapy (PT/OT)
  10. Speech & language delay — consider referral to a speech and language pathologist.
  11. HeadStart
  12. Special Education (via Individualized Education Program (IEP) or 504 Plan)
  13. Other community service agencies and programs[7][15][25]

Differential Diagnosis

Most developmental delay is idiopathic and time-limited. There is no differential diagnosis, per se. However, for some children, developmental delay is the first step toward a "development disorder," one of a large group of syndromes for which there are specific diagnostic procedures undertaken by specialists to arrive at a diagnosis. Examples of these progressions include;[1][3][19][26]

 Delays in all or many developmental milestones are at risk for:

  • Intellectual disability (ID)
  • General developmental delay (GDD)
  • Fragile X syndrome
  • Failure to thrive (FTT)
  • Anemia
  • Thyroid deficiency
  • Social deprivation

 Delayed Speech and Language

  • General speech delay
  • Developmental language disorder
  • Intellectual disability (ID)
  • Autism spectrum disorder
  • Social communication disorder
  • Developmental language disorder
  • Social deprivation

 Sensory Impairment

  • Developmental hearing disorder
  • Deaf
  • Developmental vision disorder
  • Blind
  • Poor visual acuity

 Behavior Problems

  • Attention deficit hyperactivity disorder (ADHD)
  • Oppositional defiant disorder (ODD)
  • Disruptive mood dysregulation disorder (DMDD)
  • Autism spectrum disorder (ASD)
  • Childhood-onset schizophrenia

 Mood/Affect Regulation

  •  Autism spectrum disorder
  •  Intellectual disability
  •  Mood disorder
  •  Childhood-onset schizophrenia

 Learning Problems

  •  Intellectual disability (ID)
  •  Sensory deficits (hearing or vision)
  •  Dyslexia
  •  Autism spectrum disorder (ASD)

 Movement Disorders

  • Epilepsy
  • Tourette syndrome
  • Chronic tic disorder

 Motor Delays

  • Cerebral palsy
  • Muscular dystrophy
  • Spinal muscular atrophy
  • Epilepsy
  • HIE
  • Intellectual disability
  • Autism spectrum disorder

Prognosis

Since most developmental delays resolve spontaneously, the prognosis is generally good. However, developmental delay is a significant and powerful risk for progression to a neurodevelopmental disorder or syndrome.  As a result, it is critical that each developmental delay is carefully followed until it resolves or evolves into a developmental disorder.  There are many factors associated with both poor and better developmental outcome. Some of the prognostic factor associated with poor behavior outcome or serious delay in development in children age ranges from 18 to 30 months are lack of parental education, anemia during pregnancy, malnutrition, premature babies, male gender, low birth weight (LBW), prenatal and postnatal depression, intimate partner violence (IPV), use of drugs, tobacco or alcohol in pregnancy, and poverty.[12][27] 

Moreover, some other alarming features (if not effectively addressed, may result in significant developmental deficit) are hearing and/or vision loss at any age, loss of previously learned developmental skills, persistent hypotonia or hypertonia, asymmetrical movements, no communicative speech at 16 months, and disproportionate head circumference (either > 99.6 percentile or <0.4 percentile).[1] In contrast, maternal education, access to basic life and health resources, and older child age have been associated with a better outcome.[12]

Complications

Most developmental delays resolve without complications. Those that evolve into developmental syndromes require careful assessment by skilled experts in the areas affected by the developmental disruption.[3][7]

Deterrence and Patient Education

Most developmental delays are time-limited. However, prevention of the delays themselves and shortening their duration may respond to environments that stimulate cognitive, motor, sensory, psychological, social, and emotional development across setting (home, school, daycare, etc.) It appears that parent training can foster a proper understanding of the functional impact of the needs of children and the risks intrinsic to development developmental delay.  Parent guidance should be a part of every prenatal and well-child visit.  Several well-designed parent training programs may also foster skills in other caregivers. One such program is the caregiver skills training program (CST) devised by the World Health Organization (WHO) for families of children suffering from developmental delays or disorders. It consists of the following modules:

Engagement —2 sessions,

Communication — 2 sessions

Management of behavior — 2 sessions

Play and home routine —1 session

Adaptive behavior —1 session

Caregiver self-care and continuing practice1session[13]

Additionally, communities need to provide support services for parents and children:

  • Physically safe environment
  • Appropriate Sanitary facilities
  • Safe drinking water
  • Adequate nutrition
  • Prenatal care
  • Post-natal care for women including maternity leave
  • Well-childcare for all children
  • Early childhood education
  • Universal Pre-school
  • High-quality education
  • Universal developmental guidance and support.

 Most parents are competent and concerned about their children. Clinicians need to foster competence and support parents in the difficult task of childrearing. This includes encouraging parents to voice concerns and for clinicians to take very seriously all parental comments and concerns.[6][7]

Enhancing Healthcare Team Outcomes

The developmental outcome for all children can be greatly enhanced by systematic examination and developmental monitoring of all children. Even in relatively well-developed countries like the USA, as few as 1 in 5 children have been offered an acceptable parent completed developmental screening by a health care provider in the past year. According to the NSCH report in 2016, 30.4% of children aged 9 to 35 months were provided with parent-completed developmental screening instruments in addition to evaluation for behavior and interaction in the past year, which was confirmed by the parent/caregiver. Among them, only 19.2% had obtained both developmental screening and surveillance.[20]

The results are far worse in LMIC, where the majority of children live.  An extensive medical and developmental evaluation is warranted to detect developmental delays at an early age. If this is done, it is possible that, through a collaborative effort between health care providers, parents, and society, children will have more favorable outcomes in the face of developmental delays.[15]


References

[1] Bellman M,Byrne O,Sege R, Developmental assessment of children. BMJ (Clinical research ed.). 2013 Jan 15;     [PubMed PMID: 23321410]
[2] Bélanger SA,Caron J, Evaluation of the child with global developmental delay and intellectual disability. Paediatrics & child health. 2018 Sep     [PubMed PMID: 30919832]
[3] Choo YY,Agarwal P,How CH,Yeleswarapu SP, Developmental delay: identification and management at primary care level. Singapore medical journal. 2019 Mar;     [PubMed PMID: 30997518]
[4] Mithyantha R,Kneen R,McCann E,Gladstone M, Current evidence-based recommendations on investigating children with global developmental delay. Archives of disease in childhood. 2017 Nov     [PubMed PMID: 29054862]
[5] Levy Y, 'Developmental Delay' Reconsidered: The Critical Role of Age-Dependent, Co-variant Development. Frontiers in psychology. 2018;     [PubMed PMID: 29740364]
[6] Vasudevan P,Suri M, A clinical approach to developmental delay and intellectual disability. Clinical medicine (London, England). 2017 Dec;     [PubMed PMID: 29196358]
[7] Eickmann SH,Emond AM,Lima M, Evaluation of child development: beyond the neuromotor aspect. Jornal de pediatria. 2016 May-Jun;     [PubMed PMID: 27012923]
[8] Burnside RD,Pasion R,Mikhail FM,Carroll AJ,Robin NH,Youngs EL,Gadi IK,Keitges E,Jaswaney VL,Papenhausen PR,Potluri VR,Risheg H,Rush B,Smith JL,Schwartz S,Tepperberg JH,Butler MG, Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay. Human genetics. 2011 Oct;     [PubMed PMID: 21359847]
[9] Miclea D,Peca L,Cuzmici Z,Pop IV, Genetic testing in patients with global developmental delay / intellectual disabilities. A review. Clujul medical (1957). 2015     [PubMed PMID: 26609258]
[10]     [PubMed PMID: 19117905]
[11]     [PubMed PMID: 25157020]
[12] Donald KA,Wedderburn CJ,Barnett W,Nhapi RT,Rehman AM,Stadler JAM,Hoffman N,Koen N,Zar HJ,Stein DJ, Risk and protective factors for child development: An observational South African birth cohort. PLoS medicine. 2019 Sep;     [PubMed PMID: 31560687]
[13] Salomone E,Pacione L,Shire S,Brown FL,Reichow B,Servili C, Development of the WHO Caregiver Skills Training Program for Developmental Disorders or Delays. Frontiers in psychiatry. 2019;     [PubMed PMID: 31780960]
[14] Dornelas Lde F,Duarte NM,Magalhães Lde C, [Neuropsychomotor developmental delay: conceptual map, term definitions, uses and limitations]. Revista paulista de pediatria : orgao oficial da Sociedade de Pediatria de Sao Paulo. 2015 Jan-Mar;     [PubMed PMID: 25662016]
[15] Vitrikas K,Savard D,Bucaj M, Developmental Delay: When and How to Screen. American family physician. 2017 Jul 1;     [PubMed PMID: 28671370]
[16]     [PubMed PMID: 21558103]
[17] Udagawa J,Hino K, Impact of Maternal Stress in Pregnancy on Brain Function of the Offspring. Nihon eiseigaku zasshi. Japanese journal of hygiene. 2016;     [PubMed PMID: 27725421]
[18] Ellis BJ,Boyce WT, Differential susceptibility to the environment: toward an understanding of sensitivity to developmental experiences and context. Development and psychopathology. 2011 Feb     [PubMed PMID: 21262035]
[19] Marrus N,Hall L, Intellectual Disability and Language Disorder. Child and adolescent psychiatric clinics of North America. 2017 Jul;     [PubMed PMID: 28577608]
[20] Hirai AH,Kogan MD,Kandasamy V,Reuland C,Bethell C, Prevalence and Variation of Developmental Screening and Surveillance in Early Childhood. JAMA pediatrics. 2018 Sep 1;     [PubMed PMID: 29987317]
[21] Cappiello MM,Gahagan S, Early child development and developmental delay in indigenous communities. Pediatric clinics of North America. 2009 Dec     [PubMed PMID: 19962033]
[22] WOLF RE,SMITH HD, The role of the pediatrician in the mental health of children; summary of round table discussion. Pediatrics. 1956 Aug;     [PubMed PMID: 13349347]
[23] Robins DL,Fein D,Barton ML,Green JA, The Modified Checklist for Autism in Toddlers: an initial study investigating the early detection of autism and pervasive developmental disorders. Journal of autism and developmental disorders. 2001 Apr     [PubMed PMID: 11450812]
[24] Ali AS,Syed NP,Murthy GS,Nori M,Abkari A,Pooja BK,Venkateswarlu J, Magnetic resonance imaging (MRI) evaluation of developmental delay in pediatric patients. Journal of clinical and diagnostic research : JCDR. 2015 Jan;     [PubMed PMID: 25738057]
[25] Shafi RMA,Vande Voort JL,Croarkin PE,Romanowicz M, Parent-Child Interaction Therapy in a Case of Global Developmental Delay and Leukoencephalopathy. Frontiers in psychiatry. 2018;     [PubMed PMID: 30258371]
[26] Falzarano MS,Scotton C,Passarelli C,Ferlini A, Duchenne Muscular Dystrophy: From Diagnosis to Therapy. Molecules (Basel, Switzerland). 2015 Oct 7;     [PubMed PMID: 26457695]
[27] Linsell L,Malouf R,Morris J,Kurinczuk JJ,Marlow N, Prognostic Factors for Poor Cognitive Development in Children Born Very Preterm or With Very Low Birth Weight: A Systematic Review. JAMA pediatrics. 2015 Dec;     [PubMed PMID: 26457641]