Shift work refers to hours of work occurring outside the regular daytime schedule, that is, work schedules not falling between 6 a.m. and 6 p.m. According to the May 2004 Work Schedules and Work at Home supplement to the Current Population Survey by the US Bureau of Labor Statistics, considering only the primary job of full‐time workers, 19% of male and 16% of female workers are shift workers including 3–4% each reporting working “irregular schedules” (varying with the needs of the business), rotating shifts, or night shifts. Over one half of protective service workers, for example, police and firefighters, are shift workers. Similarly the majority of employees in eating and drinking establishments work nondaytime schedules. One third of transportation workers are shift workers. Industries with 5% or less of employees working shift work schedules include construction, education, finance, and insurance.

Alertness and performance of shift workers, particularly when working schedules involving the night (graveyard) shift, may be compromised. Night workers and rotating shift workers are at increased risk of falling asleep on the job and of falling asleep when driving home after work.^1,2 Public safety has been compromised by catastrophes involving chemical plant, nuclear power plant, and transportation accidents attributed to work schedule‐related drowsiness.^3,4

Shift work also takes a toll on individuals and their families, due to conflicts between the work schedule and domestic responsibilities. Shift work has been identified as an emerging risk factor for several medical and mental health conditions, which receive extra attention in this chapter.

OCCUPATIONAL SETTING

There are many different types of shift work schedules. The type of schedule is often determined by traditional practices of the industry. For example, the Southern‐Swing schedule, a weekly, backward rotation, has been commonly used for generations in the steel industry. Worker preferences, labor union interests, and job process needs are common factors influencing schedule design.

Common shift work schedule designs include the following:

1. Fixed (“permanent”)—Each individual employee works one shift. The number of days worked in a row and the number of days off vary between industries. “Permanent” night work is, in one sense, a misnomer, because almost all workers return to daytime activity on their days off and thus still switch back and forth between night work and daytime activity.
2. Rotating—An individual employee regularly changes the shift worked. Rotating schedules vary in the direction and speed of rotation:
   • Direction of rotation: This may be clockwise (forward rotation, phase delay) or counterclockwise (backward rotation, phase advance).
   • Speed of rotation: This may be slow (greater than weekly), weekly, or rapid. Examples of rapidly rotating systems include the European metropolitan (two identical consecutive shifts are worked consecutively, followed by two of the next shift until all three shifts have been worked, 2‐2‐2) and the continental (same as the metropolitan, except three of one of the shift times are worked, 2‐2‐3) rotation schedules.
3. Split shifts—A hiatus of a few hours separates the work hours performed on the same day. For example, this may be done in the restaurant or transportation industries to cover peak business hours.
4. Alternative rotations—An increasingly popular 4‐day “compressed workweek” with 10–12 hours shifts used in a single‐, two‐, or three‐shift operation. The 8‐day week with 4 10‐hours work days followed by 4 days off is used primarily in firms operating for 10 hours/day, 7 days/week or operating 20 hours/day in two shifts. Twelve‐hour shift schedules are common in hospital nursing schedules. Schedules with “flexitime” give employees some choice in designing their own personal daily work hours to meet weekly requirements.

MEASUREMENT GUIDELINES

Several factors affect tolerance to night work and rotating shift work, including (i) individual differences in susceptibility to performance and alertness deficits related to altered sleep–wake cycles and to symptomatology from disruption of biological circadian rhythms, (ii) differences in social/family responsibilities and supportiveness, (iii) effectiveness of off‐the‐job and on‐the‐job coping strategies for maximizing sleep and minimizing performance deficits, (iv) the schedule design, and the predictability and flexibility of time off.

In order to evaluate the appropriateness of a particular work schedule for a specific industrial site, information should be gathered from human resources, from safety officers, and directly from the workers. The general categories of necessary information include (i) demographics of the workforce, (ii) frequency of cases of shift work intolerance from medical surveillance programs and/or medical claims, (iii) rates of on‐the‐job fatigue‐related accidents or performance deficits, and (iv) information from confidential worker surveys concerning sleepiness on the job, motor vehicle accidents or near misses driving home from each shift, general well‐being, and worker satisfaction with the schedule.

Tepas et al. have described a survey method for use in designing and evaluating shift work systems tailored to specific workers and plants.⁵ Their work–sleep survey has demonstrated that there are significant differences between industrial plants with respect to demographics, worker habits, and worker preferences and that “Before recommending a new work‐system shift scheme to a plant, the complexity of shift‐work issues must be recognized by assessing a wide range of personal, social, and health issues.” Education of workers with respect to the reasons for the selection and expectations of how the scheduling system will work is also important. Follow‐up surveys, conducted after the system has been in operation for some time, are recommended to evaluate the effects on the workers’ well‐being and performance. Kogi made similar recommendations based on an extensive survey of male and female shift workers in Japan working various rotating schedules.⁶ These recommendations included considering other factors, in addition to the shift rotation, when determining ways to minimize the detrimental effects of shift work on the worker and his/her family, such as social and family life responsibilities, worker commuting time, and possibilities for anchor sleep (regularly scheduled sleep periods) during night shifts.

Direct comparisons of studies looking at performance or health outcomes of shift workers are often difficult, due to differences in schedule design. Pertinent shift work exposure parameters include, in addition to the number of years employed as a shift worker, schedule design variables such the direction and frequency of shift rotation, the number of nights worked in a row, the number of days off after night shift assignment, the amount of overtime, and the length of shifts. National data collection is limited in the United States. The United States Bureau of Labor Statistics does annually collect and tabulate occupational injury data available from employers regarding the time of day the injury event occurred and hours on the job worked before the event.⁷ The Federal Occupational Safety and Health Administration’s (OSHA) Form 301 Incident Report (Rev 01/2004) which employers are required to complete and maintain in their files for 5 years also request this information, if available. The BLS includes this data in some of its published estimates.⁸ However, OSHA only requires employers to record work site‐wide annual average employment and total hours worked by all payroll employees, and BLS injury statistics do not include data regarding the composition of work force by shift, so shift work hour‐based rates are not determinable from the national labor statistics (Bureau of Labor Statistics, personal E‐mail communication, December 31, 2014).⁸ Limited opportunities therefore exist to look at US national data concerning on‐the‐job accidents and scheduling factors.

Despite the inherent design problems in shift work research and the limited national data, field and laboratory studies of 24‐hour sleep and performance rhythms, and of health outcomes in shift workers, have provided information that has been used to make reasonable recommendations concerning shift work scheduling. These are presented in the following section.

EXPOSURE GUIDELINES (SCHEDULE DESIGN)

The various combinations of individual susceptibility factors and scheduling designs make it difficult to assess the effective “exposure” to shift work and thus the “risk” that different shift systems may have on health and safety outcomes. Comparisons of groups must account for the type of shift schedule as well as years spent in shift work. Wedderburn has proposed criteria for assessing shift work schedules for potential risk for health and well‐being including the perturbation of the circadian rhythm, performance at work, health, and social life.⁹ The “Rota Risk Profile Analysis,” developed by Jansen and Kroon utilizes several physiological and psychosocial risk factors associated with the schedule design including regularity of shift timetable, periodicity (the degree to which the “biological clock” is disturbed), shift load (the average length of shifts) and week load (the average length of the work week), opportunities for nighttime sleep (between 11 p.m. and 7 a.m.) and constancy in night rest (variation in the week), predictability of the shift cycles, and opportunities and constancy for household and family tasks, for evening recreation, and for weekend recreation.¹⁰

As is true of threshold limit values® (TLVs®) for chemical exposures, which are developed to protect nearly all healthy workers, with the recognition that a small percentage of workers are susceptible to lower levels of exposure,¹¹ recommendations for shift work scheduling design, which control exposure to night work, are applicable to most workers. Shift work scheduling recommendations may not be adequate for workers with greater individual susceptibility to shift work‐related biological rhythm disruption or with family/social situations limiting daytime sleep opportunities. In addition, with respect to performance on the job, the appropriateness of recommendations for the length of shift varies with the type of industry involved and related productivity versus safety and alertness demands.

NORMAL PHYSIOLOGY

Numerous psychological and physiologic variables have been documented to have a demonstrable 24‐hour, circadian (Latin: circa = about, and dies = a day)⁹⁵ rhythm, for example, body temperature, the sleep–wake cycle, cardiovascular parameters, cognitive performance, hormonal and immunologic factors, metabolic responses including to medications and toxins, and psychological variables.^96,97

Circadian rhythms do not merely reflected responses to external time cues but also have an endogenous component, creating significant consequences for shift workers. The existence of a biological clock in humans was initially demonstrated over 50 years ago in temporal isolation studies, in which subjects were separated from all environmental and social time cues.⁹⁸ Under normal nychthermal conditions (daytime activity and nighttime sleep), the circadian system is synchronized with the 24‐hour solar day by external triggers to which the biological clock is responsive. The normal phase relationships of the multitude of biological rhythms are achieved by an orchestrated response to the internal pacemaker.

The time cues, which are capable of entraining the biological clock to an external periodicity, have been termed “zeitgebers” (German: time giver). Zeitgebers allow the biological clock, which typically runs slightly slower than the 24‐hour day, to be reset and entrained to the 24‐hour day.^99,100 Various agents have been shown to act as zeitgebers, including light, social factors, and behavioral patterns such as eating schedules and sleep–wake schedules.^101,102 Social cues, the sleep–wake schedule and the rest–activity cycle, are relatively weak zeitgebers in comparison to sunlight (or electrical lighting of at least 7 000–13 000 lx).¹⁰³

The phase‐shifting effect of light on the circadian timing system is secondary to its suppressing action on melatonin secretion by the pineal gland; melatonin induces sleep and depresses the core body temperature.¹⁰⁴ Melatonin release is controlled by the suprachiasmatic nuclei (SCN) in the hypothalamus; the SCN is the primary endogenous circadian pacemaker/master biological clock.^105,106

The scientific research regarding the molecular level of circadian rhythms has advanced rapidly over the last decade. Genetic researchers have identified clock genes and proteins in mammals that control the intracellular circadian clock via transcriptional modulators that allow the cellular recognition of time of day and preparation for expected stimuli. Circadian rhythm of electrical activity in SCN neurons reflects the expression of clock genes that are ultimately responsible for circadian biological rhythms. The circadian system is complex involving intercellular events and transcriptional–translational feedback loops. The expression of clock genes is not limited to the SCN, having been identified in several organs, for example, vasoactive intestinal peptide‐expressing cells have been shown to play a role in entrainment by light; circadian clocks identified in cardiomyocytes and vascular smooth muscle cells allow the cardiovascular system to anticipate diurnal variations in stimuli.^107–114

PATHOBIOLOGY (CIRCADIAN RHYTHMS AND SHIFT WORK)

During night shift work, activity is out of phase with the circadian body temperature and other coupled rhythms. In addition, because individual biological rhythms re‐entrain to a time shift at different rates, each time the work schedule rotates after the time shift, the circadian system will be in a desynchronized state for a period of time. For example, sodium and potassium excretions are closely linked in a stable rhythmic environment but have significant differences in their rate of re‐entrainment to phase shifts.¹¹⁵ The sleep–wake rhythm adjusts faster than the body temperature rhythm, and activity re‐entrains faster than many physiologic functions.¹¹⁶ This desynchronization of re‐entrainment of individual biological rhythms is a reflection of differences in response times of the multiple clock genes involved in maintaining the circadian system; for example, circadian oscillators in the anterior section of the SCN adapt faster than those in the posterior region¹¹⁷; oscillators in the hypothalamus adjust faster than those in peripheral tissues—resulting in temporary loss, after imposed time shifts, of the normal central control of the circadian system.¹⁰⁹

Circadian rhythms are more easily re‐entrained after a time shift if all the important zeitgebers, including the light–dark cycle and activity, are synchronously shifted, such as occurs with transmeridian flights. For shift workers, zeitgebers are shifted in a nonsynchronized manner. Knauth and Rutenfranz failed to find complete inversion of the body temperature rhythm in shift workers even after 21 consecutively worked night shifts and concluded that the circadian system never fully adapts to night work.¹⁷ Other field studies of shift workers have also found adaptation to night work to be incomplete.^118–120

The circadian system is responsible for maintaining the internal sequencing and normal relationship of physiologic events and metabolism. Biological processes are thus coordinated for optional functioning of the organism. In animal studies, circadian system disruption has been shown to result in metabolic dysregulation and misalignment of physiologic parameters and biomarkers and increase progression or susceptibility to disease.^121–128 The critical restorative functions of sleep are maximized during the nighttime hours by the normal phase relationship of biological rhythms. Overnight activity results in desynchrony between the circadian biological clock and the sleep–wake cycle. Studies in humans have provided increasing evidence of manifestations of circadian misalignment of sleep and wake activities during night work.^129–131

Workers on night shifts experience circadian misalignment of metabolic rhythms and chronic sleep loss; both contribute to the increased risk of symptoms and diseases reported. The International Agency for Research on Cancer (IARC) has recently classified shift work as a Group 2A carcinogen—“probably carcinogenic to humans.”^132,133 Other long‐term health risks have been associated with the desynchronization of circadian oscillators (biological clocks) in both central nervous and peripheral tissues, which are experienced by night and rotating shift workers. Increased risk for various medical syndromes and diseases and possible pathophysiologic mechanisms are discussed in later sections in this chapter.

DIAGNOSIS

Shift work and specific medical disorders

Gastrointestinal (GI) disorders

GI dysfunction is common in shift workers.^175–177 Gastritis or other digestive disorders have been an explanation frequently given by shift workers for absenteeism and for switching to day work for health reasons.¹⁷⁸ While some studies have not found an increased incidence of peptic ulcer disease (PUD) in shift workers, the majority of studies investigating PUD have found shift workers to at greater risk for the disease than day workers.^179,180

The etiology of GI symptoms and disorders in shift workers is probably multifactorial, involving dietary factors, psychosocial stress, sleep loss, as well as circadian disruption. Night workers’ mealtimes are in conflict with the circadian rhythms of gastric acidity and gastric emptying.^181,182 Shift workers may alter their diet due to lack of eating facilities available during the night shift.^183–185 In their recent review of GI conditions in shift workers, Knuttson and Bogglid discuss studies suggesting that disturbance of gastrin/pepsin secretion and decreased resistance to Helicobacter pylori infection are contributing factors to PUD in shift workers.¹⁸⁰

Metabolic syndrome, cardiovascular disease, and diabetes mellitus

Shift work involving night work has been found to be a risk factor for development of metabolic syndrome (obesity together with dyslipidemia, hypertension, and often impaired glucose tolerance due to insulin resistance). There is also evidence that abnormalities seen in metabolic syndrome are risk factors for development of both cardiovascular disease (CVD) and Type 2 diabetes mellitus (DM).^186–189

Results from a cross‐sectional study of 226 female hospital nurses and 134 male workers at a manufacturing firm by Ha and Park¹⁹⁰ were consistent with there being an association between metabolic risk factors for CVD or metabolic syndrome and shift work. Regression analyses revealed an association between shift work duration and the metabolic risk factors for cardiovascular disease. Duration of shift work was significantly associated with systolic blood pressure or cholesterol level among male workers aged 30 or more. Body mass index (BMI) was nonsignificantly associated with the duration of shift work in both male workers and female nurses ≥ 30 years of age. Recently Scheer et al. conducted a laboratory protocol study of metabolic measurements during inverted sleep–wake cycles.¹⁹¹ This allowed control of mealtimes. Circadian misalignment, when subjects ate and slept 12 hours out of phase from their habitual times, systematically decreased leptin, increased glucose (despite increased insulin), reversed the daily cortisol rhythm, and increased mean arterial blood pressure. In three of eight subjects, during circadian misalignment, postprandial glucose responses were in the prediabetic range. Several studies have found increased risk of hypertension, undesirable lipoprotein profiles, elevated triglyceride levels, and obesity in shift workers compared to day workers.^192–200

Cardiovascular disease

Well‐designed epidemiological studies have found an increased risk of CVD associated with shift work of, on average, around 40%.²⁰¹ Increased risk of stroke has also been reported in shift workers. Analysis of cohort study data from the Nurses’ Health Study looked at the risk of ischemic stroke related to the total number of years nurses had worked rotating night shifts.²⁰² After adjusting for multiple vascular risk factors, of the 80 108 study participants available for analysis, 60% reported working at least 1 year of rotating night work. Rotating night shift work was associated with a 4% increase in risk of ischemic stroke for every 5 years of shift work exposure (hazard ratio, 1.04; 95% CI: 1.01–1.07; p_trend = 0.01). The increased risk may be limited to women with a history of shift work for ≥ 15 years.

Prospective and historical prospective studies have found a dose–response relationship between shift work exposure and cardiovascular disease. In a small historical prospective study of rotating shift workers, Knutsson et al. found an increased risk of CVD in shift workers.²⁰³ The relative risk of ischemic heart disease (IHD) increased with increasing years of exposure to shift work (6–10 years, relative risk (RR) = 2.0; 11–15 years, RR = 2.2; 16–20 years, RR = 2.8; combined RR = 1.4). This dose–response relationship continued for up to 20 years of exposure ( p < 0.05). (Twenty‐one or more years of shift work had a RR = 0.4, attributed to the healthy worker effect). Based on multiple logistic regression analysis, the association between shift work and an increased risk of IHD was independent of age and smoking habits. Subsequently, analysis of data from the ongoing prospective Nurses’ Health Study during 4 years of follow‐up of 79 109 nurses between 1988 and 1992 found evidence that ≥ 6 years of night shift work exposure may increase the RR of CHD, consistent with the previous findings in the paper mill workers.²⁰⁴ This large study allowed for control of more confounders, in addition to age and smoking, including body mass index (BMI), hypertension, diabetes, hypercholesterolemia, physical activity, and alcohol use. The multivariate adjusted RR was 1.21 for women reporting < 6 years and 1.5 for women reporting ≥ 6 years of rotating night work. In 2005, Karlsson et al. reported findings for a total and cause‐specific mortality in pulp and paper workers in Sweden in a historical cohort between 1952 and 2001.²⁰⁵ Plant records provided accurate shift work exposure information to rotating night work shifts; mortality data were obtained from the national cause of death register. A longer duration of shift work was associated with increased risk of CHD. Shift workers with > 30 years of shift work exposure had the highest risk (SRR, 1.24, 95% CI: 1.04–1.49).

Additional analysis of data from the Helsinki Heart Study by Tenkanen et al. demonstrated an interaction of shift work exposure with lifestyle factors known to increase the risk of coronary heart disease (CHD).²⁰⁶ For shift workers, the relative risk of CHD rose gradually with increasing numbers of adverse lifestyle factors, but for day workers, no clear dose–response pattern was found. Overall the results of this study were consistent with the notion that shift work may have a triggering effect on other lifestyle factors that can increase the risk of CHD, and that active preventive medicine intervention is particularly important for shift workers.

There is evidence that chronobiological factors independently contribute to the increased risk of CVD reported in shift workers. Young has provided a discussion of evidence supporting that notion that disruption of the normal diurnal sleep–wake activity which occurs during night work results in desynchrony of circadian clocks within the cardiovascular system interfering with its ability to anticipate the variations in neurohormonal stimuli, which may contribute to the development of cardiovascular disease in shift workers.²⁰⁷ Shift work has been shown in studies controlled for differences in work demands and work stress to be an independent risk factor for CVD.²⁰⁸

Peter et al. studied the association between shift work and cardiovascular risk factors of hypertension and elevated blood lipids, in the context of the psychosocial work environment.²⁰⁹ In addition to finding direct effects of shift work on cardiovascular risk, mediating effects of psychosocial work factors (effort–reward imbalances) were found, supportive of the hypothesis that a stressful work environment can act as a mediator of adverse effects of shift work on hypertension and partly on atherogenic lipid levels.

Boggild and Knutsson²⁰¹ have previously presented evidence for a complex mechanistic model involving interdependent pathways involving circadian system disruption, behavioral lifestyle changes, disruption of social interactions, as well as changes in biomarkers of CVD, for example, development of dyslipidemia and hypertension. Most recently, Puttonen et al.²¹⁰ reviewed current research information regarding mechanisms between shift work and CVD finding sufficient epidemiological evidence for several possible disease mechanisms. They described an updated model of interrelated pathways stemming from “circadian” stress brought on by shift work. The model describes mechanisms whereby the interaction of psychosocial, behavioral, and physiologic stress factors may contribute to cardiovascular disease outcomes (see Figure 10.1).

Diabetes mellitus (DM) Type 2

As noted above, changes in glucose tolerance with postprandial glucose levels in prediabetic ranges have been demonstrated in laboratory studies of circadian misalignment of sleep–wake cycle. Several studies have supported an association of night work and an increased risk of obesity and metabolic syndrome, conditions known to be related to Type 2 DM.^{187,188,211–214}

In addition to the increased risk of CHD reported in 2005 by Karlsson et al., the risk of diabetes was also increased as the number of years of shift work exposure increased.²⁰⁵ Kroenke et al. analyzed data over 6 years regarding work characteristics and incidence of Type 2 diabetes mellitus (DM), from the prospective Nurses’ Health Study (NHS) II.²¹⁵ They found a positive association (p_trend < 0.001) between years in rotating night shift work and diabetes, mediated by BMI. Subsequently, Pan et al. performed an updated analysis of cohort data from the Nurses’ Health Study I (1988–2008, 69 269 women) and Nurses’ Health Study II (1989–2007, 107 915) studies; statistical analysis adjusted for diabetes risk factors revealed a monotonic association with duration of rotating night shift work and increased risk of Type 2 DM in both cohorts.²¹⁶ Compared to women with no shift work exposure, the hazards ratio (95% CI) for women with 1–2 years of shift work was 1.05 (1.00–1.11), for 3–9 years 1.20 (1.14–1.26), for 10–19 years 1.40 (1.30–1.51), and for ≥ 20 years 1.58 (1.43–1.74), p_trend < 0.001. After adjustment for updated BMI, there was attenuation in the association. These findings were consistent with an increased risk of Type 2 DM in women, in part related to body weight; women with > 20 years of shift work exposure still had a 44% increased risk of developing diabetes after the adjustment for BMI. In 2005, Japanese researchers reported the results from a longitudinal study of male blue‐collar and white‐collar workers over 8 years using data from annual health examinations and glycosylated hemoglobin levels.²¹⁷ Relative risk of DM for two‐shift workers and three‐shift workers, compared with fixed daytime workers, was 1.73 and 1.33, respectively, after adjustment for confounding factors, but these increases were not statistically significant. Using white‐collar workers as the reference group, there was a significantly increased risk of DM for the two‐shift workers (RR = 2.01), but not for three‐shift rotators, or daytime blue‐collar workers. Another Japanese longitudinal study, a year later, of 5629 male steelworkers compared onset of DM in day workers with alternating shift workers over a 10‐year period using data from annual health examinations.²¹⁸ Analysis of this data revealed an increased odds ratio (OR) for alternating shift workers compared to day workers of 1.35 (95% CI: 1.05–1.75); OR for BMI was also increased 1.28 (1.23–1.33).

Reproductive health

Preterm delivery (Ptd), small for gestational age (Sga), and low birth weight (Lbw)

McDonald and colleagues conducted a large cross‐sectional study in Montreal, in which 22 761 live births were assessed for maternal employment risk factors for LBW and preterm delivery (PTD).²¹⁹ Observed‐to‐expected (O/E) ratios for LBW and PTD were increased significantly for long hours of work (46 hours/week or more), with ratios of 1.34 (p < 0.01) and 1.24 (p = 0.03), respectively. Rotating shift work was also associated with LBW, O/E = 1.38 (p < 0.01). A significant association was found in the services sector between rotating shift work and PTD, O/E = 1.88 (p < 0.01). Analysis of prematurity factors from the Montreal study, in which gestational age was allowed for in the analysis of birth weight data, done by Armstrong et al. suggested that shift work might slow fetal growth and increase the risk of PTD.²²⁰

In a retrospective cohort study, Axelsson et al. looked at the effect of night work, evening work, working irregular hours outside the period of 0645–1745, and rotating shift work compared to permanent day work on pregnancy outcome.²²¹ They found an association between irregular working hours and an increased risk of LBW. For nonsmoking mothers with infants of birth order 2+, an increased risk of LBW was associated with irregular hours (p < 0.01) or rotating shift work (p < 0.05).

Xu and colleagues found higher proportions of preterm birth and LBW for rotating shift workers compared to regular day workers, with adjusted OR of 2.0 for PTD and 2.1 for LBW.²²² Subsequently Fortier et al. reported the results of a Canadian study of 4390 women who had recently delivered live‐born singleton infants.²²³ No deleterious effect was found for those doing shift work (defined as occasional evening or night work), OR = 1.03. No increase in the risk of delivering a small‐for‐gestational‐age (SGA) baby was found related to working shift work or regular evenings or nights. Interestingly, long work hours (40 or more) were also not related to PTD or SGA outcomes.

Nurimen found a small association between shift work (varying types of nonregular day work including two‐ and three‐shift rotations) and SGA infants in a study comparing 1475 mothers of infants with certain structural malformations to mothers of babies without malformations.²²⁴ Mothers who had worked shift work schedules during most of their pregnancy had a slightly increased risk of having SGA infants compared to day‐working mothers (adjusted rate ratio = 1.4).

Research data is limited for permanent night work. Saurel‐Cubizolles and Kaminski did not find an association between night work and preterm delivery or low birth weight.²²⁵ However, only 4% of the female hospital employees interviewed were night workers, and some of them worked nights only occasionally. In another study, no increased risks were found for pregnancy outcome of permanent night workers; however, 91% of the night workers questioned were part‐time employees.²²¹ Fortier et al. reported an increased OR of 1.45 for delivering preterm for women working regular evening or night shifts who continued to do so after 23 weeks of pregnancy.²²³

Croteau et al. conducted a case–control study by evaluating the relationship of occupational conditions during pregnancy and the increased risk of delivering a small‐for‐gestational‐age (SGA) infant and whether taking measures to eliminate these conditions decreases that risk.²²⁶ 1 536 cases and 4 441 controls were selected from 43 898 women who had single live births between January 1997 and March 1999 in Québec. The women were interviewed by telephone after delivery. The risk of having an SGA infant increased with an irregular or shift work schedule alone; and there was a cumulative index of at least two of the following occupational conditions: night work, irregular or shift work schedule, standing, lifting loads, noise, and high job strain with low social support. As the number of job conditions that were not eliminated during pregnancy increased, the risk increased ( p_trend = 0.004; ORs = 1.00, 1.08, 1.28, 1.43, and 2.29 for 0, 1, 2, 3, and 4–6 conditions, respectively). Elimination of the conditions before 24 weeks of pregnancy brought the risks close to those of unexposed women.

Bonzini et al. reported the results of a systematic review of the epidemiological research between 1966 and February 2010 relating shift work and pregnancy outcomes including PTD, LBW, small for gestational age (SGA), and preeclampsia.²²⁷ Twenty‐three relevant studies were retrieved. Preterm delivery was consistently defined as birth at < 37 weeks of gestation. LBW was defined as a birth weight < 2500 g, except for one study that reported risk estimates for birth weight < 3000 g. SGA was defined as birth weight < 10th percentile for gender and gestational age, with one study including infants < 5th percentile. Pooled estimates of relative risk (RR) were calculated in random‐effects meta‐analyses. Their search identified 17 original studies that investigated the association between shift work and PTD: 10 studies concerning SGA and 6 studies concerning LBW. The pooled estimate of RR (16 studies) for PTD was 1.16 (95% CI: 1.00–1.33); when five reports of poorer methodological quality were excluded, there was no longer statistical significance. Increased RRs for LBW were also observed (RR 1.27, 95% CI: 0.93–1.74) and for SGA (RR 1.12, 95% CI: 1.03–1.22). Estimates of risk for PTD tended to reduce with inclusion of more recent studies in meta‐analyses. The authors pointed out that one explanation of this time trend could be that in most countries, precautionary legislation had been introduced, allowing pregnant workers to be assigned to nonshift work schedules, or to take earlier prenatal leave, so that fewer women continued shift work during the later stages of pregnancy. Night shifts may have been voluntarily suspended if women suspected that it could be detrimental to their pregnancy, and thus risks in women who continue to work shifts late in pregnancy might be underestimated due to a healthy pregnant worker effect (healthier women with uncomplicated pregnancies being less likely to change work schedules). Two studies were noted to support the notion that the risk of PTD associated with shift work was higher in women whose work conditions did not change during the pregnancy^226,228; and a study comparing European countries found that significant associations of PTD with shift work were mainly observed in countries where long prenatal leaves were infrequent and legislative support for preventive measures was weaker.²²⁹ Ten studies were analyzed looking at the association between shift work and the risk of delivering an SGA baby, including five prospective cohort investigations. With the exception of one, the studies tended to rule out a more than moderate effect (RRs ranging from 0.8 to 1.5). The pooled risk estimate was 1.12 (95% CI: 1.03–1.22, test for heterogeneity p = 0.39). When a poor quality study was removed from the analysis, the RR was 1.10 (95% CI: 1.00–1.20). Six studies were analyzed looking at the association between shift work and risk of delivering an LBW infant. One of the three cohort studies showed a significantly elevated risk. In the pooled meta‐analysis, the combined risk estimate was 1.27 (95% CI: 0.93–1.74, test for heterogeneity p = 0.39). Overall, the authors concluded their findings suggest that the risk of preterm delivery, low birth weight, or small for gestational age from working shift work in pregnancy is small; and the available data does not make a compelling case for mandatory restrictions on shift working in pregnancy. Pooled estimates of risk for specific patterns of work schedules were not calculated because of the small number of studies with sufficient information. The authors point out that further studies are needed to address the question of whether adverse birth outcomes are related to different types of rotating work schedules or to fixed night work and suggest, as circumstances permit, pregnant women who wish to reduce their exposure to shift and night work be allowed to do so.

Fetal loss and spontaneous abortion

In a 1988 cross‐sectional analysis of 22 613 previous pregnancies, in 56 067 Montreal women, McDonald et al. found a small but significant increase in spontaneous abortion associated with working 46 hours or more per week (O/E 1.19, p < 0.01) and for rotating shift work (O/E 1.25, p < 0.01).²³⁰ Axelsson et al. studied the relation between shift work and spontaneous abortion in a cross‐sectional study of 3358 Swedish midwives.²³¹ Hours of work information was divided into day workers, permanent night work, and two‐ or three‐shift rotators. The OR was increased for night work and three‐shift work (OR = 1.63 and 1.49, respectively) for women who worked during the first trimester. After restricting analysis to first pregnancies, a significant increased risk was also found for night work (OR = 6.89). The OR was significantly elevated for two‐shift workers (OR = 2.70), but not significantly increased for three‐shift schedules. When analysis was done separately for early and late spontaneous abortions, night work, but not rotating shift work, was associated with an elevated risk of late (beyond the 12th week of pregnancy) abortions (OR = 3.33).

In a case–control study, Infante‐Rivard et al. compared the work schedules of 331 women who had experienced pregnancy loss to 993 pregnant women matched for gestational age. For fixed evening schedules, the adjusted OR was substantially elevated at 4.17, and for fixed nights the adjusted OR was also elevated, but to a lesser degree (OR = 2.68).²³² Axelsson et al. reported the results from their retrospective cohort study included a slight, but not statistically significant, increase in the risk for miscarriage (RR = 1.44; 95% CI: 0.83–2.51) associated with irregular working hours including rotating shift work.²²¹ Axelsson and Molin found an increased miscarriage rate of borderline significance in shift workers (OR = 2.07; 95% CI: 0.98–4.34).²³³ In a retrospective cohort study of laboratory workers, a significantly increased risk of miscarriage was reported for shift workers (RR = 3.2; 95% CI: 1.36–7.47).²³⁴ Two other studies, as reviewed by Nurimen, also found an increased risk of miscarriage in shift workers.^235–237

Zhu et al. reported the results of a prospective cohort study using the Danish National Birth Cohort. Fixed night work was associated with fetal loss.²³⁸ Over 33 000 pregnancies were identified in day workers and over 8 000 pregnancies in shift workers between 1998 and 2001. Fetal loss included spontaneous abortion and stillbirth. The hazard ratios for fetal loss compared to day workers, adjusted for potential confounders, was increased for fixed night shift work: for all fetal loss, HR = 1.85 (CI: 1.00–3.42); for spontaneous abortion, HR = 1.81 (0.88–3.72); and for stillbirth, HR = 1.92 (0.59–6.24). No high risk was found for rotating shifts.

Two case–control studies of spontaneous abortion and shift work did not find an increased risk.^239,240 As pointed out by Nurimen, in these two negative studies, rotating shifts were part of broad‐based exposure categories and were not analyzed explicitly.²³⁷

Bonde et al. recently conducted a systematic review and meta‐analysis of published studies between 1996 and 2012, which looked at the risk of miscarriage related to shift work, working hours, and physical stressors.²⁴¹ Working fixed nights was associated with a moderately increased risk of miscarriage (pooled RR 1.51; 95% CI: 1.27–1.78), as determined by the fixed model OR in five better quality studies reporting RRs for fixed night work compared with day work. Pooled fixed meta‐OR for studies (n = 7) reporting risk of miscarriage for three‐shift schedules or evening/night shifts compared to day or two‐shift workers was associated with a small increased risk (OR 1.12; 95% CI: 0.96–1.42).

Shift work and subfecundity

Ahlborg et al. studied subfertility in Swedish midwives in a survey sent to 3985 midwives (84% response rate).²⁴² Those who worked rotating shifts or permanent nights had decreased fertility compared to day workers. Bisanti et al. surveyed women during prenatal clinic visits or after giving birth to determine the time of unprotected intercourse prior to conception.²⁴³ Rotating shift work was associated with an increased risk of subfecundity (OR = 2.0). Spinelli et al. interviewed new mothers who had delivered within the preceding week. After adjustment for confounders, fertility was not significantly reduced in shift‐working mothers [fecundability (conception rate) ratio = 0.9; p > 0.10].²⁴⁴ A Japanese questionnaire study on working conditions found pregnancy rates lower for women doing shift work (10.0%) compared to day workers (18.1%) (p < 0.01).²³⁶

Tuntiseranee et al. recently reported no association between shift work and subfecundity, but did find long hours of work to increase time to pregnancy.²⁴⁵ This effect was greatest when both partners were working over 70 hours/week (OR = 4.1 in primigravid women and 2.0 for all pregnant subjects). There was no increased OR when only the male partner worked long hours.

Zhu et al. analyzed data from the Danish National Birth Cohort (DNBC), including 39 913 pregnant women who were enrolled from March 1, 1998, to May 1, 2000, to examine whether shift work was associated with reduced fecundity as estimated by time to pregnancy (TTP).²⁴⁶ Data on job characteristics and TTP (0–2, 3–5, 6–12, and > 12 months) were used for 17 531 daytime workers and 3 907 shift workers who had planned pregnancies. Fecundity odds ratios were calculated (OR > 1 indicating a shorter TTP). Fixed evening workers and fixed night workers had a longer TTP. Compared with daytime workers, the adjusted ORs were 0.80 (95% CI: 0.70–0.92) for fixed evening workers, 0.80 (95% CI: 0.63–1.00) for fixed night workers, 0.99 (95% CI: 0.91–1.07) for rotating shift (without night) workers, and 1.05 (95% CI: 0.97–1.14) for rotating shift (with night) workers. The proportions of unplanned pregnancies and contraceptive failures were higher among fixed evening and fixed night workers. The researchers concluded that the slightly reduced fecundity among fixed evening workers and fixed night workers may be mediated by pregnancy planning bias or differential options for sexual contacts; and there was no unequivocal evidence of a causal association between shift work and subfecundity.

Cancer

Taylor and Pokock were the first to report an increased risk of cancer in shift workers in a 1972 mortality study.²⁴⁷ A 1990 mortality study by Raffnsson and Gunnarsdottir also reported an increased risk of cancer associated with night work.²⁴⁸

A 1996 Norwegian nested case–control study of breast cancer incidence in radio and telegraph operators, working at sea, followed 2619 mostly postmenopausal women for about 30 years.²⁴⁹ Cancer cases were identified from National Norwegian Cancer Registry. Job histories of work on ships were collected for shift work, as well as travel through time zones classified for each ship mentioned in the job histories to define shift work. After controlling for duration of employment and after adjustment for age and year of birth of first child, there was an excess risk of breast cancer associated with exposure to night shift work (SIR, 1.5; 95% CI: 1.1–2.0). Breast cancer risk was highest in women with the highest cumulative shift work history compared to no shift work, RR = 6.1(95% CI: 1.5–24.2). There appeared to be an increased risk of breast cancer in women ≥ 50 years of age with increasing cumulative exposure to shift work compared to no shift work (low exposure 0–3.1 years, adjusted for duration of employment, RR = 3.2, 95% CI: 0.6–17.3; high exposure 3.1–20.7 years, adjusted for duration of employment, RR = 4.3, 95% CI: 0.7–26.0; p_trend = 0.13).

Subsequent studies looking at the risk of breast cancer in shift workers followed between 2001 and 2007 includes the following:

• A 2001 case–control study by Davis et al. looked at sleep patterns and habits, lighting in bedrooms, and shift work history in 813 cancer cases (identified by the Cancer Surveillance System of Seattle) and 793 age‐matched controls.²⁵⁰ Information about sleeping habits, light‐at‐night exposure, and lifetime occupational history was obtained from in‐person interviews. Night work was defined as at least one “graveyard” (beginning after 19:00 and ending before 09:00) shift/week in the 10 year prior to diagnosis. After adjusting for parity, family history of breast cancer, contraceptive use, and history of hormone replacement therapy, there were an increased risk for breast cancer associated with graveyard shift work (OR 1.6, 95% CI: 1.0–2.5), a 13% increase in risk for additional year of having worked at least one such shift per week (OR 1.13; 95% CI: 1.01–1.27), and a 14% increase risk in women reporting, for any reason, frequently not sleeping during the middle of the night (when melatonin levels are typically highest) (OR, 1.14; 95% CI: 1.01–1.28, per night/week; OR 1.7 for the group with at least 2.6 nights/week of interrupted sleep).
• A population‐based case–control study nested in a cohort of all female employees in Denmark based on national pension fund data found that women who worked at night for at least 6 months had a 50% greater risk for breast cancer compared to age‐matched controls (OR, 1.5; 95% CI: 1.2–1.7).²⁵¹ A positive trend was noted with increasing duration of work at night. 7035 women with incident breast cancer were identified in the Danish Cancer Registry. Individual employment histories were reconstructed using information from the pension fund. Night work definition was based on information from the nationwide interview survey of living and working environment conditions; trades with at least 60% of female responders working at night were considered to have a predominant nighttime schedule; trades with < 40% reporting nighttime schedules were classified as day workers. The RR of breast cancer was 1.5 (95% CI: 1.3–1.7; 434 cases) among women who worked in night work trades at least a half year, at least 5 years before diagnosis. Analysis was done after controlling for age, social class, parity, and age at birth of first child and last child. For the subgroup of women with more than 6 years predominantly working at night, the RR was 1.7 (95% CI: 1.3–1.7; 117 cases). In a subanalysis of nurses (41% having predominantly night work), the RR of breast cancer was also significantly evaluated (RR, 1.3; 95% CI: 1.1–1.4).²⁵²
• Two large prospective cohort studies of night shift work and breast cancer risk used data from the Nurses’ Health Study cohorts (Nurses’ Health Study I and Nurses’ Health Study II).^253,254 The Nurses’ Health Study began in 1976, when 121 701 registered nurses in the United States, 30–55 years of age, were enrolled and completed a questionnaires about their health status, medical history, and known or suspected risk factors for cancer. Since baseline, questionnaires have been mailed biannually with the exception of lifetime history of night work (total number years working rotating night shifts at least three nights per month), which was assessed in 1988. In 2001 Schernhammer et al. reported the results of follow‐up of 78 562 women in the Nurses’ Health Study who answered the 1988 questionnaire and were cancer‐free at baseline over 10 years (1988–1998).²⁵³ 2441 incident breast cancer cases were documented during that time. After adjustment for known breast cancer risk factors, their analysis revealed a significantly increased risk of breast cancer in women who had worked ≥ 30 years of rotating night work compared to women who never worked rotating night shifts (RR 1.36; 95% CI: 1.04–1.78). The risk increased with numbers of years of shift work (test for trend, p = 0.02). The similarly designed Nurses’ Health Study II study was established in 1989, when the prospective cohort of 116 671 registered female nurses (no overlap with Nurses’ Health Study) were enrolled and completed the baseline questionnaire, including questions on total months worked on rotating night shifts at least three nights per month. Information was updated in 1991, 1993, 1997, and 2001. In 2006, Schernhammer et al. reported, in 115 022 mostly premenopausal women, an elevated breast cancer risk of 1.79 (95% CI: 1.06–3.01; p = 0.65) among those who worked ≥ 20 years of rotating night shift work compared with women with no work history of rotating night shifts.²⁵⁴
• In 2006, Lie et al.²⁵⁵ reported the results of a nested case–control study within a cohort of 44 835 Norwegian nurses. Using the nationwide cancer registry, 537 breast cancer diagnoses during 1960–1982 were identified. Work history was reconstructed from the nurses’ registry (self‐report of work history periodically updated) and census information. It was assumed that nurses doing clinical work at infirmaries worked at nights (with the exception of physiotherapy and outpatient departments); it was assumed that work sites other than infirmaries involved day work only. An association was found between duration of night work and breast cancer risk (p_trend = 0.01). The RR associated with > 30 years of night work was 2.21.
• In 2006, O’Leary et al. published results of their case–control study in New York—the Electromagnetic Fields and Breast Cancer on Long Island Study (EBCLIS).²⁵⁶ They did not observe an association between night work and breast cancer risk. To evaluate the effects of electromagnetic frequency, women from within this case–control study were selected according to their degree of residential stability (EBCLIS component). EBCLIS comprised 576 breast cancer cases and 585 matched population‐based controls. Occupational history was obtained in personal interviews as well as history of residential light‐at‐night exposures. Shift work was defined as “ever” working in at least one job during the past 15 years that included evening shifts (could start in the afternoon and end as late as 02:00) and overnight shifts (starting as early as 19:00 and continuing until the next morning). Results were adjusted for age, parity, education, family history of breast cancer, and history of benign breast disease.
• Results of a retrospective registry‐based cohort study were reported in 2007 comprising all 1 148 661 Swedish women active in the workforce per 1960 and 1970 census reports.²⁵⁷ Workers were followed up for breast cancer morbidity using the Swedish Cancer Registry. Annual surveys of living conditions among 46 438 randomly selected subjects who participated in a personal interview were used for assessing night work. Shift workers were defined as those who reported their workplace had a rotating schedule with at least three possible shifts per day or had any night work hours (between 01:00 and 04:00) at least 1 day during the week preceding the interview. Participants working in job titles and industry combinations (from census data regarding workers’ industry and socioeconomic status) with at least 40% shift work were classified as shift workers. The reference group comprised subjects in occupation–industry combinations in which < 30% reported being shift workers. In analyses using the census information for the definition of exposure, no increase in risk was found for women classified as shift workers.

In October 2007, a panel of 24 scientists who reviewed the epidemiological, experimental, and mechanistic research for International Agency for research on Cancer (IARC) concluded that there is “limited evidence in humans for the carcinogenicity of shift work that involves night work”; “sufficient evidence in experimental animals for the carcinogenicity of light during the daily dark period (biological night)”; and “shiftwork that involves circadian disruption is probably carcinogenic to humans (Group 2A).”¹³² The research included in the IARC panel analysis is reviewed in the subsequent IARC Monograph published in 2010.²⁵⁸ The epidemiological data was primarily based on the seven breast cancer studies reviewed above.^249–257 The IARC panel discussion noted that each of the studies used different definitions of shift work; that six of the eight breast cancer studies, including the two prospective cohort studies from the Nurses’ Health Study, “consistently pointed towards a modestly increased risk of breast cancer among long‐term employees who performed night shiftwork, defined in different ways”; and that one of the two negative studies had important limitations in design. Other points included the following: there were a relatively limited number of studies, most focusing on the single profession of nursing; there was some potential for confounding by unknown risk factors, and inconsistent and inaccurate exposure assessments of shift work, which may have biased the results toward the null; the evidence for an association with breast cancer and night work was consistent in the studies specifically designed to address this question; and studies of the incidence of breast cancer in female flight cabin crews provided additional support.

The conclusions of the IARC working group drew attention to the evidence of an association of night work with risk for developing cancer, prompting additional reviews, meta‐analysis of the existing data of the breast cancer studies, and new research.

Costa et al.²⁵⁹ reviewed the epidemiologic studies included in the IARC report and a recent case–control study, published in 2010, using data from the German Gene–Environment Interaction and Breast Cancer (GENICA) study²⁶⁰ and concluded that the loose definitions of exposure to night work in the published studies did not allow for proper assessment of the risk of cancer associated with circadian disruption. In the GENICA study, shift work exposure (defined as working the full period between 24:00 and 05:00) was based on personal interview information; cases experience about 800 night shifts compared to 300 among controls. Long‐term night work, ≥ 20 years, was associated with a statistically nonsignificant increase in breast cancer risk, OR 2.48 (95% CI: 0.62–9.99). Limitations of the GENICA study include low prevalence of night work, especially long‐term exposure, and the retrospective assessment of work history.

In 2011 Hansen and Stevens published results from a Danish case–control study of breast cancer in nurses (identified from the national cancer registry) and collected detailed information on lifetime shift work history.²⁶¹ Overall, nurses working rotating shifts after midnight had significantly increased risk of developing breast cancer compared to permanent day‐working nurses (OR 1.8, 95% CI: 1.2–2.8). The greatest increased risk was seen associated with long‐term day–night rotating shift schedules (OR 2.6, 95% CI: 1.8–3.8).

Three meta‐analysis of breast cancer studies in shift workers were published in 2013. Kamdar et al. identified 15 studies published by 2012 that met their inclusion criteria.²⁶² Using a random‐effects model, they found the pooled RR for women with ever night shift exposure to be 1.21 (95% CI: 1.00–1.27, p = 0.056). For long‐term night work, defined as ≥ 8 years, RR was 1.04 (95% CI: 0.92–1.18). Subgroup analysis for nurses with long‐term exposure was reported to suggest an increased risk of breast cancer. Jia et al. reported, in their analysis of 13 studies through 2012, a pooled adjusted RR of 1.20 (95% CI: 1.08–1.33) for risk of breast cancer associated with ever working versus never working night shift work.²⁶³ Later, in August 2013, Wang et al. published results of their meta‐analysis of cohort and case–control studies published in May 2013.²⁶⁴ They summarized evidence by frequency and duration of cumulative exposure to night shift work and used a dose–response regression model to evaluate the relationship between exposure to night work and risk of breast cancer. Ten studies were included. The pooled adjusted RR for association between “ever exposed to night shift work” and breast cancer was 1.19 (95% CI: 1.05–1.35). Analysis of the dose–response relationship revealed a 3% increase in risk of breast cancer for every 5 years of exposure to night work (pooled RR 1.03 (95% CI: 1.01–1.05) p_{heterogeneity} < 0.001). This meta‐analysis also suggested that an increase of 500‐night shifts increases the RR 13%.

Also, in August 2013, results of an Australian case–control study were published by Fritschi et al. Women diagnosed with breast cancer between 2009 and 2011 were identified from the Western Australian Cancer Registry (mandatory reporting of invasive cancer); randomly selected controls were from the Western Australian electoral roll (compulsory adult enrollment). 1202 cases and 1785 controls completed the study.²⁶⁵ Questionnaires followed by telephone interviews were used to obtain work history. A statistically significant association was found between breast cancer and phase shift caused by night work (OR 1.22, 95% CI: 1.01–1.47). There was evidence of a dose–response relationship, but no duration–response relationship.

In 2014, Hansen looked at the influence of night shift work on the survival of breast cancer.²⁶⁶ Women participating in two separate Danish case–control studies of breast cancer were interviewed by phone to obtaining information including night shift work history and known risk factors for breast cancer. The national cause of death register was used to follow up for death. Time‐to‐event analyses were done using Cox proportional hazards models and Kaplan–Meier survival plots. There was a significant tendency of decreasing survival in fixed and rotating night shift workers compared to day workers and by increasing years of prior nondaytime work (p = 0.04).

The current research provides support for biological plausibility and potential mechanisms for an association of long‐term exposure to night shift work with increased risk of cancer. For example, animal studies have demonstrated that the development of neoplasias has been associated with disruption of the rhythmicity of the circadian period 2 gene.²⁶⁷ Additional findings have been reviewed in detail by Costa et al.²⁵⁹ and in the IARC monograph²⁵⁸ including alteration of endocrine rhythms and immune system function due to sleep deprivation, nocturnal suppression of melatonin by light at night (LAN), and circadian disruption at the cellular and molecular level. The phase shifts experienced by night and rotating shift workers result in molecular level desynchronization in circadian oscillators in peripheral tissues, as well as the CNS, which provides a pathophysiological basis for the reported increased risk for shift workers of developing cancers. Immune responses may be suppressed via circadian disruption of the central oscillator in the SCN. Immune suppression reflects multiple events including decreased number of natural killer (NK) cells, cytotoxic lymphocytes, and proinflammatory cytokines, interferon, and tumor necrosis factor (TNF). Suppression of melatonin may lead to estrogen elevation with clinical significance in endocrine‐dependent tumors; melatonin counteracts the enhancing effects of estradiol on breast cancer cell activity; melatonin can act as a free radical scavenger by activation of antioxidative pathways and has antiproliferative effects on human cancer cells in vitro. Melatonin has been shown to be oncostatic in certain tumor cells; exogenous melatonin has been shown to have anti‐initiating and oncostatic activity on chemically induced cancers.^268–272 Clinical trials in humans have also demonstrated favorable responses to melatonin in cancer patients, alone or in combination with standard treatment regimens.²⁷³ Chronobiologists have also noted the effects of loss of normal diurnal rhythm in cortisol levels associated with sleep disruption which support a mechanistic shift work role in the observed association between shift work and increased risk of breast cancer.²⁷⁴ The circadian clock may act as a tumor suppressor at systemic and molecular levels via clock‐controlled genes involved in controlling cell cycles and tumor suppressor genes. Processes relevant to carcinogenesis, for example, DNA repair and cellular proliferation, have circadian variation.

In the very recent study of molecular mechanisms, Liu et al. followed up on previous findings indicating that long‐term exposure to LAN in night workers may result in dysregulated patterns of methylation, inducing alteration of microRNAs relevant to cancer.²⁷⁵ They found a 49% increase in miR‐34b promotor methylation in shift workers—with results suggesting that long‐term shift work may increase the risk of breast cancer via methylation‐based suppression of miR‐34b, with a related reduction in immune‐mediated antitumor capacity.

In another recent study, Monsees et al. hypothesized that circadian genes influence breast cancer risk in women and investigated gene–environment interactions in nurses working rotating shift work.²⁷⁶ Using blood samples collected from > 29 000 cancer‐free participants in the Nurses’ Health Study II study between 1996 and 1999, the researchers looked at variants of genes relevant to the circadian system in women in the Nurses’ Health Study II cohort. They tested for associations between certain genotypes and breast cancer risk and potential interactions between genotype and rotating shift work in a subset. Data was available for cumulative exposure to rotating shift work prior to the last blood sample collection on the subset (438 cases; 880 controls). Analysis of interactions between clock genes and shift work was limited to incident cases as diagnosis of cancer may influence work schedule. The researchers tagged genes with known key roles in circadian regulation. The results provided evidence that a coding single‐nucleotide polymorphism (SNP) in NPAS2 (Ala394Thr;rs2305160) may modify the influence of shift work on risk of breast cancer. None of the selected genetic variants were significantly associated with breast cancer risk; however rs23051560 (Ala394Thr), in the largest circadian gene, was most strongly associated with breast cancer risk (p = 0.0005). Among women with minimal (< 2 years) exposure to rotating night work, NPAS2Ala394Thr variant Thr genotypes (Ala/Thr and Thr/Thr) were associated with significantly less risk of breast cancer compared to the Ala/Ala genotype. Women homozygous for the minor allele, Thr/Thr genotype, who had ≥ 2 years of rotating shift work exposure had 2.83 times higher risk for breast cancer compared to women of the same genotype with < 2 years exposure (95% CI: 1.47–5.56). In their discussion of their findings, the authors pointed out that Asian populations have lower frequencies of Thr compared to Europeans, and if the interaction observed is causal, a weaker effect of shift work would be expected in populations with a lower prevalence of Thr genotype at Ala394Thr. They also noted that the prospective Shanghai Women’s Health Study observed no association between lifetime history of shift work and risk of breast cancer and that genetic interactions modifying the effects of night work may explain the lack of association of shift work with risk of breast cancer observed in the Asian population.²⁷⁷

Overall there are increasing epidemiologic support and molecular research evidence that a history of working several years of shift work involving nights increases a woman’s risk of developing breast cancer and the magnitude of the risk is similar to other known risk factors for breast cancer. There is also some epidemiological evidence of increased risk of developing other cancers in women. In the Nurses’ Health Study, the RR for colorectal cancer in women working rotating nights 15 years or more compared to women who had never worked rotating night shifts was 1.35 (95% CI: 1.03–1.77; p_trend = 0.04).²⁷⁸ 602 incident cases of colorectal cancer were documented among 78 586 women followed from 1988 to 1998. Study participants were asked how many years in total they had worked in rotating night shifts, at least three nights per month in addition to working days or evenings. Working rotating night shifts for 20 or more years has also been found to be associated with a significant increase in risk for endometrial cancer, especially in obese women (multivariate relative risk  = 1.47 (95% CI: 1.03–1.14)).²⁷⁹ Stratified analysis of obese rotating night workers found a doubled risk of endometrial cancer (MVRR = 2.09, 95% CI: 1.24–3.52). A nonsignificant increase was found in obese women who did not do rotating night work.

There are also epidemiological studies implicating that shift work is a risk factor for cancer in men. Limitations of the epidemiological studies available in 2010, looking at shift work‐related circadian disruption and the risk of cancer in men and women, were critically reviewed by Costa et al.²⁵⁹ The issues highlighted were mostly related to the diversity of shift work ascertainment methods, varying exposure durations, different definitions of exposure windows, assessment of changes in night shift schedules during the working lifetime, and adjustment for confounders. Parent et al. specifically addressed some of these issues in their recent report of a population‐based case–control study of night work and cancer in men conducted in Canada, in the 1980s, by (i) including the period between 1:00 and 2:00 a.m. in the definition of night work precluding evening shift work being considered night work exposure; (ii) calculating a cumulative index of night work exposure; and (iii) incorporating adequate analytic control for several potential confounders.²⁸⁰ Cases were male patients, 35–70 years old, diagnosed at any of the 18 major Montreal hospitals with incident, pathologically confirmed cancer. Participation of all large hospitals in this area ensured a nearly complete (97%) population‐based identification of cases. Between 1979 and 1985, 4576 eligible cancer patients were accrued; 3730 patients (82%) were successfully interviewed. Controls were recruited from the general population using electoral lists (a nearly complete list of voting age citizens in Quebec). Interviews were conducted from 1979 to 1986. For each job held, history of shift work was obtained including the start and finish times of shifts. The results suggest that night work may increase cancer risk at several anatomic sites in men. Compared with men who never worked at night, the adjusted ORs among men who ever worked at night were 1.76 (95% confidence interval (CI): 1.25, 2.47) for lung cancer, 2.03 (95% CI: 1.43, 2.89) for colon cancer, 1.74 (95% CI: 1.22, 2.49) for bladder cancer, 2.77 (95% CI: 1.96, 3.92) for prostate cancer, 2.09 (95% CI: 1.40, 3.14) for rectal cancer, 2.27 (95% CI: 1.24, 4.15) for pancreatic cancer, and 2.31 (95% CI: 1.48, 3.61) for non‐Hodgkin’s lymphoma. The significant increased risks of cancer in the prostate and colon were irrespective of the timing of night work. There was an effect of long‐term night work (> 10 years) for cancers of the prostate, colon, and bladder and for non‐Hodgkin’s lymphoma; the evidence was weaker for other cancer types. There were too few men in the study who had worked in jobs involving night work for over 20 years to conduct analyses for longer exposure. As the authors point out, the findings of increased risks across a wide array of cancer types suggest a common underlying mechanism, with the anticancer effects of melatonin being the most often evoked theory.

Lahti et al. reported the results of a retrospective cohort study in 2008 showing a modest increased risk of non‐Hodgkin’s lymphoma in men with high shift work exposure based on a job‐exposure matrix.²⁸¹ Cancer cases were identified from the Finnish Cancer Registry. 6307 cases were identified diagnosed between 1971 and 1995. Exposure to night work for 10 years was associated with an RR of 1.10 (95% CI: 1.03–1.19).

Three of the four studies looking at the risk of prostate cancer in shift workers have found an elevated risk for prostate cancer associated with shift work exposure. In 2006, Kubo et al. reported the results of a prospective cohort study of Japanese shift workers.²⁸² Individual questionnaires were used to collect shift work history. The RR for fixed night work was 2.3 (95% CI: 0.6–9.2) and 3.0 for rotating shifts (95% CI: 1.2–7.7). The following year, Conlon et al. reported the results of a Canadian case–control study.²⁸³ Study participants completed a questionnaire including what was their “usual work time (daytime, evening/nightshift, rotating shift, other).” OR for rotating shift workers with ≤7 years’ shift work exposure was 1.44 (95% CI: 1.10–1.87); for 7.1–22 years, 1.14 (95% CI: 0.86–1.52); for 22.1–34 years, 0.93 (95% CI: 0.70–1.23); and for > 34 years, 1.30 (95% CI: 0.97–1.74). The Parent et al. study, discussed above, also found a significantly increased risk of prostate cancer.²⁸¹ A retrospective cohort study by Schwartzbaum et al., which included job sectors with 40% rotating shift workers, did not identify a statistically significant elevated risk, reporting an SIR of 1.04 for shift work in 1970 (CI: 0.99–1.10) and 1.02 for shift work in 1960 and 1970 (CI: 0.95–1.10).²⁵⁷

Flynn‐Evans et al. reported a strong positive association with shift work and elevated prostate‐specific antigen (PSA) level, supporting the hypotheses that sleep or circadian disruption is associated with elevated PSA and that shift‐working men are at some increased risk of developing prostate cancer.²⁸⁴ Shift work and PSA test data was obtained as part of the National Health and Nutrition Examination Survey (NHANES) study. Data was combined from three NHANES surveys (2005–2010) to obtain current work schedule among employed men aged 40–65 years with no prior history of cancer (except nonmelanoma skin cancer). Men who reported working regular night shifts or rotating shifts were considered shift workers. Using multivariable logistic regression models, PSA levels were compared among current shift workers and nonshift workers. Statistical analysis revealed a statistically significant age‐adjusted association between current shift work and elevated PSA ≥ 4.0 ng/mL (odds ratio = 2.48, 95% CI: 1.08–5.70; p = 0.03). The confounder‐adjusted odds ratio was 2.62 (95% CI: 1.16–5.95; p = 0.02). The confounder‐adjusted odds ratio for those with total PSA ≥ 4.0 ng/mL and free PSA ≤ 25% was 3.13 (95% CI: 1.38–7.09; p = 0.01).

TREATMENT (COUNTERMEASURES)

In order for individual coping strategies to be effective, families must be involved. The shift worker needs to be aware of the toll that the shift work schedules may take on the family, and the family to be aware of the effect of the shift work schedule on the worker. The provision of educational programs for both the worker and family is essential for employees to successfully cope with shift work schedules in terms of performance at work, responsibilities at home, and health considerations. Educational materials addressing shift work issues, including countermeasures published in laymen’s terms, are available which will assist employers and employees in this endeavor.^81,350,351

MEDICAL SURVEILLANCE

Although there are no US federally mandated requirements for medical evaluations for night work exposure, the International Labor Organization (ILO) 1990 Convention (No. 171) includes provisions for a health assessment for workers before beginning their night work and health assessments of night workers at regular intervals as well as for work‐related problems that may be secondary to the work schedule.³⁹⁶ In addition, the European Directive No. 93/104/EC, “Concerning certain aspects of the organization of working time,” also considers it a right of workers to have a free health assessment before beginning their first assignment to the night shift.³⁹⁷

Recommendations for medical evaluations of workers before they begin night work assignments have been made by occupational medicine practitioners and by chronobiologists who have studied health effects of shift work. Identification of individual characteristics that are associated with poor tolerance of night work is recommended, not with the goal of disqualifying workers for night work but with the recognition that, for some, night work may medically not be advisable. In most situations, the preplacement examination will provide an opportunity to make susceptible workers aware of their individual risks and plan appropriate medical supervision and develop coping strategies.^{15,96,97,173,398,399}

The frequency of medical surveillance examinations is somewhat arbitrary. However, recommendations are consistent in advising evaluation during the first few months after beginning shift work and at regular but less frequent intervals, depending on the work schedule and the age of the worker. A reasonable schedule has been outlined by Harma which includes the following: the first follow‐up health check scheduled no later than 2 months after night/shift work has begun; subsequently, for workers between 25 and 45 years of age, 3–5 year intervals; for those under 25 or over 45 years of age, 2‐year intervals; and for those over 60, 1‐year intervals are advised.¹⁶⁹ More frequent evaluations may be needed for individuals with underlying conditions that may be aggravated by shift work. Costa has made more general recommendations for the first medical surveillance health check to be during the first year of shift or night work, for those under 45 years successive evaluations to be at least every 3 years, and for those over 45 successive checkups to be every 2 years.⁴⁰⁰ Ongoing medical surveillance programs, including periodic medical screening examinations and appropriate laboratory testing, have been recommended for rotating and permanent night workers. In addition, follow‐up evaluations of day workers who have left shift work for medical reasons have also been advised.^15,173

Common conditions that may be exacerbated by shift work have already been reviewed in this chapter. Smolensky et al. have recently reviewed numerous other medical and psychiatric conditions exhibiting circadian fluctuation in symptoms and response to external temporal triggers and pharmacological treatments.²⁸⁹

Potential contraindications to working shift work involving night shifts are summarized in Table 10.1. For example, due to the recognized increase in likelihood of seizure events in epileptic individuals associated with circadian rhythm disruption and sleep deprivation, clearance from the neurologist managing a potential shift worker with epilepsy before initial assignment to a night work schedule is a reasonable requirement. For asthmatics, medical surveillance with involvement of the treating physician is essential for monitoring any changes in frequency of bronchoconstriction and response to prescribed medications. Both rotating and permanent night workers with diabetes should be monitored for changes in response to dietary and pharmacological management of glucose control. Circadian disruption in glucose tolerance has been noted. Studies of permanent night workers have shown only partial adjustment of glucose and insulin rhythms after 2 years of regular night work.⁴⁰¹ Sleep restriction can also lower glucose tolerance.^402,403 Changes in the timing and quality of meals and metabolism related to working nights also necessitate monitoring for increased levels of undesirable triglycerides and lipoproteins.

Based on the available epidemiological evidence, medical conditions exacerbated by shift work may be absolute or relative contraindications to shift work.^96,173,402 Identification of individual characteristics that are associated with poor tolerance of night work is recommended not with the goal of disqualifying workers for night shifts but providing appropriate medical counseling and medical surveillance for those for whom night work may not be medically advisable. Depending on the severity of the condition and stability of treatment needed, the individual’s overall tolerance to shift work, and the particular shift work schedule involved, temporary or permanent restriction from night work may be in the best medical interest of the worker. Occupational health physicians should remember that shift work intolerance is a manifestation of complex medical and psychosocial interactions and individual worker responses will vary in terms of severity and timing of onset of clinical signs and symptoms.⁴⁰³

While medical surveillance programs for shift workers are important for early detection of shift work‐related health problems, Kogi has pointed out that medical surveillance examinations alone cannot adequately meet the health needs of shift workers.⁹³ The medical surveillance program for shift workers should include educational/counseling opportunities related to the assessment and optimization of shift work coping strategies.^169,173 Joint efforts by occupational health and safety teams, in conjunction with working with supervisors and workers, are necessary to provide necessary preventive medicine programs and address scheduling considerations. Adjustments may be needed in medical surveillance schedules for chemical exposures to account for quick turnover times or extended hours of work.

PREVENTION AND ADMINISTRATIVE CONTROLS

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