Newborn Screening Conditions: Early Intervention and Probability of Developmental Delay

Abstract

Objectives: 

The purpose of this study is to explore which newborn screening (NBS) conditions are automatically eligible for early intervention (EI) across states and to determine the extent to which each disorder should automatically qualify for EI because of a high probability of developmental delay.

Methods: 

We examined each state's EI eligibility policy and reviewed the literature documenting developmental outcomes for each NBS condition. Using a novel matrix, we assessed the risk of developmental delay, medical complexity, and risk of episodic decompensation, revising the matrix iteratively until reaching consensus. Three NBS conditions (biotinidase deficiency, severe combined immunodeficiency, and propionic acidemia) are presented in detail as examples.

Results: 

Most states (88%) had Established Conditions lists to autoqualify children to EI. The average number of NBS conditions listed was 7.8 (range 0–34). Each condition appeared on average in 11.7 Established Conditions lists (range 2–29). After the literature review and consensus process, 29 conditions were likely to meet national criteria for an Established Condition.

Conclusion: 

Despite benefiting from NBS and timely treatment, many children diagnosed with NBS conditions are at risk for developmental delays and significant medical complexity. The results demonstrate a need for more clarity and guidance regarding which children should qualify for EI. We suggest that most NBS conditions should automatically qualify based on the probability of resulting in a developmental delay. These findings suggest a future opportunity for collaboration between NBS and EI programs to create a consistent set of Established Conditions, potentially expediate referrals of eligible children, and streamline children's access to EI services.

In Brief

This article has supplementary material on the web site: www.jdbp.org.

In the United States, newborn screening (NBS) identifies children with conditions on the Recommended Uniform Screening Panel (RUSP) that benefit from early detection and treatment.¹ Although treatability and net benefit are essential for RUSP inclusion, not all symptoms are necessarily resolved.¹ Many children still experience developmental delays, have health problems, or require ongoing surveillance and management to maintain benefit. For example, over half of children with critical congenital heart disease and maple syrup urine disease (MSUD) need early intervention (EI) services, including physical and occupational therapy.^2,3

EI refers to the services provided for children from birth through age 3 years and their families through Part C of the Individuals with Disabilities Education Act.⁴ Services always include comprehensive evaluations and individualized family service plans and can also include specialty services, such as speech therapy, occupational therapy, physical therapy, and developmental therapy. EI programs operate at the state level with their own policies, but states must comply with Part C guidelines to receive federal funds. Those guidelines require states to serve children who meet 1 of 2 eligibility criteria: (1) a documented developmental delay or (2) an Established Condition that has a “high probability of resulting in a developmental delay.”⁴ There is no nationally accepted definition for what constitutes a high probability of resulting in a developmental delay, and a list of federally approved Established Conditions does not exist.⁵ As a result, considerable variability occurs across states in conditions that automatically qualify for EI.⁵ Some states use the broad regulatory language, whereas others list specific diagnoses that automatically qualify for EI.⁵ Because most children diagnosed with an NBS condition will not have obvious delays at birth, they must meet the Established Conditions criteria in their state to receive EI services. The frequency with which these conditions are included on state Established Conditions lists is not known, nor is it clear whether they should be included based on probabilities of developmental delays.

Challenges of Determining the “Probability of Resulting in a Developmental Delay” for NBS Conditions

Determining whether NBS conditions have a high probability of causing developmental delays is challenging. First, the conditions themselves vary considerably. For some, delays may be related to underlying pathology of the disease even after available treatment. For others, medical complexity of the condition or intervention puts children at a higher probability of delay. Frequent and prolonged hospitalizations, treatment toxicity, surgeries, and associated child and family stress may cause delayed development and psychiatric morbidities.^6–8 Conditions also vary in whether they are progressive or episodic. Episodic decompensation puts children at risk of acute crises such as a stroke, seizure, or metabolic acidosis that can rapidly transform the probability of a delay.

Second, the clinical severity of NBS conditions falls on a spectrum. Severity may be related to disease genotype, responsiveness to treatment, or unknown factors; variation in severity may express as frequency and severity of episodic decompensations, spectrum of system involvement, and age at which morbidity is observed. Individual outcomes are also related to early detection, access to medical care, timely treatment, and treatment compliance.

Third, knowledge about natural history, treatment-modified natural history, and developmental trajectories of NBS conditions may be based on small and potentially skewed sample sizes, case studies, and the lack of standardized developmental assessments (Supplemental Digital Content 1, https://links.lww.com/JDBP/A417). Limited long-term follow-up precludes a full understanding of the evolution of delays in children over time.¹

These challenges, in conjunction with variability in how “high probability of resulting in a developmental delay” is defined, pose a problem for both NBS and EI programs and could confuse families and pediatricians when deciding whether to refer children to EI. This uncertainty could lead to a watch-and-wait approach, which may be less beneficial to children's long-term outcomes. Clear guidance on the developmental risks associated with specific NBS conditions on the RUSP could streamline the referral and eligibility processes, but an inventory of a long-term risk for all NBS conditions does not currently exist.

Aims

We designed our analysis to fill a gap in understanding how practitioners consider NBS conditions when they are determining eligibility for EI, with 2 broad goals. First, we explored which recommended NBS conditions were automatically eligible for EI across states, including the District of Columbia (referred to jointly henceforth as “states”). We reviewed states' eligibility policies, determined which states had Established Conditions lists, and assessed the extent to which NBS conditions were included. Second, we reviewed each condition to determine the extent to which it had a high probability of resulting in delay, even when recommended treatments were provided. We considered the risk of delay in treatment-altered natural history, extent of medical complexity, and likelihood of episodic decompensation. We present 3 conditions as examples: biotinidase deficiency (BIOT), severe combined immunodeficiency (SCID), and propionic acidemia (PA). We excluded hearing loss from our study because of the existing links among NBS, Early Hearing Detection and Intervention, and EI. We conclude with recommendations about which NBS conditions should be considered Established Conditions for EI, in hopes of advancing national harmonization and providing guidance for pediatricians and specialists who are often responsible for referring children to EI.

METHODS

We first reviewed each state's eligibility information on the Early Childhood Technical Assistance Center (ECTA) website.⁹ ECTA is a national assistance center focused on building state and local systems' capacities to improve outcomes for children with disabilities and their families. ECTA reviews and updates each state's information at least once a year. Next, our research team contacted each state's EI Part C coordinator to confirm that this eligibility policy was accurate and up to date. Coordinators were contacted up to 3 times. Once our team was confident that we had the most up-to-date eligibility policy for each state, we determined whether the state had an Established Conditions list. To be defined as having an Established Conditions list, the state had to have an eligibility policy that included any medical conditions beyond federal Part C regulatory language.

We then searched each list to determine which NBS conditions were included. We asked experts familiar with genetic disorders and NBS to cross-check conditions with multiple names (e.g., primary carnitine deficiency and carnitine uptake disorder). If the Established Conditions list stated that all NBS conditions were automatically eligible, we coded all conditions as included. However, other broad categories were not counted for specific conditions (e.g., we did not code spinal muscular atrophy [SMA] as included if the policy said “genetic disorder”; similarly, we did not code classic phenylketonuria [PKU] as indicated if the policy said “inborn errors of metabolism”). If states included qualifiers for specific conditions, we coded these conditions as included (e.g., “galactosemia—only eligible for 1 year then requires developmental assessment”). To ensure accuracy, 2 research analysts coded each Established Conditions list. The analysts compared and discussed differences until reaching consensus.

Next, we developed Table 1 to help us assess the risk of delay in treatment-altered natural history, extent of medical complexity, and likelihood of episodic decompensation. We conducted a literature review to identify documented neurodevelopmental outcomes and medical risks associated with each NBS condition (see Supplemental Digital Content 1, https://links.lww.com/JDBP/A417, for a summary of the outcomes and risks). Specifically, for each condition, we broadly searched outcomes related to developmental delays. Notably, few studies reported on standardized developmental measures. Our literature review summarized studies that documented a wide range of outcomes—cognitive, physical, behavioral, neurological, speech, special education, hearing and/or vision loss, and learning disability. Next, we documented the medical complexity of each condition. For each, we described the effectiveness of available treatment, the treatment burden on children and families, risk of episodic decompensation, neurological complications of the disorder (e.g., abnormalities revealed by magnetic resonance imaging and seizures), and whether the condition is a multisystemic disease.

Table 1. - Guiding Principles for Constructing the Matrix

Construct	Question	Definition
Risk of resulting in a developmental delay in treatment-altered natural history	What is the risk that a child with this disorder has a developmental delay after receiving treatment?	Low risk: Medical treatment and standard medical care are effective at managing disorder and preventing cognitive, physical, developmental, and/or neurodevelopmental delays. High risk: Even with best medical treatment, children will experience cognitive, physical, developmental, and/or neurodevelopmental delays.
Medical complexity	What is the medical complexity of this disorder?	Low medical complexity: A single body system is affected. Treatment is straightforward and effective. Treatment burden is low. High medical complexity: Disorder is multisystemic and chronic. Condition is often associated with technology dependence and medical fragility. Multiple service providers are involved. Treatment burden is high. Treatment or disease may prevent school participation and normal social interactions. Family burden is significant—children and families are at elevated risk for psychological and emotional problems.
Episodic decompensation	Is a child with this condition at risk of episodic decompensation?	Yes: Children are at risk for rapid deterioration of their condition, resulting in a rapid decline in health or function. Onset can be caused by illness or fasting. No: With treatment, children are not at risk for rapid deterioration of their condition.

Two authors (E.J. and P.C.) who are medical experts independently classified each condition in terms of risk of delay in treatment-altered natural history, extent of medical complexity, and likelihood of episodic decompensation. These authors are both pediatric geneticists, with extensive clinical and research experience focusing on metabolic diseases, genetic disorders, and newborn screening. They determined the classifications based on their clinical experience, the literature review, and—when necessary—outside input from colleagues. After the initial classifications, all the authors including the medical experts discussed each disorder to finalize the classifications in the form of a matrix; see Figure 1. When initial expert reviewer classifications differed, the final classification was determined based on the literature review, clinical experiences, and prioritizing public health utility. For example, when reaching a consensus was most difficult, the expert reviewers frequently chose the ranking that represented the more severe consequences of the disorder (e.g., higher developmental delay and higher medical complexity).

Figure 1.: Matrix: Risk of developmental delay (DD) in treatment-altered natural history, extent of medical complexity, and likelihood of episodic decompensation.

RESULTS

At the time of analysis (December 2022), 88% of states (n = 45) had an Established Conditions list (Table 2). Each state included an average of 7.8 NBS conditions (range 0–34). Eight states with an Established Conditions list did not include any NBS conditions. Conversely, on average, each NBS condition was on 11.7 states' Established Conditions list, with a range of 2 to 29 states (Table 3). SMA was listed most frequently (29 states), followed by mucopolysaccharidosis type 1 (MPS 1; Hurler syndrome; 25 states) and MSUD (25 states) and PKU (23 states) and galactosemia (GALT; 23 states). Holocarboxylase synthetase deficiency (MCD) and SCID were listed least frequently (2 states). Four states (Georgia, Michigan, North Dakota, and Virginia) explicitly referenced the NBS program in their EI eligibility policies. Michigan and North Dakota EI programs automatically qualified any child diagnosed through NBS.

Table 2. - Established Conditions Lists, by State

State	Year Established Conditions List Updated	Number of Recommended Uniform Screening Panel (RUSP) Conditions on the Established Conditions List
No Established Conditions list (n = 6)
Indiana	NA	0
Maryland	NA	0
Nebraska	NA	0
Pennsylvania	NA	0
Vermont	NA	0
Wyoming	NA	0
Established Conditions list (n = 45)
Alabama	2022	6
Alaska	No date provided	0
Arizona	2022	1
Arkansas	2015	0
California	2022	0
Colorado	2020	10
Connecticut	2021	14
Delaware	2021	8
DC	2014	5
Florida	2020	10
Georgia	2017	23
Hawaii	2022	2
Idaho	2013	3
Illinois	2022	1
Iowa	No date provided	10
Kansas	2015	5
Kentucky	2022	12
Louisiana	No date provided	13
Maine	2021	29
Massachusetts	2015	13
Michigan a	2022	34
Minnesota b	2020	9
Mississippi	No date provided	17
Missouri	2013	2
Montana	2019	8
Nevada	2021	4
New Hampshire	No date provided	0
New Jersey	2012	0
New Mexico	2021	4
New York	2005	0
North Carolina	2006	0
North Dakota a	2021	34
Ohio	2020	4
Oklahoma	2017	14
Oregon	2019	2
Rhode Island	2018	13
South Carolina	2022	11
South Dakota	No date provided	0
Tennessee	2021	10
Texas	No date provided	13
Utah	2022	2
Virginia	2016	29
Washington	2019	13
West Virginia	2013	3
Wisconsin	2021	7

Hearing loss was excluded.

^aMichigan and North Dakota policy explicitly stated that all NBS conditions were automatically eligible for EI.

^bMinnesota used Colorado's list as a guide.

Table 3. - NBS Conditions, by State

NBS Condition (Abbreviation)	States Including Condition on the Established Conditions List	States Including Condition on the NBS Panel
3-Hydroxy-3-methylglutaric aciduria (HMG)	6	51
3-Methylcrotonyl-CoA carboxylase deficiency (3-MCC)	4	50
Argininosuccinic aciduria (ASA)	14	51
Biotinidase deficiency (BIOT)	6	51
Carnitine uptake defect/carnitine transport defect (CUD)	5	51
Citrullinemia, type I (CIT)	9	51
Classic galactosemia (GALT)	23	51
Classic phenylketonuria (PKU)	23	51
Congenital adrenal hyperplasia (CAH)	3	51
Critical congenital heart disease (CCHD)	16	51
Cystic fibrosis (CF)	11	51
Glutaric acidemia type I (GA I)	10	51
Glycogen storage disease type II (Pompe)	21	29
Holocarboxylase synthetase deficiency (MCD)	2	50
Homocystinuria (HCY)	13	51
Isovaleric acidemia (IVA)	9	51
Long-chain L-3 hydroxyacyl-CoA dehydrogenase deficiency (LCHAD)	8	51
Maple syrup urine disease (MSUD)	25	51
Medium-chain acyl-CoA dehydrogenase deficiency (MCAD)	9	51
Methylmalonic acidemia (cobalamin disorders; MMA Cbl A,B)	15	50
Methylmalonic acidemia (methylmalonyl-CoA mutase; MMA MUT)	15	50
Mucopolysaccharidosis type 1 (MPS 1; Hurler syndrome)	25	28
Primary congenital hypothyroidism (CH)	18	51
Propionic acidemia (PA)	14	51
S, beta-thalassemia (Hb S/βTh)	5	51
S,C disease (Hb SC)	5	51
S,S disease (Hb SS)	5	51
Severe combined immunodeficiencies (SCID)	2	51
Spinal muscular atrophy (SMA)	29	30
β-Ketothiolase deficiency (BKT)	4	51
Trifunctional protein deficiency (MTP)	4	51
Tyrosinemia, type I (TYR I)	8	51
Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD)	10	51
X-linked adrenoleukodystrophy (X-ALD)	22	23
Average	11.7	48.1

As we assigned each condition to a category in the matrix (Figure 1), initial agreement between the 2 clinical experts was 59% for medical complexity and 65% for the risk of developmental delay. Conditions for which we encountered disagreement are presented in Table 4. Specific factors made assigning risk and complexity difficult, such as risk of episodic decompensation (methylmalonic acidemia cobalamin A, B type [MMA Cbl A,B]), rarity (trifunctional protein deficiency [MTP]), age at which developmental delay is realized (X-linked adrenoleukodystrophy [X-ALD]), and public health utility versus individual risk. To resolve discrepancies under such complex circumstances, in some situations, the medical experts' final consensus was the ranking that represented the more severe consequences of the disorder (e.g., higher medical complexity and higher risk of developmental delay). For example, when expert #1 rated argininosuccinic aciduria (ASA) as “low medical complexity” and expert #2 rated ASA as “moderate medical complexity,” the final consensus was “moderate medical complexity.” Similarly, when expert #1 rated critical congenital heart disease (CCHD) as “moderate risk of developmental delay” and expert #2 rated CCHD as “low risk of developmental delay,” the final consensus was “moderate risk of developmental delay.”

Table 4. - Conditions with Initial Expert Disagreement and Final Consensus Ratings

Conditions on Which Experts Disagreed	Expert #1 Initial Rating	Expert #2 Initial Rating	Final Consensus
Medical complexity
ASA	1	2	2
BKT	2	1	2
CH a	1	2	1
GA I	2	3	3
GALT a	1	2	1
Hb SS	3	1	3
Hb S/βTh a	3	1	3
Hb SC	3	1	3
LCHAD a	2	3	3
MMA Cbl A,B a	2	3	3
MTP a	2	3	3
PKU	1	2	2
TYR I	2	3	2
VLCAD a	1	2	2
Risk of developmental delays
CCHD	2	1	2
CAH	2	1	1
CH a	1	3	2
GALT a	3	2	3
Hb S/βTh a	2	3	1
LCHAD a	3	2	2
MMA Cbl A,B a	2	3	3
MPS 1	3	2	3
MTP a	3	2	2
VLCAD a	2	1	2
X-ALD	2	1	2

Medical complexity: 1 = low medical complexity, 2 = moderate medical complexity, and 3 = high medical complexity. Risk of developmental delays: 1 = low risk of developmental delay in treatment-altered natural history, 2 = moderate risk of developmental delay in treatment-altered natural history, and 3 = high risk of developmental delay in treatment-altered natural history.

See Table 3 for full definitions of the conditions named in this table.

^aDisorders for which experts' initial ratings differed for both medical complexity and risk of developmental delays.

We determined that 29 conditions (85%) met the criteria for Established Conditions that would be eligible for EI. Recommendations for each condition are provided in Table 5.

Table 5. - Recommendations

Recommendations	Conditions
Recommendation 1: Children with conditions in the dark gray cells in Figure 1 should automatically qualify for EI. These conditions should be on states' EI Established Conditions lists (26 of 34 NBS conditions).	ASA a BKT a CCHD CF CH CIT a GA I a GALT Hb S/βTh Hb SC Hb SS HCY a HMG a IVA a LCHAD a MMA Cbl A,B a MMA MUT a MPS 1 MSUD a MTP a PA a Pompe SCID SMA VLCAD a X-ALD
Recommendation 2: Children with conditions in the light gray cells in Figure 1 who are at risk for episodic decompensation (asterisked) should automatically qualify for EI. These conditions should be on states' EI Established Conditions lists (3 of 34 NBS conditions).	CAH a MCAD a MCD a
Recommendation 3: Children with all other conditions in the light gray cells in Figure 1 should be monitored and evaluated for behavioral and developmental delays in the first year of life. Children should be referred to EI if a delay is present (5 of 34 NBS conditions).	3-MCC BIOT CUD PKU TYR I

These recommendations are for referrals to EI based on the presence of an Established Condition. For any condition, if a developmental delay is present, children should be referred. This is a guidance tool and not inclusive of all qualifying medical conditions.

^aCondition that puts children at risk for episodic decompensation.

Example Conditions

Three conditions from our matrix (Figure 1) exemplify the decision-making context: biotinidase deficiency, severe combined immunodeficiency, and PA. We chose to highlight these conditions because they represent the variability of types of condition on the RUSP. For example, these conditions differ in treatability, medical complexity, and potential causes of developmental delays.

Biotinidase Deficiency

BIOT is a metabolic condition that occurs when the body cannot reuse and recycle biotin. Without treatment, children can develop hearing loss, vision problems, skin rash, alopecia, respiratory problems, hypotonia, lethargy, seizures, and intellectual disability.¹⁰ Coma and premature death can occur.¹⁰

Early detection of BIOT with NBS has dramatically improved health and neurodevelopmental outcomes. Treatment with pharmacologic doses of biotin is straightforward and effective, leading to excellent outcomes when treatment is started before symptom onset.^10,11 In a recent study, Zengin Akkus et al.¹² found no difference between early treated children with BIOT and their unaffected peers in terms of developmental and behavioral outcomes.

Nonetheless, if children do not receive a diagnosis or families are unable to comply with treatment protocols, children are at risk for irreversible neurodevelopmental and cognitive problems.¹³ In such cases, children could need audiology services, occupational and physical therapy, and/or speech and special education services. Given the importance of compliance to biotin therapy, some children could benefit from EI services that support family education, training, counseling, and/or transportation required to receive appropriate and timely medical care. All states indicated that they screened for BIOT, and 6 states listed BIOT as an Established Condition.

Our review and consensus rating indicated that BIOT had low medical complexity and low risk of delay in treatment-altered natural history. We concluded that although it may be appropriate to refer children with BIOT to EI, this disorder does not necessarily need to be considered an Established Condition. However, children presenting with the condition should be monitored and evaluated for behavioral and developmental delays. If a delay is present, children with BIOT should be referred for EI.

Severe Combined Immunodeficiencies

SCID is a group of primary immune deficiency diseases that affect the function of T cells, with some also affecting B cells and natural killer (NK) cells. Children present early in life with infection, diarrhea, and failure to thrive.⁸ Without treatment, SCID is often fatal in the first year of life.¹⁴

NBS and early treatment have improved survival for children with SCID.¹⁴ Nonetheless, SCID is a complex medical diagnosis with a high burden for families and children. Families and babies must isolate to prevent infection. Treatment frequently includes hematopoietic stem cell transplantation (HSCT). There is evidence that HSCT is related to slower gain in developmental skills for children with SCID. For example, Lin et al.⁸ examined children pre- and post-HSCT and reported a decrease in cognitive scaled scores, although not a loss of skills. Other longitudinal studies have reported that some children with SCID experience developmental delays.¹⁵ A consensus statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference suggested that delays likely result from chronic infections, conditioning regimens (chemotherapy), prolonged hospitalization, isolation from other children, lack of exposure to cognitive stimuli, and significant family stresses.^8,16

After treatment, children with SCID could benefit from specific EI services, such as physical and occupational therapy to regain functional skills after weeks or months in the hospital.¹⁷ Additional services may include speech and feeding therapy because mouth sores, persistent nausea, gastrointestinal pain, and taste changes can result in feeding and swallowing disorders during and after transplant.¹⁸ Finally, HSCT carries a significant risk of emotional and psychological consequences (e.g., anxiety, depression, and behavior problems) for young children and their families. Cognitive-behavioral interventions and psychological support may benefit children's social and emotional skills.¹⁹ We found that all states indicated that they screened for SCID, but only 2 states include SCID as an Established Condition.

Our review and consensus ratings indicated that SCID is associated with high medical complexity. We concluded that it should be considered an Established Condition and automatically qualify for EI.

Propionic Acidemia

PA is an inborn error of organic acid metabolism. Clinical symptoms often begin at birth or within a few weeks and include poor feeding, vomiting, low appetite, hypotonia, and acute encephalopathy. Without treatment, children experience episodic decompensation that could lead to coma or death.²⁰

Early detection and long-term management reduce mortality²¹ but have not been linked to better neurological outcomes.²² Treatment includes careful medical management during acute periods of illness (e.g., fluids, bicarbonate, and hemodialysis); a restricted, lifelong, low-protein diet; and supplementation. However, treatment is not curative, and many children experience developmental, ophthalmological, and neurological complications before age 2 years.^21–24

Children with PA could benefit from a variety of EI services. Occupational therapy and physical therapy may support children with movement disorders or hypotonia.²³ Behavioral and psychological services may be beneficial given the prevalence of emotional disturbances, conduct problems, hyperactivity/inattention, and peer relationship problems.²⁴ Speech and occupational therapy may support feeding.²³ Hearing loss and vision problems can occur with PA,^23,24 and children may benefit from audiology and vision services. All states indicated that they screened for PA, and 14 states listed PA as an Established Condition.

Based on our consensus ratings, PA has high medical complexity and risk of delay, even in treatment-altered natural history. Thus, we recommend that PA be considered an Established Condition and automatically qualify for EI services.

DISCUSSION

For our study, we identified the NBS conditions included on the states' Established Conditions lists and assessed the likelihood of delay for each.

Consistent with previous research,⁵ we found variability across states in whether children qualified for EI based on medical diagnoses. Most states used an Established Conditions list but included few NBS conditions (average 7.8 conditions). The low frequency may have been caused by the rarity of these conditions (EI programs may be unlikely to list a condition if they have never served an affected child), by the lack of state coordination between EI and NBS, or by a limited understanding of developmental outcomes.

The most comprehensive EI policies related to NBS that we found were in Georgia, Maine, Michigan, North Dakota, and Virginia. Except Maine, each policy explicitly referenced the NBS program.^25–28 These states had the most frequently listed NBS conditions, all with 23 conditions or more. Georgia's list included 23 conditions and named the NBS program as a resource to identify children who might need services. Michigan specified that “all disorders tested for in the Michigan Newborn Screening Program” were Established Conditions. North Dakota also specified “disorders identified through newborn screening” were automatically eligible. Virginia incorporated 29 conditions plus an NBS Fact Sheet that described the clinical and developmental outcomes of most of the RUSP conditions. Future research in these states may illuminate whether coordination is occurring between the EI and NBS programs and provide a framework for future collaboration.

There was a wide range (from 2 to 29) in how frequently each condition was included on the states' Established Conditions lists. Even the most commonly included condition (SMA) was on only 29 of the 51 lists. Generally, according to our matrix, the more frequently listed conditions were also those more likely to result in a developmental delay, although that was not always the case. For example, trifunctional protein deficiency (MTP) was included on only 4 state lists, despite documented neurodevelopmental problems.²⁹ Some of the highest risk conditions in terms of developmental delay and medical complexity (e.g., citrullinemia, type I [CIT]) appeared on fewer than 10 state Established Conditions lists.

A significant challenge to categorizing conditions based on the risk of developmental delay and medical complexity was the lack of a definition for “high probability of resulting in a developmental delay.” Phenotypic variability further complicated this effort. For example, the risk of developmental delay and medical complexity can vary depending on the form of disease (e.g., classical vs attenuated very long-chain acyl-CoA dehydrogenase deficiency [VLCAD]) or responsiveness to medication (e.g., medication-responsive MMA vs nonresponsive MMA). Finally, the age at which developmental risk is realized can vary (e.g., PKU and X-ALD are associated with the risk of delays at a later age). Because our goal was to be able to provide EI programs, pediatricians, and families with a best estimate of the probability of developmental delays for children who may benefit from EI services, we used the public health utility of our findings to guide our final consensus determinations and thereby support EI professionals in developing Established Conditions lists.

Of the 34 NBS conditions examined, we suggest that 29 (85%) should be considered Established Conditions (Table 5), compared with the current average we found of 7.8.

LIMITATIONS AND FUTURE DIRECTIONS

There are limitations specific to this study, and also more broadly to the EI and NBS programs, that are important to identify for future research. First, there are significant gaps in EI and NBS data tracking. Problematically, the rates in which children with specific NBS conditions are referred and enrolled into EI are not known. Most state coordinators do not know the frequency NBS conditions are referred or enrolled,³⁰ and there are very few condition-specific studies that document EI usage (Supplemental Digital Content 1, https://links.lww.com/JDBP/A417). Similarly, it is not known whether physicians or other referral sources document the medical condition for which they are referring children, whether there are also developmental delays present, or how these data are tracked and shared across states. Without these data, it is difficult to know to what extent children with specific NBS disorders are referred to EI, and whether changes in eligibility policies and Established Conditions lists increase enrollment. Consistent documentation, improved data tracking, and cross-state policies for data sharing are necessary to support future research.

Relatedly, there is wide variation across states about the types of services provided to infants who have an Established Condition but do not necessarily present with delays. EI service provision may range from developmental monitoring to automatic provision of specific services. Better data tracking of the types of services used for specific conditions could help formulate individualized family service plans to best meet the child's current and future needs.

In addition, it is not clear whether EI eligibility policies that list specific conditions (e.g., classic galactosemia [GALT]) help children with those conditions receive quicker and more reliable referrals when compared with listing broad categories (e.g., inborn errors of metabolism). It is possible that broader categories allow for wider interpretation and may benefit children with ultrarare diseases. Similarly, some states' lists only include a few exemplar conditions, along with an explicit statement that lists are nonexhaustive. Funding and personnel issues may not allow Established Conditions lists to be continuously updated and monitored, and this might be especially true given the expansion to NBS that could happen over the next decade. Thus, comparisons across states with varying types of eligibility policies would be informative and could help guide the future development of eligibility policies.

Finally, it is important to acknowledge that assessing the benefits of EI is challenging, and few NBS disease-specific studies have reported outcomes after EI. Although we recommend that many NBS conditions be named as Established Conditions, it is up to the family and pediatrician to determine whether a particular child should be referred to and enrolled in EI. After a diagnosis, families must coordinate doctors' appointments, adapt to new diet and medication schedules, or understand treatment protocols. Although EI could provide an important support system, it could also add to families' burden and stress.

CONCLUSION

Despite benefiting from NBS and timely treatment, many children diagnosed with conditions on the RUSP are at risk for developmental delays and significant medical complexity. Our results demonstrate a need for more clarity and guidance regarding which children should qualify for EI. We recommend 29 NBS conditions that should automatically qualify children for EI based on the probability of resulting in a developmental delay. These findings suggest a future opportunity for collaboration between NBS and EI programs to create a consistent set of Established Conditions, potentially expediate referrals of eligible children, and streamline children's access to EI services.