We used the Bayley Scales of Infant and Toddler Development (BSID)-III to analyze the incidence and risk factors of developmental delay in very-low-birth-weight infants without severe brain lesions. We further examined the correlation between the cumulative dexamethasone dose and developmental assessment results.
We retrospectively analyzed data of preterm infants (birth weight <1,500 g) admitted to our neonatal intensive care unit between January 2014 to December 2020. The BSID-III scores obtained between the corrected ages of 12 and 24 months and after 24 months were analyzed. Developmental delay was defined as a composite score of <85 for the cognition, language, and motor domains. Univariate and multivariate analyses of developmental delay risk factors and developmental changes from the first to second BSID-III were performed. Correlations between the accumulated dexamethasone dose used for bronchopulmonary dysplasia (BPD) and the first and second test scores were analyzed.
Seventy-one and thirty-six infants completed the first and second tests, respectively. In both tests, developmental delay was most commonly observed in the language domain (26.8%, 47.2%). In multivariate analysis, mild BPD was identified as a developmental delay risk factor (
Very-low-birth-weight infants typically experience language delay, which can persist as they age.
The survival rate of very-low-birth-weight infants (VLBWIs) is increasing, while the incidence of major complications in such infants is decreasing in many countries owing to medical advances and the development of various drugs and respiratory assist devices [
For preterm infants, the primary goal is survival and independent and autonomous living as adults. Severe brain lesions, which commonly include severe intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) are major risk factors for poor development. Brain ultrasonography and, if needed, brain magnetic resonance imaging (MRI) can be used to detect severe brain lesions during hospitalization. An imaging study reported that preterm infants without severe brain lesions can still experience severe developmental delay [
Imaging to examine severe brain lesions is often performed as a screening procedure, and developmental follow-up of individual infants after discharge is necessary. The Bayley Scales of Infant and Toddler Development (BSID) is one of the most widely used developmental assessment tools. The BSID-III assesses development across five domains (cognition, receptive language, expressive language, gross motor, and fine motor), in greater detail than does the BSID-II [
Understanding the developmental state of preterm infants is important to ensure not only survival, but also a good quality of life. This study used BSID-III scores to analyze the incidence and risk factors of developmental delay and developmental changes observed in VLBWIs without severe brain lesions who were discharged from a single institution during a 7-year period. Additionally, this study investigated whether the cumulative dexamethasone dose and developmental assessment results were correlated with each other.
Data collected from preterm infants with a birth weight of <1,500 g who were admitted to the neonatal intensive care unit (NICU) of our institution between January 2014 and December 2020 were retrospectively analyzed. Infants who completed the BSID-III test at the corrected age of 12 months after discharge were selected. Those with severe brain lesions, defined as IVH of grade III or higher, PVL, or brain deformities detected on ultrasonography or brain MRI, were excluded.
The BSID-III scores obtained between the corrected ages of 12 and 24 months and after 24 months were analyzed to examine development at the corrected ages of 1 and 2 years, respectively. Developmental delay was defined by a composite score of <85 on each of the following domains: cognition, language, and motor [
To investigate the effect of dexamethasone use on BPD development, we analyzed the correlations between the cumulative dose of dexamethasone and the first and second BSID-III scores.
Gestational age, sex, multiple gestations, birth weight, head circumference, delivery mode, 1- and 5-minute Apgar scores, and prenatal steroid use were examined as perinatal factors potentially affecting developmental delay. Maternal age, hypertension, and gestational diabetes were also examined. In terms of morbidities of the enrolled preterm infants in the NICU, we examined respiratory distress syndrome, BPD, postnatal steroid use, and retinopathy of prematurity (ROP), for which an intravitreal injection of bevacizumab or laser therapy was performed; patent ductus arteriosus, for which pharmacotherapy or ligation was performed; necrotizing enterocolitis for which a laparotomy was performed; inguinal hernia surgery; culture-proven sepsis; referred otoacoustic emission or auditory brainstem response; and weight and head circumferences at the time of discharge [
Postnatal steroids were used for two main reasons in the NICU. Hydrocortisone was administered at 3 mg/kg/day for refractory hypotension not treated by dopamine administered at ≥10 µg/kg/min. The dose of hydrocortisone was gradually reduced, and administration was stopped once the blood pressure stabilized. Dexamethasone was administered from at least 3 weeks of age when the infant was exposed to oxygen therapy or positivepressure ventilation for a long period after being diagnosed with BPD or when progression to severe BPD was predicted and weaning from invasive mechanical ventilation was deemed difficult even before 28 days after birth. Two administration schemes were used and selected by neonatologists based on the patient’s lung condition and the need for respiratory assistance: 10-day administration (with an initial dose of 0.1 mg/kg/day gradually reduced over 10 days or a total dose of 0.55 mg/kg) or 2-week administration (with an initial dose of 0.25 mg/kg/day gradually reduced over 14 days or a total of 1.62 mg/kg). When the infants could not be weaned off mechanical ventilation even after 3 to 4 days of dexamethasone administration, steroid administration was deemed ineffective and was ceased. When weaning from mechanical ventilation was delayed, steroids were administered at regular intervals.
All analyses were performed using R version 3.6.1 (R Core Team 2017, R Foundation for Statistical Computing, Vienna, Austria;
A total of 254 VLBWIs weighing <1,500 g were admitted to the NICU of our institution between January 2014 and December 2020. Of these, 149 infants who did not complete the BSID-III test, 1 infant who completed the Korean Denver Development Screening Test II, and 2 infants who completed the BSID-III at times other than during the specified period were excluded. The remaining 102 infants completed their first BSID-III test at the corrected ages of 12 to 24 months. Thirty-one infants with severe brain lesions (six with IVH grade III or higher, 21 with PVL, and four with IVH grade III or higher with PVL) were excluded. Finally, 71 infants were included in this study (
Seventy-one infants without severe brain lesions who completed the BSID-III test completed their first test at the mean corrected age of 14.7±3.3 months. Developmental delay was most commonly observed in the language domain (n=19, 26.8%), followed by the cognition (n=17, 23.9%) and motor domains (n=13, 18.3%). However, in the comparison of the mean composite scores and the percentage of infants with severe developmental delay among the domains, the motor domain had the lowest mean composite score (70.9±7.0) and involved the highest number of infants with severe developmental delay (n=6, 8.5%) (A in
Of the 71 infants analyzed, 36 completed the second BSID-III test at a mean corrected age of 28.2±6.5 months. Developmental delay was most commonly observed in the language domain (n=17, 47.2%). The language domain had the lowest mean composite score (68.9±9.7) and involved the highest percentage of infants with severe developmental delay (n=7, 19.4%) (B in
The risk factors for developmental delay were analyzed for each BSID-III domain. In the multivariate logistic regression analysis, mild BPD was identified as a risk factor of cognitive developmental delay (OR, 13.21; 95% CI, 1.75 to 139.35;
Thirty-six infants completed the two BSID-III tests. The trends in developmental delay were analyzed by comparing the first and second BSID-III tests. The infants scored lower in the second test than in the first test across all domains, indicating developmental delay (
Of the 71 infants who completed the first BSID-III test, 37 were administered dexamethasone. The time of the first administration was 48.8±19.6 days (range, 23 to 111) after birth, and the total duration of administration was 21.4±14.3 days (range, 3 to 75). The cumulative dose of dexamethasone used was 3.8±3.7 mg/kg (range, 0.5 to 21.0).
Among the infants who completed the second BSID-III test, 23 had a history of dexamethasone use. The first administration was performed 48.5±19.7 days (range, 27 to 111) after birth, and the total duration of administration was 19.1±12.3 days (range, 3 to 50). The cumulative dose of dexamethasone was 2.8±1.9 mg/kg (range, 0.5 to 7.0).
No significant correlation was observed between the cumulative dose of dexamethasone and developmental delay based on the first BSID-III test scores; meanwhile, the second BSIDIII scores for the cognition (
Compared with full-term infants, preterm infants have underdeveloped executive functions, reduced receptive and expressive vocabularies, and poor motor function. The later a developmental delay is managed, the more likely it is that a preterm infant will experience cognitive, language, and motor disabilities that can require additional treatment. Therefore, early developmental assessment of preterm infants is important [
In this study, the incidence of language developmental delay was 26.8% and 47.2% at the corrected ages of 1 and 2 years, respectively. Language developmental delay is the most common and long-lasting developmental delay. This result is consistent with a report by the KNN, which stated that language developmental delay had the highest incidence of 26.5% to 48.7% among other types of delays [
Low gestational age, low birth weight, low Apgar score, BPD, ROP, IVH, and PVL are known risk factors for developmental delays. Conversely, several studies have reported that prenatal steroid use reduce the risk of developmental delay [
Dexamethasone exerts adverse effects on neurodevelopment and is more dangerous the earlier it is used [
In this study, some infants without severe brain lesions, who were not administered dexamethasone, showed developmental delay. Among them, five patients showed diffuse excessive high signal intensity (DEHSI). While prior studies have reported a correlation between severe white matter damage and neurodevelopmental delay, more recent studies have reported no such correlation [
This study has several limitations. This study had a small sample size given that it was a single-center study, and the incidence of BSID-III test administration was low (40%) among the participating infants. Additionally, as this was a retrospective study, the time at which the BSID-III test was administered varied among the infants and the history of rehabilitative therapy before the developmental assessments was not considered. Finally, hydrocortisone use was not considered, even though some infants had a history of hydrocortisone administration; therefore, the total effect of steroid uses could not be assessed.
However, because this study was conducted at a single institution, it was possible to assess the developmental state of VLBWIs discharged without severe brain lesions after they receiving uniform care under the same guidelines. This study differed from previous studies that have reported severe brain injuries as a major risk factor for developmental delay, as it assessed the risk factors for developmental delay in preterm infants without severe brain lesions. Additionally, this study monitored improvements in or worsening of developmental delay during the follow-up appointments. In NICUs, it is common to observe parents obsess over the brain MRI results of their preterm infants during hospitalization. If no severe brain lesions are detected, parents tend to ignore the doctor’s recommendation to pursue followup developmental assessment. This study demonstrated that preterm infants without severe brain lesions can still experience developmental delay that may persist as age. This finding may help healthcare professionals and parents of preterm infants recognize the importance of developmental follow-up. A multidisciplinary effort from healthcare professionals is needed to ensure systematic, long-term follow-up and management, in addition to a large-scale prospective study examining the positive effects of such efforts on the development of VLBWIs.
This study was approved by the Institutional Review Board of the Pusan National University Hospital (IRB No. 05-2021-297). The requirement for informed consent was waived by the board.
No potential conflict of interest relevant to this article was reported.
Conception or design: M.H.J., Y.M.H.
Acquisition, analysis, or interpretation of data: M.H.J., S.H.J., S.J.P., N.L., M.H.B., K.H.P., S.Y.B., C.K., Y.M.H.
Drafting the work or revising: M.H.J., Y.M.H.
Final approval of the manuscript: All authors read and approved the final manuscript.
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Enrollment of the study group. Abbreviations: VLBW, very low birth weight; BSID, Bayley Scales of Infant and Toddler Development; K-DDST, Korean Denver Developmental Screening Test; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia.
Simple linear regression for the results of the Bayley Scales of Infants and Toddler Development within and after 'the' corrected 'age' of 24 months according to the development domain. (A) Cognition domain, (B) language domain, (C) motor domain, (D) mean composite score of three domains.
Scatter plots and Pearson correlation coefficients (
Demographic Characteristics of the Enrolled Preterm Infants (n=71)
Variable | Value |
---|---|
Neonatal characteristics | |
Gestational age (wk) | 29.3±2.6 |
Male sex | 34 (47.9) |
Multiple gestation | 18 (23.4) |
Birth weight (g) | 1,087.5±252.4 |
Birth head circumference (cm) (n=63) | 22.1±9.6 |
Cesarean section | 56 (78.9) |
1-minute Apgar score | 4.1±1.2 |
5-minute Apgar score | 6.4±1.0 |
Antenatal corticosteroid | 53 (74.7) |
Maternal characteristics | |
Maternal age (yr) | 34.1±4.5 |
Maternal hypertension | 23 (32.4) |
Gestational diabetes | 5 (7.0) |
Values are expressed as mean±standard deviation or number (%).
Morbidities of the Enrolled Preterm Infant in the Neonatal Intensive Care Unit (n=71)
Variable | Value |
---|---|
RDS | 57 (80.3) |
BPD | |
BPD, mild | 7 (9.9) |
BPD, moderate to severe | 44 (62.0) |
Postnatal corticosteroid | 38 (53.5) |
Hydrocortisone and dexamethasone | 10 (14.1) |
Dexamethasone | 27 (38.0) |
Prednisolone | 1 (1.4) |
PDA | 28 (39.4) |
ROP | 8 (11.3) |
NEC, laparotomy | 3 (4.2) |
Inguinal hernia, repair operation | 17 (23.9) |
Blood culture proven sepsis | 17 (23.9) |
Abnormal OAE, ABR | 4 (5.6) |
DEHSI | 24 (33.8) |
Discharge weight (g) | 2,803.5±666.5 |
Discharge head circumference (cm) (n=69) | 32.3±4.9 |
Values are expressed as number (%) or mean±standard deviation.
Abbreviations: RDS, respiratory distress syndrome; BPD, bronchopulmonary dysplasia; PDA, patent ductus arteriosus; ROP, retinopathy of prematurity; NEC, necrotizing enterocolitis; OAE, otoacoustic emission; ABR, auditory brainstem response; DEHSI, diffuse excessive high signal intensity.
Overview of the Bayley Scales of Infant and Toddler Development Test Outcome of the Enrolled Infants
Variable | Cognition | Language | Motor |
---|---|---|---|
A. Between the corrected ages of 12 and 24 months (n=71) | |||
No delay | 54 (76.1) | 52 (73.2) | 58 (81.7) |
Mean±SD | 98.1±10.1 | 97.5±7.7 | 98.1±9.1 |
Delay | 17 (23.9) | 19 (26.8) | 13 (18.3) |
Mean±SD | 72.9±8.1 | 75.4±6.5 | 70.9±7.0 |
Severe delay | 4 (5.6) | 3 (4.2) | 6 (8.5) |
Mean±SD | 61.3±4.8 | 63.0±1.7 | 65.0±2.5 |
B. After the corrected age of 24 months (n=36) | |||
No delay | 22 (61.1) | 19 (52.8) | 25 (69.4) |
Mean±SD | 98.0±6.8 | 90.0±9.3 | 95.3±7.6 |
Delay | 14 (38.9) | 17 (47.2) | 11 (30.6) |
Mean±SD | 72.5±8.0 | 68.9±9.7 | 70.8±8.9 |
Severe delay | 3 (8.3) | 7 (19.4) | 3 (8.3) |
Mean±SD | 60.0±5.0 | 59.4±7.0 | 59.0±7.6 |
Values are expressed as number (%) or mean±standard deviation.
Abbreviation: SD, standard deviation.
Univariate and Multivariate Logistic Regression for Cognitive Outcomes of Preterm Infants between the Corrected Ages of 12 and 24 Months (n=71)
Variable | Univariate logistic |
Multivariate logistic |
||||
---|---|---|---|---|---|---|
OR | 95% CI | OR | 95% CI | |||
Gestational age (wk) | 0.98 | 0.95–1.01 | 0.30 | 1.07 | 0.98–1.19 | 0.13 |
Birth weight (g) | 1 | 0.99–1.00 | 0.02 | 0.99 | 0.99–1.00 | 0.01 |
Antenatal corticosteroid | 0.42 | 0.15–1.08 | 0.08 | 0.19 | 0.03–0.84 | 0.04 |
BPD, mild | 5.23 | 1.03–29.45 | 0.04 | 13.21 | 1.75–139.35 | 0.02 |
The multivariate analysis included parameters that showed association in the univariate analysis.
Abbreviations: OR, odds ratio; CI, confidence interval; BPD, bronchopulmonary dysplasia.