Abstract
Aim:To clarify the frequency and characteristics of patients with attention deficit hyperactivity disorder (ADHD) born with low birth weight (LBW), very low birth weight (VLBW), small for gestational age (SGA), or preterm, we examined the clinical characteristics of ADHD patients. Methods:We collected data for 168 ADHD children, and the patients were retrospectively divided into each group according to birth weight, height, and gestational age. Results:1) Patients with ADHD born with LBW, VLBW, SGA, or preterm accounted for 10.1%, 3.0%, 3.6%, or 6.5% of all patients, respectively. 2) ADHD-RS scores for hyperactivity disorder and the frequency of patients requiring ADHD drugs in the LBW infant group were higher than those in the non-LBW infant group. 3) ADHD-RS scores for hyperactivity disorder and total in the VLBW infant group were higher than those in the non-VLBW infant (birth weight:1,500-2,500 g) group. 4) The ADHD scores for attention-deficit and trouble score at the most recent follow-up patients born with SGA were higher than for non-SGA patients. Conclusions:These results suggest that it is necessary to pay attention to the appearance of neurodevelopment disorders such as ADHD when monitoring the progress of patients born with LBW or VLBW, and it is important to provide more appropriate management and therapeutic guidance for patients born with VLBW or SGA.
Introduction
ADHD is a neurodevelopmental disorder that manifests as inattention, hyperactivity, and impulsivity1,2). The pathogenesis of ADHD is still unknown, but many disease susceptibility genes related to its onset and pathology have been reported, suggesting that genetic and environmental factors may be involved3-6). Perinatal factors are one of the environmental factors related to the onset of ADHD. Among these, low birth weight (LBW), small for gestational age (SGA) have been reported as risk factors. Observational studies of neurodevelopmental processes in preterm infants have shown reduced executive function, attention problems, and severe deficits in academic performance in very preterm and very low birth weight (VLBW) children7-17). A longitudinal birth cohort study of Japanese children showed that birth weight less than 2,000 g was significantly associated with elevated ADHD trait scores at age 8 to 9 years16). However, the proportion of ADHD children born with LBW among whole ADHD children and their characteristics remain unclear, and few reports compare in detail the frequency and characteristics of patients diagnosed with ADHD born with LBW and those born with a mature infant in Japan. The paper is the first to compare in detail the frequency and characteristics of patients with ADHD born with LBW and those born with a mature infant in Japan. To clarify these points, we examined the epidemiological and clinical characteristics of ADHD patients born with LBW, VLBW, SGA, or preterm.
Methods
Patients
The Fukushima Rehabilitation Center for Children is the only facility in Fukushima prefecture that combines a Child Development Center and a Support Center for patients with neurodevelopmental disorders, and treats 300-400 new patients with neurodevelopmental disorders each year. We collected data for 168 patients diagnosed with ADHD in the Department of Pediatrics of the Fukushima Rehabilitation Center for Children between January 2013 and December 2022. Entry criteria included:(1) a diagnosis of ADHD based on the diagnostic criteria of The Japanese versions of Diagnostic and Statistical Manual of Mental Disorders DSM-59,10), with autism excluded, (2) under 12 years of age as of the start of therapy with follow up for more than one year;and (3) no previous treatment with drugs for ADHD.
The children were retrospectively classified based on birth weight and whether they were SGA or preterm. Based on birth weight, they were divided into LBW infant (LBWI) group (n=17) and non-LBW infant (non-LBWI) group (n=151), and the LBWI group was further divided into VLBW infant (VLBWI) group (n=5) and non-VLBW infant (non-VLBWI) group (1,500-2,500 g, n=12). Based on the presence or absence of SGA, they were further divided into SGA infant (SGAI) group (n=6) and non-SGA infant (non-SGAI) group (n=162), and based on the presence or absence of preterm, they were divided into preterm group (n=11) and non-preterm group (n=157).
We investigated patient’ characteristics, laboratory findings, ADHD Rating Scale IV (ADHD-RS) scores (including scores for attention-deficit, hyperactivity disorder, and total scores), Intelligence Quotient (IQ), Social Intelligence Quotient (SQ), trouble score, and treatment response for each group.
The protocol for this study has been approved by the auspices of the Committee for Human Experiments at the Fukushima Rehabilitation Center for Children and conforms to the provisions of the Declaration of Helsinki (Institutional Review Board Approval No 2023-05-2). In addition, informed consent was obtained from the patients or their parents for all investigations in this study, and patient anonymity was maintained.
Definitions
The Japanese versions of Diagnostic and Statistical Manual of Mental Disorders (DSM)-4 and DSM-5 were used to diagnose ADHD. Patients who were diagnosed with ADHD using the Japanese version of DSM-4 before 2015 were re-diagnosed using the Japanese version of DSM-5, and those who did not qualify were excluded from this study18,19). We classified birth weight into three categories:normal birth weight (2,500～4,000 g) and LBW (<2,500 g), and VLBW (<1,500 g). SGA was defined as an infant with birth weight and birth height below the 10th percentile. A preterm infant was defined as an infant born at less than 37 weeks’ gestation.
For evaluation of ADHD traits, the main outcome was the behavioral traits associated with ADHD, consisting of the inattention and hyperactivity domains. To quantify these domains, we used the ADHD-RS based on parental reports to assess the severity of ADHD at the initial consultation. The ADHD-RS comprises 18 items covering the spectrum of inattention (9 items) and hyperactivity/impulsivity domains (9 items). Responses are rated on a 4-point Likert scale ranging from 0 (“never” or “rarely”) to 3 (“very often”19,20). Similarly, concerning trouble score20), the items relating to family, friends, submitting homework, grades, behavioral inhibitions, and self-confidence were halved to a score ranging from 0 (no problem), 1 (slight problem), 2 (some problems), to 3 (severe problems) and the total score was used to evaluate the feeling of distress. The improvement rate was calculated as (difference in score before and after intervention/score before intervention) × 100 (%).
Psychological tests
Psychological tests such as the Kyoto scale of Psychological Development 2001, Tanaka-Binet Intelligence Scale21), Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV)22), and Social Intelligence Quotient (SQ) were conducted before diagnosis. The SQ was calculated using the Social Maturity Scale, Third Edition23). The SQ is commonly used as one of the indicators for judging a child’s adaptability in kindergartens and schools and their suitability for inclusion in support classes.
Therapeutic selection
Treatment and support for ADHD mainly consists of non-drug therapy, including environmental adjustment, psychosocial treatment for parents and children, parent training, and collaboration with related specialized institutions such as schools. However, if these psychosocial treatments are insufficiently effective, drug therapy is initiated. Each patient’s doctor explained the effects and side effects of ADHD drugs to the patients and their parents, and made subsequent decisions regarding oral medications based on the patient/family wishes.
Statistics
Data are expressed as the mean values ± SD. The statistical analysis was performed using a Macintosh computer with a software package for statistical analysis (Version 4 of Stat View, Abacus Concepts, Berkeley, Calif., USA). Differences in the clinical and laboratory findings between the two groups were assessed using the Mann-Whitney rank sum test or contingency tables (chi-square test). A value of p<0.05 was considered statistically significant.
Results
1) Comparison of baseline characteristics, laboratory and clinical findings at the time of diagnosis and at the most recent follow-up between the LBWI and non-LBWI groups
There were 205 patients diagnosed with ADHD at our center over the 10-year period, of which 168 patients were able to be followed up for more than 1 year (Figure 1). Patients with ADHD born with LBW accounted for 10.1% (17 patients) of all patients with ADHD. ADHD-RS scores for hyperactivity disorder, the improvement rates in ADHD RS scores for hyperactivity disorder, and the frequency of patients requiring ADHD drug in the LBWI group were higher than those in the non-LBWI group (Table 1). There were no differences in the age at first examination, the frequency of male patients among all patients, the co-occurrence rate of specific learning disorders, the co-occurrence rate of developmental coordination disorders, IQ, and SQ between the LBWI group and the non-LBWI group.
2) Comparison of baseline characteristics, laboratory and clinical findings at the time of diagnosis and at the most recent follow-up between the VLBWI and non-VLBWI (birth weight:1,500-2,500 g) groups
Patients with ADHD born with VLBW accounted for 3.0% (5 patients) of all patients with ADHD, and patients with ADHD born with non-VLBW (birth weight:1,500-2,500 g) accounted for 7.1% (12 patients) of all patients with ADHD. ADHD-RS scores for hyperactivity disorder and total in the VLBWI group were higher than those in the non-VLBWI (birth weight:1,500-2,500 g) group (Table 1).
3) Comparison of baseline characteristics, laboratory and clinical findings at the time of diagnosis and at the most recent follow-up between the SGA and non-SGA groups
Patients with ADHD born SGA accounted for 3.6% (6 patients) of all patients with ADHD. The age of the father at birth and the age of the mother at birth in the SGAI group were lower than those in the non-SGAI group. At the most recent follow-up, ADHD-RS scores for attention-deficit and trouble scores in the SGAI group were higher than those in the non-SGAI group (Table 2).
4) Comparison of baseline characteristics, laboratory and clinical findings at the time of diagnosis and at the most recent follow-up between the preterm group and the non-preterm group
Patients with ADHD born preterm accounted for 6.5% (11 patients) of all patients with ADHD, and the prescription rates of ADHD medication in the preterm group were higher than those in the non-preterm group (Table 2). At the most recent follow-up, there were no differences in each ADHD RS score or TS between the two groups, and the improvement rates of ADHD RS scores for hyperactivity disorder in the preterm group were higher than those in the non-preterm group.
Discussion
In recent years, as part of the evaluation of the growth process of LBWIs, including VLBWIs, there have been a number of reports indicating that VLBW, LBW, and SGA are associated with behavioral abnormalities9-15). McCormick et al. showed that VLBWIs are at risk of problems at school, which are in part associated with hyperactive behavior11). In addition, a study conducted in Sweden examining birth body weight and subsequent mental health outcomes found that a LBW was associated with increased incidence of depression, anxiety, bipolar disorder, ADHD, and autism10).
On the other hand, regarding the percentage of children with ADHD born with LBW among all children with ADHD, in the US, Mick et al. investigated 252 patients with ADHD and 231 controls with non-ADHD and reported that 1 (0.4%) and 0 (0.0%) of the patients were born with VLBW, and 17 (6.7%) and 5 (2.2%) of the patients were born with LBW, respectively, and that the patients with ADHD were three times more likely to be born with LBW than the non-ADHD controls24). In general, the incidence of LBWIs, VLBWIs, SGAIs, and preterm infants in Japan has been reported to be 8-9%, 0.8-0.9%, 4-4.5%, and 5-6%, respectively25,26). According to the Fukushima Prefecture Eco-Children’s Study (JECS), an analysis of 12,804 newborns born between 2011 and 2014 revealed that the incidence rates of LBW, VLBW, and preterm infants were 9.5%, 0.8%, 5.6%, respectively25). In addition, as to SGA, Fujita et al. reported that the incidence of SGA babies was 4.3% in a study of babies born in Kobe City26). In our study, the incidence of LBWIs, VLBWIs, SGAIs, and preterm infants among ADHD patients was 10.1%, 3.0%, 3.6%, and 6.5%, respectively. The incidence of LBWIs, SGAIs, or preterm infants among ADHD patients was no different from that in the general pediatric population, but the incidence of VLBWIs among ADHD patients was approximately more than three times that of the general pediatric population. These results suggest that patients born with VLBW have a higher incidence of ADHD throughout their development and should be closely monitored for the emergence of behavioral abnormalities such as inattention and hyperactivity. In addition, our results differ from those reported by Mick et al. Our results suggest that VLBW birth may have a greater influence on the development of ADHD than LBW birth.
Regarding the characteristics of ADHD patients born with LBW, VLBW, SGA, and preterm, in our study, the ADHD scores for hyperactivity disorder at diagnosis and the frequencies of patients requiring ADHD drug of patients with ADHD born with LBW were higher than those of non-LBW patients, furthermore, the ADHD scores for hyperactivity disorder and total at diagnosis of patients with ADHD born with VLBW were higher than those of non-VLBWI group (1,500-2,500 g). When managing patients with ADHD born with LBW, including VLBW, it is important to consider the possible need for ADHD medication. And, the frequencies of patients requiring ADHD medication and improvement rate in ADHD RS scores for hyperactivity disorder in the preterm group were higher than those in the non-preterm group. These findings may be influenced by the fact that the ADHD-RS score for hyperactivity disorder at the time of diagnosis in the preterm group tended to be higher (p = 0.054) than in the non-preterm group.
In general, parental risk factors for the onset of SGA include the mother’s young age and advanced age at birth, while for ADHD, advanced age of both parents at birth has been reported. In our study, the age of the father at birth and the age of the mother at birth in the patients born with SGA were lower than those in the patients born with non-SGA. The results of this study may involve the characteristics of patients diagnosed with ADHD born with SGA, and further studies with a larger number of subjects are needed to obtain accurate results.
According to the Origins of Health and Disease (DOHaD) hypothesis, it is known that patients born with SGA are at high risk of developing metabolic disorders (dyslipidemia, obesity, hypertension, insulin resistance) that can lead to lifestyle-related diseases27,28). Regarding the psychomotor development of patients born with SGA, it has been shown that they are at higher risk of mild developmental disorders, depression, and schizophrenia, and lower educational attainment29,30). In terms of neurodevelopmental disorders, it has been shown that the IQ of patients born with SGA is slightly lower than that of the general population, and that SGA is a risk factor for the development of ASD and ADHD26-30). In our study, there was no significant difference in ADHD characteristics at the time of diagnosis between patients born with SGA and patients born with non-SGA, but in the most recent follow-up survey after treatment intervention, patients born with SGA had more ADHD inattention traits and more sense of trouble than patients born with non-SGA. Thus, it is necessary to be aware of mental disorders resulting from continued inattention throughout development for patients born with SGA.
Limitation
The present study may have been affected by factors such as the fact that it was a retrospective study, there were inconsistencies in the timing of assessment of ADHD-RS scores and TS during follow-up, there was no protocol regarding the dosage of drug treatment, non-drugs medication was not uniform as each doctor gave independent advice, and the small number of patients studied. Therefore, the conclusions of the paper may be subject to potential confounding factors. In the future, we would like to conduct a prospective study including multiple centers to compensate for the effects of these confounding factors.
Conclusions
Our results suggest that it is necessary to pay attention to the appearance of neurodevelopment disorders such as ADHD when monitoring the progress of patients born with LBW or VLBW. In addition, children born with VLBW have a higher prevalence of ADHD and are more likely to be hyperactive than children with ADHD in the general population, and patients born with SGA may still exhibit inattention or problems, making it important to provide more appropriate management and therapeutic guidance for patients born with VLBW or SGA.
Compliance with ethical standards
The study was carried out under the auspices of the Committee for Human Experiments at the Fukushima Rehabilitation Center for Children (Institutional Review Board Approval No. 2023-05-2).
Informed consent Informed consent was obtained from all patients or their parents.
Author contributions
YK was responsible for designing the study, conducting the study, and analyzing the data. YS, NS, and KM were responsible for guiding the study design. YK, YS, AK, MH, HM, and HG reviewed the manuscript and finalized the submitted version.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
We wish to thank all of the patients and their families for their cooperation in this study. In addition, we would like to thank the Fukushima Rehabilitation Center for Children staff who cooperated in the examination implementation.
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