Epidemiological association between multiple chemical sensitivity and birth by caesarean section: a nationwide case-control study

Individuals with multiple chemical sensitivity (MCS), also called idiopathic environmental intolerance, exhibit nonspecific multi-organ symptoms after exposure to trace amounts of various chemical substances and/or environmental conditions [1, 2]. Although several patient-based studies describe the clinical symptoms of MCS [3, 4], its risk factors remain unclear.

In a telephone survey in the United States, the self-reported prevalence of MCS was 12.6–15.9% [5], whereas the prevalence of physician-diagnosed MCS was 3.1–6.3% [6]. A population-based study in Germany showed self-reported and physician-diagnosed prevalence rates of MCS of 9.6 and 0.5%, respectively [7]. In Japan, a survey by the National Public Health Institute (now the National Health Science Medicine Institute) in 2000 reported that 0.74% of adults had MCS [8].

The aim of this study was to elucidate the risk factors for MCS and the association between MCS and birth by caesarean section. Because MCS is relatively rare in the general population and patients with MCS often avoid hospitals owing to potential exposure to trace amounts of chemicals en route [5–7], we utilized a case-control study design and recruited subjects from a large-scale web-based research panel. We compared sociodemographic characteristics, birth history, medical history, and environmental exposures between patients with and without MCS.

Social/environmental factors also significantly correlated with MCS. As determined via multivariate regression analysis adjusted for the variables listed above, these factors were a history of agricultural work, mouth breathing, residing in a new home (within 1 year of its construction) ≥3 times, and ≥ 11 vaccinations in the past 10 years (Table 3).

To the best of our knowledge, our study is the first to show an epidemiological link between MCS and birth by caesarean section in Japan. Moreover, our data indicate that factors other than chemical exposure may result in the development of MCS.

The prevalence of MCS among the individuals in our study was 0.9%. Interestingly, MCS was significantly more prevalent in men than women in the younger age groups but significantly higher in women than men in the older age groups. The reason for this age-based sex difference remains unknown. Although the prevalence of MCS is generally higher in women than men [5, 6], no inversion of the sex predominance between younger and older age groups has been reported. The prevalence of MCS in this study is lower than that reported in a large-scale survey in the United Sates [5, 6], but about the same as that reported in surveys in Germany [7] and Japan [8].

In our study, the proportion of subjects with a history of smoking was significantly higher in the case (MCS) group than the control group. Although patients with MCS are sensitive to environmental tobacco smoke (ETS) [5], their smoking history and ETS exposure did not correlate with the development of MCS in a previous study [14]. Hence, the association between smoking and MCS requires further research.

Our finding that comorbidities such as allergic diseases were significantly associated with MCS is in agreement with the findings of a survey in the United States [5]. Central sensitization, which involves hyper-excitation of the neurons in the central nervous system due to stimulation from the peripheral nervous system [15, 16], has been suggested as a biopsychological explanation for MCS [17, 18]. MCS, fibromyalgia, chronic fatigue syndrome, and migraine are all considered central sensitization syndromes [17]. Therefore, the association between MCS and comorbidities in this study is likely related to central sensitization.

Birth by caesarean section significantly correlated with MCS in our study even after adjustments for potential confounders. This finding adds to the list of conditions associated with caesarean section. For example, two meta-analyses in 2008 showed a 20% higher asthma risk in children delivered by caesarean section than in those delivered vaginally [19, 20]. Although the mechanism is unknown, mothers with MCS are at increased risk of having a child with autism spectrum disorders (ASD) or attention deficit hyperactivity disorder (ADHD) [21]. Infants born by caesarean section are not exposed to the bacteria in the birth canal, which can cause abnormalities in the gut microbiome [22–24]. Owing to the brain-gut interaction, such abnormalities can lead to brain dysfunction [25–27] and perhaps contribute to the development of MCS. Brain sensitivity and central sensitization may also be associated with MCS [17, 18, 28]; central sensitization enhances the activity of the neurons involved in nociception, resulting in hypersensitivity to stimuli [29, 30]. Abnormalities in the gut microbiome caused by birth by cesarean section might therefore contribute to the development of MCS. Moreover, unlike vaginal delivery, a caesarean section may indirectly expose a fetus or newborn to surgical chemicals (e.g., analgesics and anesthetics administered to the mother). Understanding the mother’s background and reasons for receiving a caesarean section is necessary to evaluate the influence of caesarean sections on MCS.

Mouth breathing was associated with MCS in our adjusted regression model. Adaption to olfactory hypersensitivity, a characteristic of MCS, may account for mouth breathing in MCS patients [31]. However, the likely association of bronchial asthma and allergic rhinitis with MCS indicates that upper and lower respiratory tract diseases may trigger MCS [5]. Mouth breathing bypasses the protective functions of the nose such as warming, humidifying, and filtering the air [32, 33]. Studies with small sample sizes reported that mouth breathing adversely affected lung function and caused exercise-induced bronchoconstriction in patients with mild asthma [34] and that enforced mouth breathing impaired lung function [35]. Although the causal relationship between mouth breathing and MCS is not clear, it is possible that mouth breathing initiates or exacerbates MCS via comorbidities such as bronchial asthma and allergic rhinitis.

Having been vaccinated ≥11 times in the past 10 years was significantly associated with MCS in our adjusted regression model. Although it would have been ideal to investigate the subjects’ entire vaccination history, we considered the recall bias to be large and therefore limited the vaccination history to the last 10 years. To reduce the occurrence of infectious diseases, regular vaccination during childhood is recommended. However, the Vaccine Safety Datalink study showed a significant association between exposure to high levels of mercury in thimerosal-containing children’s vaccines and the subsequent risk of atypical autism [36]. Thimerosal is an organomercury preservative that is often added, even today, to multiple-dose vials of many vaccines. In a previous case-control study, maternal chemical intolerance correlated with attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in the offspring (282 AHD cases, 258 ADHD cases, and 154 cases without these disorders) [21]. Although it is not clear how, vaccination and MCS might be linked.

Having lived ≥3 times in a new house (i.e., a house < 1 year-old) was significantly associated with MCS in our adjusted regression model. Sick building syndrome (SBS) is defined as occupancy-dependent nose, eye, and skin irritations: the symptoms occur within a building but disappear or weaken outside the building. SBS is grouped under the more general definition of MCS/idiopathic environmental intolerance [37]. Indoor environmental factors in a newly built house like inadequate ventilation, high total levels of volatile organic compounds, and dampness could be risk factors for both SBS [38–41] and MCS.

Having been an agricultural worker was significantly associated with MCS in our adjusted regression model. Such workers are exposed to pesticides [42] when working in recently sprayed fields as well as during the preparation and application of the pesticide [43]. Pesticide exposure is a major health hazard that can lead to various illnesses including respiratory disorders [44–49]. Although the mechanism remains unknown, MCS is often complicated by upper and lower respiratory tract diseases [5]. Exposure to pesticides during agricultural work can affect a worker’s respiratory tract and might cause the development of MCS.

This study has several limitations. First, MCS was defined through self-reported physician-diagnosis. However, we ascertained the history of the physician diagnosis by obtaining the name of the hospital or clinic where the MCS diagnosis was made. Moreover, self-reported and actual physician diagnoses have been shown to correlate significantly [5]. Second, no objective measurement was used for diagnosing MCS. Although some studies have identified abnormalities in cerebral blood flow as well as mutations in several genes and metabolic enzymes in MCS [50–53], these are not considered evidence-based indicators of MCS at present. We used the QEESI to define patients with MCS as this tool has been internationally validated [9, 11–13]. Third, we may have overlooked individuals who do not typically access the web; we note that most MCS patients have electromagnetic hypersensitivity [54], which prevents them from using a personal computer. However, some MCS patients have difficulties visiting healthcare facilities owing to potential exposure to chemical substances (such as perfumes and exhaust gases) while on route. A web-based survey can overcome this limitation as the patients do not need to leave their homes.

The main strength of this study was its use of a sizeable web-based survey to identify cases and controls in the general population. Patients with rare diseases are identifiable only in large-scale surveys.

In conclusion, this study showed an epidemiological link between MCS and birth by caesarean section. Our data also suggest that factors other than chemical exposure may result in the development of MCS.