We categorized our retrospective cohort into short-gap (n = 54) and long-gap (n = 16) EA surgical groups. At our institution, the latter group undergo the Foker process (5, 6) that involves: (1) Foker I thoracotomy or thoracoscopy to place traction sutures onto the esophageal ends; (2) Time-on-traction with traction system adjustments; (3) Foker II thoracotomy or thoracoscopy to perform esophageal anastomosis; and (4) Postoperative sedation and subsequent weaning of sedation to allow for healing of the esophageal anastomosis (8, 16).

Most patients in this retrospective analysis were born with co-existing cardiac anomalies (10) (Table 1). Due to the known increased risk of neurodevelopmental delays following cardiac repair (19, 20), co-existing cardiac anomalies were categorized into (1) major (requiring cardiac surgical repair), or (2) minor (not requiring surgical correction) as previously summarized [Table 2 in (10)]. Neurological findings of our cohort were obtained from clinically indicated cranial ultrasound and/or brain MRI findings [Table 2 in (21)]. Cranial imaging findings included the presence of abnormal head shape (e.g., plagiocephaly, brachycephaly, etc.), and/or signs of traumatic perinatal injury (e.g., cephalohematoma). Brain imaging findings ranged from likely benign (e.g., a simple cyst) to more serious findings [e.g., cerebral ventriculomegaly, brain atrophy, intracranial hemorrhage; see Figure 5 in (15)].

In this retrospective review, our chart analysis focused on any mention of developmental delay, as documented in clinical notes from a variety of specialties, including developmental medicine, primary care, and physical therapy consultations. We categorized the frequency of neurodevelopmental outcomes in our cohort based on clinical documentation into three categories: (1) documented developmental delay, (2) documented normal development, and (3) not known—in cases when no clinical notes pertaining to neurodevelopmental assessment were available. The term “neurodevelopmental delay” refers to any type of neurodevelopmental impairment documented in the patients' clinical charts (e.g., motor delay, speech/language delay, cognitive delay, or failure to meet age-appropriate milestones) as recorded by a medical professional. Notably, feeding difficulties and/or dysphagia, which are common consequences of EA repair, were not considered a symptom of neurodevelopmental delay. We further categorized frequency of neurodevelopmental delay into three domains: (1) motor delay, (2) speech/language delay, and (3) cognitive delay, based on terminology used in the clinical notes. According to the clinicians’ reports, motor delay was characterized by abnormalities in gross-motor (e.g., large body complex movements and mobility) and/or fine-motor skills (e.g., visual-motor coordination, visual-spatial skills, and hand motor control). Speech/language delay, as noted in clinical reports, referred to delays in speech production, expressive language, and/or receptive language. Cognitive delay findings included memory, learning, and/or problem-solving delays as identified through neurodevelopmental assessments conducted by clinicians. Lastly, we collected the frequency of global developmental delay (GDD) as mentioned in the clinical notes. GDD refers to significant delays in two or more developmental domains (motor, language, cognitive, social interaction, and daily livings skills) (22).

We report the presence of neurodevelopmental delay documented in (i) the first year only, (ii) the second year only, or (iii) both the first and the second years of life. Additionally, we collected the earliest age (in months) of initial clinical documentation of any type of neurodevelopmental delay. For premature infants, we used corrected post-natal age that adjusted for gestational age at birth (in weeks) (23).

At our institution, early intervention (EI) programs (24) that include a range of services and supports, are recommended for pediatric patients who show signs of developmental delays, as identified through neurodevelopmental assessments. Thus, we additionally retrospectively quantified the frequency of EI implementation by 2 years of age, based on clinical documentation. Additionally, we recorded the earliest age (corrected post-natal age in months) at which EI implementation was first documented.

The earliest documentation of developmental delay of any type was noted in the first 6 months of life (Figure 1A): 48% (15/31) in the short-gap group, and 85% (11/13) in the long-gap group. Indeed, neurodevelopmental delay was first documented over the course of the first year of life for most of the infants born with short-gap (24/31; 77%) and long-gap EA (12/13; 92%). For short-gap EA group (Figure 1B), nearly half had documented developmental delay in the first year (24/54; 44%) and the second year of life (28/54; 52%). For the long-gap EA group (Figure 1C), the majority had neurodevelopmental delay documented in the first (12/16; 75%) and the second year of life (11/16; 69%). The remainder of the cohort had documented normal neurodevelopment throughout the first two years of life, and only one short-gap EA patient lacked documentation regarding neurodevelopment (Figure 1B).

We report equal sex distribution of documented developmental delay by the second year of life: 50% (14/28) male for short-gap, and 55% (6/11) male for long-gap EA. Sex distribution for the remaining infants with no developmental delay and those with incomplete records is also illustrated in Figure 2.

As illustrated in Figure 3, our retrospective cohort (n = 70) has about two-thirds term-born (n = 44) and about one-third premature infants (n = 26). Nearly half of term-born infants with short-gap (16/37; 43%) and long-gap EA (4/7; 57%) had documented developmental delay by the second year of life (Figures 3A,C, respectively). In contrast, the majority of premature patients had documented developmental delay regardless of the surgical type of EA: 71% (12/17) short-gap, and 78% (7/9) long-gap EA (Figures 3B,D). Interestingly, for short-gap EA infants with developmental delay in the first (n = 24/54) and the second year of life (n = 28/54), there is nearly equal distribution between term-born [58% [14/24] in the first; 57% [16/28] in the second year of life] and premature groups. In contrast, long-gap EA patients with developmental delay (n = 12/16 in the first; n = 11/16 in the second year of life) were more frequently premature [67% [8/12] in the first; 64% [7/11] in the second year of life] rather than term-born.

It was previously reported [Table 2 in (10)] that most of the short-gap (38/54; 70%) and long-gap EA patients (13/16; 81%) in our cohort had minor co-existing cardiac anomalies that did not require surgical repair. Here, we report that the majority of short-gap (n = 28/54) and long-gap EA infants (n = 11/16) with documented developmental delay by the second year of life also had minor co-existing cardiac anomalies: 64% (18/28) short-gap (Figures 4A,B), and 91% (10/11) long-gap EA (Figures 4C,D). Interestingly, minor cardiac anomalies were also clinically noted in most of the infants with documented normal development in both surgical groups (Figure 4).

We previously summarized the type and frequency of neurologic diagnostics and neurological findings of the cohort [Table 2 in (18)]. Nearly half of short-gap EA patients with developmental delay (n = 24/56 in the first; n = 28/56 in the second year of life) had cranial/brain findings: 46% (11/24; Figure 5A) in the first, and 39% (11/28; Figure 5B) in the second year of life. Similar frequency of cranial/brain findings were also identified in long-gap EA patients with documented developmental delay (n = 12/16 in the first; n = 11/16 in the second year of life): 50% (6/12; Figure 5C) in the first, and 45% (5/11; Figure 5D) in the second year of life.

Our retrospective data show that infants born with EA, irrespective of the surgical type, are at risk of developmental delay throughout the first and the second year of life, documented as early as the first six months of life. Similarly, a study by Francesca et al. (25) reported development delays at 6 and 12 months, with lower average developmental scores at 12 months compared to 6 months. Another study by Walker et al. (26) reported developmental delay at 12 months of age in 52% of their cohort of EA patients. Neurodevelopmental delay in patients born with EA was also reported between 12 and 36 months in yet another study by Mawlana et al. (27). Neurodevelopmental delay was also noted as early as 12 months of age in other cohorts of infants that underwent complex critical care following repair of non-cardiac congenital anomalies (13), cardiac anomalies (20), and congenital diaphragmatic hernias (28).

In addition to high occurrence of documented developmental delay in long-gap EA patients, nearly half of infants born with short-gap EA in our retrospective cohort had developmental delay documented in the first two years of life. This finding suggests risk of early developmental delay irrespective of the complexity of surgical repair. Literature suggests that surgery for thoracic noncardiac congenital anomalies was associated with high-risk of brain injury (14–16) possibly leading to delay in neurocognitive and motor development (12), including those with EA (13). Given that infants with congenital gastrointestinal anomalies experience multiple stressors early in life, and the fact of improved survival rates of infants born with EA over the recent decade (10), prospective follow up studies are needed to comprehensively examine the impact of complex perioperative critical care on long-term neurodevelopmental outcomes in infants born with EA irrespective of the surgical type (short-gap and long-gap EA).

We report findings of documented motor delay in both short- and long-gap EA groups in the first and the second year of life. This finding is consistent with the most recent reports of motor delays throughout the first two years of life in group of infants following EA repair (25, 26). Early assessment and detection of motor delays before 12 months old is important, as fine and gross motor functions such as grasping, sitting independently, and crawling typically appear during this timeframe. Assessment in the second year is similarly important as delays in gross motor functions such as standing and walking typically emerge between 12 and 15 months old (29). Nearly half of our cohort patients had also documented speech/language delays in the second year of life (Figure 7), which is when expressive and receptive language delays become apparent (29). A study by Mawlana et al. (27) similarly reported evidence of speech/language delays during this timeframe. As evaluation of cognitive functions are difficult to interpret before age two by non-psychologists lacking in specialized cognitive assessment expertise, our data regarding cognitive delays should be interpreted with caution. Previous reports by other groups also failed to detect cognitive developmental delay at this early age (9, 25, 26). Lastly, only a minority of short-gap and long-gap EA patients had documented GDD (Figure 6B). However, the frequency of GDD increased from the first to the second year of life, which in the context of GDD definition (see Methods), reflects increased detection of multiple types of developmental delays over time. Future studies in infants born with EA should involve administered neurobehavioral assessments (e.g., Bayley Scales of Infant and Toddler Development) at several time points in the first 3 years of life.

Equal sex distribution of the cohort (10) and nearly equal sex distribution with respect to the frequency of documented developmental delay per surgical type (Figure 2) implies that there is no sex-specific vulnerability to developmental delay in infants born with EA. As such, future studies could potentially combine sex data with a goal of increasing the study power.

As it is well known that prematurity is a risk factor for neurodevelopmental delay (30), it is not surprising that we report higher frequency of early documented neurodevelopmental delay in premature infants (born 28 to <37 weeks of gestation) compared to term-born infants irrespective of the surgical group of EA (Figure 3). Our report highlights that the frequency of neurodevelopmental delay in term-born patients is higher than that in the general population. As such, our study represents a “call to action” to address the gap in our knowledge regarding the underlying mechanisms that lead to neurodevelopmental vulnerability of term-born infants following EA repair.

It is well known that infants are at risk for adverse neurodevelopmental outcomes following neonatal cardiac surgery (19, 20). As EA often presents with other congenital anomalies that can impact complexity of care (10, 21), the frequency of neurodevelopmental outcomes in relation to co-existing cardiac anomalies represent novel findings. We identified that most EA patients with documented early neurodevelopmental delay had only co-existing minor cardiac anomalies that did not require surgical repair (Figure 4).

Documented neurodevelopmental delay was found both in the presence and absence of known cranial/brain findings irrespective of the surgical group (Figure 5). As we previously reported (21), the frequency of cranial/brain findings in our group (67% of those imaged; 22/33) may be underestimated, as neurologic diagnostic imaging was performed in only about half of the cohort (47%, 33/70). A study by Stolwijk et al. (14) reported that infants born with noncardiac congenital anomalies are at risk of postoperative brain injury following neonatal surgery, potentially contributing to the increased frequency of observed developmental delay in this population (11–13). Furthermore, our recent pilot MRI study following long-gap EA repair with Foker process reported clinically significant incidental imaging findings (15, 16) and reduction of brain volumes (15, 31, 32). Although EA is not known to be associated with neurological imaging findings or specific neurological sequelae (2), future prospective research is warranted to evaluate neurologic vulnerability and its impact on the risk of long-term neurodevelopmental sequelae.