Parental age and developmental milestones: pilot study indicated a role in understanding ADHD severity in Indian probands

Attention Deficit Hyperactivity Disorder (ADHD) is a neuro-developmental disorder, mostly detected in school-going children/adolescents [1, 2]. Apart from the cardinal symptoms of age inappropriate inattention (IA), hyperactivity (HA) and impulsivity (Imp), behavioral problem (BPr) and cognitive deficit are major traits in ADHD [3, 4]. A number of co-morbid conditions like oppositional defiant disorder, conduct disorder, mood disorder, learning difficulties, etc. are also often detected in ADHD probands [5] making accurate diagnosis even more difficult.

Being a multigenic disorder, disease etiology is influenced by complex interplay between biological and environmental factors. As compared to age matched healthy children, ADHD probands often suffer from delayed maturation of the brain [6, 7]. Maternal health during pregnancy, along with genetic and familial factors, was suggested as a variable for disease susceptibility as well as symptom severity [8]. Maternal thyroid dysfunction [9] and mental health issues also showed association with disease onset in later life. A meta-analytic study indicated almost double ADHD frequency, impaired cognitive functions, learning problems, behavioral outburst among preterm children [10]. Investigators further claimed a role of parental age in disease susceptibility [11‐16]. Maternal age, birth order, peri-natal complication, and parenting, were also speculated to add up to the disease incidence [17‐19]. Perinatal hypoxia, crucial factor for the well being of neurons and dopaminergic cells, was also suggested to have a primary role in ADHD [20]. Though a few researchers have explored the role of parental influences on the occurrence as well as severity of ADHD, a high range of inconsistency has been portrayed.

Several reports show that prevalence of ADHD is increasing in India [21‐25]. However, in spite of appreciating a possible role of birth related variables in disease penetrance, reports from India are little scanty. Based on this lacuna, we investigated whether any pre- or post-natal factor has any influence on ADHD associated symptoms in this ethnic group.

Decades of research has established a firm neuro-psychological basis for ADHD, though the actual remediation is still far away. Two central neuro-psychological models were hypothesized [1]. The first one is the executive or top down model indicating ADHD as a disorder of executive dysfunction affecting goal directed self organized flexible actions. The other theory is bottom up sensory/reward theory which suggest that ADHD patients lack motivation, reward and emotional regulation [1]. A combination of these two models gave rise to an integrated model portraying a complex clinical scenario. However, ADHD symptoms are highly heterogeneous and every domain of impairment may add up to a new level of complexity, making proposition of any individual model difficult [29‐31].

In India, prevalence of ADHD was reported to be 11.33% among primary school children [22], 7.2% among adolescents [23], and 5.48% among college students [24]. However, detailed report on birth histories and their possible influence on the symptom severity were less frequently studied. Here, we report for the first time a role of birth related factors in the symptom severity of Indian ADHD probands. Significant influence of parental age, B_weight, delivery process, age of onset and developmental milestones were noticed on the trait scores. Based on the significant correlations detected amongst the predictable variables, we present a schematic diagram to understand the trajectory (Fig. 3). Parental age was identified as the principal independent factor. B_weight and term of delivery were not influenced by parental age, though the two were correlated amongst themselves. Thus, we have put birth term as another primary variable along with B_weight. After this primary level, three intermediate levels became evident. Birth order, being influenced by parental age was placed as the first intermediate variable. Process of delivery was the next in the same level; it was related to M_Age and B_weight. Milestone was also placed in the same level as it was influenced by the primary predictor B_weight. Since age of onset was only related to the delivery procedure, it was placed at the next intermediate level. Finally multiple regressions led to the isolation of multi- influential predictors that modified the symptom scores. All the predictor variables excepting the birth order and term were found to influence the symptoms and so the path diagram originated from Parental age, and ended in different trait scores traversing through birth weight, birth order, delivery procedure, developmental milestones and age of onset.

Studies from the western countries revealed a relationship between lower maternal age and higher vulnerability to ADHD [12‐14]. Investigators also proposed association of lower maternal age with symptom intensity [11‐16] and parenting was suggested to be better by older mothers [32]. Association between higher oppositional behavior as well as HA /Imp score of ADHD probands and higher maternal age were also reported [15]. However, effect of paternal age was not evident in Danish patients [13]. Our analysis revealed negative influence of maternal age on the Imp of probands; individuals born to younger mothers were more impulsive. Furthermore, higher paternal age was related to higher scores for BPr and Imp. We assume that these inconsistencies in associations may result from age differences, variation in sample size or a confounded effect of socio-demographic variations warranting further investigation.

A recent study from the Finland suggested association between low Apgar score and C_S with higher risk of ADHD [33]. We found correlation between higher maternal age and Caesarean/forcep delivery, associated with lower HA. Whether this contradictory finding is due to the presence of an actual socio-demographic difference warrants further in depth analysis in large cohort.

In the Caucasoid population, birth weight was speculated as a prime risk factor for developing ADHD symptoms, primarily inattention [30, 34‐36]. In the Indo-Caucasoid population, we have noticed substantial influence of B_weight on the delivery process and developmental milestones which were associated further with symptom scores; preterm children showed lower score for BPr/AI. It can be speculated that B_weight showing negative association with developmental delay could be a marker for overall development and along with various intermediate factors, may affect ADHD associated traits.

Earlier investigators reported delay in motor development of ADHD probands [37]. Our study group showed delayed motor development in 26% probands. However, interestingly it showed negative influence on BPr; children with developmental delay exhibited reduced Imp. In an MRI based study on the developmental chronology of healthy brain, it was found that the affect and reward processing circuitry involving amygdale and nucleus accumbens develop faster than the cognitive control domain [38]. Nucleus accumbens, important for emotional circuitry, also has a role in motor control. Thus, it may be hypothesized that developmental delay in these regions may interfere with affective behavior as well as motor response while balancing the delayed cortical maturation, as reported in ADHD earlier [6]. However, the observed effect of delayed motor development on reduced impulsivity may also be partly due to seeking professional help at an early age. Our earlier study showed higher HA in the late onset group [39]. The present study revealed influence of late onset on increased AI and gradual decrease in HA on a continuous scale, indicating necessity of further analysis in larger cohort.

Bio-demographic factors may assist in understanding the disease more clearly thereby providing chances for better rehabilitation. In an earlier study, we have reported that ADHD probands sustain impairment in attention while organizational efficiency improves with time and those with learning difficulties exhibit even more scholastic backwardness [40]. Our current analysis on the same group of probands suggests that parental age, low birth weight, and delivery process may affect symptom severity of ADHD probands, a finding which could be useful for monitoring growth of a child leading to early intervention. However, our number of subjects was limited. Successful replication in larger cohort and proper attention to birth related/ developmental factors may widen a contemporary window to provide more efficient management of ADHD related symptom severity.