Sleep problems among children with Fetal Alcohol Spectrum Disorders (FASD)- an explorative study

Fetal alcohol spectrum disorders (FASD) is an umbrella term used to describe a spectrum of conditions resulting from prenatal alcohol exposure (PAE) including: fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (pFAS), alcohol related neurodevelopmental disorder (ARND) and alcohol related birth defect (ARBD) [1]. Characterized by high global prevalence [2, 3], FASD is one of the most common neurodevelopmental conditions.

An impaired brain function associated with PAE is the main clinical concern among patients with FASD [4]. The variety of brain functions or domains can be affected including domains such as: cognition [5, 6]- especially executive functions [7] and social skills [8]. However, each individual with FASD can present with a different clinical picture. Many patients experience not only the neurobehavioral issues but also disorders of urination [9, 10], defecation [9, 10], nutrition [11, 12] and sleep, also known as “neglected problems”. It is now well established that sleep disorders are an important concern among children with neurodevelopmental conditions [13‐15]. Sleep disorders affect daytime performance of children and can influence the diagnostic process creating a complex clinical picture [16‐19]. Clinical experience, case reports and qualitative studies [6, 20, 21] suggest that sleep disorders are a major complaint among individuals with FASD.

Several studies used quantitative, questionnaire methods to assess the sleep problems among individuals with FASD. Results of this studies illustrate that the sleep disorders are more prevalent in patients with FASD as compared to typically developing children [13, 22‐25].

The reports including objective sleep assessment in patients with FASD are scarce [13, 22, 23]. Pesonen at al [26], Wengel at al [27], and Mughal et al. [18] demonstrated sleep disturbances among individuals with FASD using actigraphy. Goril at al [28] and Chen et al. [29] examined children with FASD with polysomnography and pointed at some specific problems such as increased sleep fragmentation. However, due to the lack of a control group in the first study and small sample size (5 patients) of the latter, their data can be considered exploratory.

Given the little attention paid so far to sleep, the aim of this study was to characterize sleep in children with FASD in depth.

The study was conducted as a prospective study in the years 2018–2020. The study included children diagnosed with FASD and a control group and consisted of two phases. In the 1st phase, the screening of sleep problems was performed with Child Sleep Habit Questionnaire (CSHQ) filled in by a caregiver. The subjects with positive CSHQ results were qualified to the 2nd phase of the study, an in-lab attended polysomnography (PSG) (Fig. 1).

A written consent was obtained by the researchers from the parent/caregiver. A separate consent was obtained from the children above 12 years of age. Children younger than 12 were informed about the study and all their questions about the study were answered. The study protocol was approved by the regional ethical committee of the Regional Board of Physicians (approval number: 123/kbl/oil/2018).

According to our results, every second child with FASD experiences sleep disorders. This finding is consistent with the result of the research published by Goril et al. [28] who estimated the prevalence of sleep disorders among individuals with FASD to 58%. On the other hand, Chen et al. [29] established a prevalence rate at 85%. Although similarly to our study, Chen et al. used the CSHQ, they classified children with the borderline Total Score of 41 as having sleep disturbances whilst we, following the CSHQ instruction [30, 38], qualified only the results above 41 as positive. However, 7 children from the FASD group (17.5%) and 7 children from the control group (17.5%) had a Total Score equal with 41. Our subscale analysis revealed that sleep onset delay, night wakings, parasomnias, sleep disordered breathing and daytime sleepiness occur more frequently among individuals with FASD as compared to controls. These results are in general agreement with the data of Chen et al. [29] who reported an increased frequency of sleep problems in all 8 subdomains of CSHQ. Our observations are also in line with the findings of Wengel et al. [27] who indicated that patients with FASD complained about shortened sleep duration, night awakenings and parasomnias. Hayes et al. using a simple 3-question online questionnaire (asking about difficulty falling to sleep; difficulty staying asleep and/or frequent waking during the night; and waking early in the morning) established a frequency of sleep problems among individuals with FASD to 65,6% finding difficulty falling asleep being the most common complaint [24]. The reported frequency is similar to our findings, moreover, in our study the sleep onset delay was also more common among FASD patients than in the control group. Increased odds of sleep problems reported by us corroborates with the findings presented by Chandler-Mather at al. [25] who assessed sleep problems with a yes-no, 4-question questionnaire (“getting off to sleep at night”, “not happy to sleep alone”, “waking during the night”, and “restless sleep”).

Polysomnography data on FASD patients are scarce. Our findings match those published by Chen et al. [29], although we observed that not only obstructive but also central apneic events were more frequent among individuals with FASD. Also, our findings are in line with the report of Goril et al. [28] who indicated an increased sleep fragmentation in children with FASD and an increased predisposition to apneic/hypopneic events. Interestingly, the increased AHI was only observed in the young children in their sample. Moreover, Alvik et al., Troese et al. and Scher et al. [39‐41] demonstrated that infants with PAE tend to present fragmented sleep and experience more arousals. This is in concordance with our findings, although these studies did not use PSG and the results cannot be directly compared to ours. A similar observation was documented by Volgin et al. [42] on an animal model of PAE.

In our study, sleep in FASD subjects was less stable than in the PSG laboratory control group which is mainly expressed in a greater number of stage shifts, an increased amount of N1 stage and a higher number of arousals. The lack of association between arousals and breathing events suggests that the subset of arousals has other than a respiratory cause. The comparison of our findings regarding sleep architecture to the general population samples (Table 5) is difficult due to inconsistencies in published pediatric population data [36, 37]. Montgomery-Downs et al. [36] reported the amount of N1 sleep higher than in our subjects but Goodwin et al. [37] reported it approximately at the same level. The amount of N3 in our patients with FASD is comparable to the Montgomery-Downs sample [36] but much higher than in the Goodwin sample [37]. Of note, the percentage of REM sleep is lower in our FASD group in comparison to both studies [36, 37]. Moreover, these results seem to be consistent with experimental data [43] of a decreased quantity of REM sleep in rats with PAE, however, this observation was only significant for female rats.

In our study, both FASD and control children examined by polysomnography had much more breathing events detected than reported in general population samples [36, 37]. It is clearly visible in all compared indices (Table 5). It must be acknowledged that the changes in the hypopnea definition which were introduced in version 2 of AASM manual published in 2018 [34] led to an increased number of detected hypopnea events. According to the authors’ knowledge, there are no published reports about how those recent changes affect hypopnea index results in children population. Still, the hypopnea index in our study is larger by an order of magnitude as compared to previously published population data [36, 37] which is more than a potential impact of the definition changes. Moreover, the central apnea index in our FASD group is greater by a factor of two, even though the current pediatric central apnea definition is more restrictive.

The cause of sleep problems among individuals with FASD remains uncertain. Prenatal alcohol exposure may cause structural defects of central nervous system [4, 44‐46], corpus callosum anomalies being the most common finding [47‐50]. It has been demonstrated that corpus callosum anomalies may result in sleep alteration [23], especially decreased REM sleep. This finding of decreased REM sleep is in accordance with what we observed in our FASD group. The potential mechanisms lying behind sleep problems in FASD include not only structural defects of some parts of the brain but also important dysfunction of neurotransmission [16]. Olateju et al. [51] established a relationship between PAE and the alterations of orexinergic and cholinergic neurons in brain structures responsible for cicardian rhythms. Moreover, the destructive influence of PAE, direct or secondary do the epigenetic mechanisms, on the neurons of the suprachiasmatic nuclei (SCN) responsible for the natural rhythms, was also postulated [52]. Chen et al. [53] suggested, using the animal model, that PAE affects expression of the genes responsible for the circadian function of β-endorphin neurons in the hypothalamus. On the other hand, Goril et al. [28] determined that children with FASD have an altered melatonin profile, which can affect the sleep cycle. The central apneic/hypopneic events likely result from the central nervous damage secondary to PAE, as it has been established that alcohol affects the neurons in the variety of experimental modes [4, 44‐46, 54]. It is worth mentioning that obstructive apneic/hypopneic events were frequent among children with FASD, although none of the patients were obese. Nevertheless, the anatomical features connected to FASD – micrognathia or high-arched palate may result in the airway obstruction [55, 56]. It is also possible that sleep disturbances, especially parasomnias and difficulties falling asleep are secondary to the behavioral problems that children with FASD are facing [18, 57].

This is one of the first studies that comprehensively assess the sleep problems among children with FASD. The second phase of our study was the first attempt to objectively characterize sleep alterations present in children with FASD using polysomnography in a significant group of prospectively recruited patients. Nevertheless, several limitations of our study should be acknowledged. Due to organizational reasons, the enrollment to the both FASD and control groups was performed simultaneously which resulted in the negligible age difference between the groups. However, patients from both groups were within the age frame for CSHQ (3–17 years) and all differences observed between the groups were independent of age. CSHQ is a subjective sleep problems assessment. Only the patients screened by CSHQ were offered the objective sleep evaluation. The majority of parents in the study group were either foster or adoptive parents yet the patients from the control group were in biological families. It is well established that foster and adoptive parents of FASD children experience a lot of distress and they present a tendency to an overprotective attitude [24, 58] which can be a potential source of bias in the self-report.

Notwithstanding the limitations, the study offers the overview of the frequency and nature of sleep problems among individuals with FASD. As the results point to an increased frequency of sleep issues in FASD, further research is required to confirm and expand this finding. Moreover, further experimental investigations are needed to determine the exact mechanisms that contribute to this phenomenon as well as potential treatment options. From the clinical perspective it is important for the physicians and psychologists taking care for patients with FASD to include the question about the sleep quality in the history taking and try to address this issue.

FASD is one of the leading preventable forms of neurodevelopmental disorders. The pathophysiological understanding of FASD is insufficient. The sleep problems are until now not well understood in relation to FASD. Our study supports previous observations that sleep problems can be a part of the clinical picture in FASD and that a distorted sleep architecture and apneic/hypopneic events can be present, what needs further studies.