Birth weight

Seasonal factors were repeatedly shown to influence prenatal human development and affect birth characteristics. The seasonality of birth weight has been reported across countries. For example, in the Chodick et al. ^{Reference Chodick, Flash, Deoitch and Shalev11} review of global patterns, individuals born during the winter period tended to have low birth weight and those born during the summer period tended to have high birth weight in the high- and low-latitude regions, while the opposite association was found in the midlatitude regions. In a more recent study by Day et al. ^{Reference Day, Forouhi, Ong and Perry12}, summer-born infants also had higher birth weights compared to those born in other seasons in the UK population. In comparing the extreme differences between birth months, those individuals who were born in February had 1.23 times higher odds to have low birth weight than those who were born in September (p < 0.001). An association between the month of birth and future anthropometric measures has been reported in a recent systematic review by Hemati et al. ^{Reference Hemati, Keikha and Riahi13} More specifically, those persons who were born in winter months tended to have higher weight and body mass index (BMI) in childhood across countries. Interestingly, this association is opposite to that reported by Chodick et al. ^{Reference Chodick, Flash, Deoitch and Shalev11} for the birth weight. The catch-up growth phenomenon (i.e. a development mode when those individuals who are born with low birth weight subsequently exhibit accelerated weight gain in infancy^{Reference Martin, Connelly, Bland and Reilly14}) could be one potential explanation for this inconsistency.

Life cycle events

Associations between season of birth and age at female life cycle events such as menarche and menopause have been also demonstrated. In determining whether month of birth can affect the maturation rate of Polish females, girls born in summer were found to have the first menstruation at younger ages than girls born in other seasons.^{Reference Kliś, Jarzebak and Borowska-Strugińska15} Remarkably, no association between birth season and age at menarche in Central India, where differences between seasons in temperature and photoperiod are very small, has been observed.^{Reference Liczbińska, Gautam, Dubey, Ahirwar, Chaurasia and Kosińska16} In China, more early ages of both menarche and menopause were revealed in women born in spring compared to ones born in other seasons.^{Reference Si, Meng and Lyu17} In Italy, menopause was found to occur earlier in women born in the spring than in the autumn.^{Reference Cagnacci, Pansini and Bacchi-Modena18} The earliest menopause has been observed in women born in March and the latest one in women born in October.

Adult physiological characteristics and health status

Since birth weight is, in turn, associated with adult-life health outcomes,^{Reference Vaiserman19} it is not surprising that seasonality of birth is seen for many human chronic disorders, including the later life-onset ones. Association between season of birth and human health status has been reported repeatedly. An important point in the context reviewed is that seasonality of birth has been found not only for childhood diseases, but also for age-related late-onset disorders, indicating that season-of-birth effects can persist lifelong, thereby contributing to aging-associated processes.

In a recent research where a health deficit indices have been calculated for 21 European countries included in the Survey of Health, Aging, and Retirement in Europe (SHARE) dataset, elderly European men were shown to age faster if they were born in spring and summer compared to those born in autumn.^{Reference Abeliansky and Strulik20} At any given age, spring- and summer-born persons developed about 3.5% more health deficits than autumn-born individuals. These differences were not mediated by potentially confounding factors such as body size or education level. Interestingly, the birth season played a nonsignificant role for old-age health in a subsample of Southern Europe countries. The authors assumed that this might be due to the smaller seasonal variation in sunlight in these regions. In a subsample of Northern Europe countries, in contrast, the season of birth was shown to significantly affect most of the indices calculated. At any age, spring-born elderly Northern European men had developed about 8.7% more health deficits than those born in autumn. The estimated aging rates were also associated with birth season in this research.

Findings suggesting that season of birth can affect later life characteristics have been also obtained in other recent population-based large (n = 502,536) study conducted using the UK Biobank cohort (Didikoglu et al., 2019, 2020).^{Reference Didikoglu, Maharani, Payton, Pendleton and Canal21,Reference Didikoglu, Canal, Pendleton and Payton22} In this research, evidence was obtained that season of birth can affect the basal metabolic rate, which is regarded as one of the important determinants of the aging rate (Frisard and Ravussin, 2006).^{Reference Frisard and Ravussin23} More specifically, individuals who were born in July had a higher basal metabolic rate (Fig. 1b) and frequency of having allergy later in life (Fig. 1c) compared to those born in December.^{Reference Didikoglu, Canal, Pendleton and Payton22} Moreover, findings from this study indicated that season of birth may affect growth parameters (Fig. 1a).

Fig. 1. Month of birth and (a) frequency of being taller at the age of 10, (b) basal metabolic rate, and (c) frequency of having allergy in the UK Biobank cohort. Red scatter plots show prevalence in (a) and (c) and mean ± standard error in (b). Reproduced from the article by Didikoglu et al. ^{Reference Didikoglu, Canal, Pendleton and Payton22} with permission of the publisher. © 2020 Wiley Periodicals, Inc.

Sleep characteristics

Season of birth was also shown to program adult-life sleep characteristics. In particular, spring and summer birth seasons were found to be associated with a higher insomnia rate compared to autumn and winter birth seasons. It seems important because sleep pattern can significantly influence the health status and ultimately affect longevity. In particular, evening-oriented sleep timing preferences (chronotype) have been shown to be associated with a higher risk of type 2 diabetes, obesity, cardiovascular diseases, psychiatric disorders, and also with increased mortality than the morning-oriented ones.^{Reference Knutson and von Schantz24} Importantly, the adult chronotype was shown to be differently programmed depending on the season of birth.^{Reference Didikoglu, Maharani, Payton, Pendleton and Canal21}

Neurological disorders

In the context reviewed here, the seasonality of birth has been most thoroughly studied for its role in developing schizophrenia. Schizophrenia is obviously not an age-related disease (its symptoms usually begin between ages 16 and 30), although it shortens life expectancy by up to 15–20 years, primarily owing to the high risk of cardiovascular disease and obesity likely related to the lack of physical activity, unbalanced diet, smoking, and substance abuse.^{Reference Ringen, Engh, Birkenaes, Dieset and Andreassen27} A significant excess of winter–spring births and a decrease of summer births have been observed consistently among schizophrenia patients. Such a pattern was described in more than 200 papers to date.^{Reference Demler28} Recently, in studying whether effects of season of birth can be confounded by gene-environment interactions, it has been demonstrated in the UK Biobank cohort (n = 136,538) that season-of-birth effect in schizophrenia does not depend on genetic factors and reflects a true pathogenic effect of early life environmental exposures.^{Reference Escott-Price, Smith and Kendall29} Among the factors most likely contributing to this season-of-birth pattern, there are nutrition, ambient temperature, sperm quality, and also exposures to infections, maternal hormones, and external toxins.^{Reference Tochigi, Okazaki, Kato and Sasaki30} Birth seasonality was also found for some other neuropsychiatric disorders. Seasonal variation in autism spectrum disorder births with modestly increased risk for children born in the fall and decreased risk for children born in the spring was observed in Finland and Sweden.^{Reference Lee, Gross and Francis31}

The effects of month of birth on adult depression were also demonstrated. In the US, a significant association between month of birth and subsequent depression risk, with spring and summer month births corresponding to significantly more depression, has been reported.^{Reference Schnittker32} Remarkably, this association was strong in earlier cohorts born at the beginning of the 20th century, but it has largely disappeared in the 1940 birth cohort when living conditions have improved and seasonal variation in the food supply has decreased. The consistent seasonal pattern was also observed in epilepsy, with an excess of patients born in December and January and a deficit of those born in September, compared to the general population.^{Reference Procopio, Marriott and Williams33}

Neurodegenerative diseases

An association between the season of birth and the risk for Alzheimer’s disease (AD), a neurodegenerative disorder which is the most common cause of aging-related dementia worldwide, was investigated in several studies. A substantial excess of first-quarter births among AD patients has been revealed compared to the expected general population birth rates in the UK.^{Reference Philpot, Rottenstein, Burns and Der37} Similar season-of-birth pattern in AD was subsequently found in California.^{Reference Frazee, Russell and Chicota38} In Québec, a significant deficit of AD births was observed in May.^{Reference Vézina, Houde and Charbonneau39} In Chinese elderly aged 60 and above, the risk for dementia was shown to be substantially lower among those born in winter than that for the summer-born.^{Reference Ding, He, Song and Zheng40} These findings, however, have not been confirmed in studies conducted in other Northern Hemisphere countries, where no evidence for seasonality of birth in AD patients was found.^{Reference Dysken, Kuskowski and Skare41–Reference Tolppanen, Ahonen and Koponen44} No seasonal pattern was also observed in the Southern Hemisphere (Australia) (Henderson et al., 1991).^{Reference Henderson, Korten and Jorm45}

The association between season of birth and the risk of developing Parkinson’s disease (PD), the second most common neurodegenerative disease affecting 1%–2% of people over 60 years of age,^{Reference de Lau and Breteler46} was also evaluated in several studies. The reported findings are, however, modest and inconsistent. For example, a 30% higher risk of PD associated with spring versus winter birth was observed in the US study.^{Reference Gardener, Gao and Chen47} This association was, however, modest and nonsignificant only. No evidence for the systematic season-of-birth variations for PD incidence was found in the Postuma et al. ^{Reference Postuma, Wolfson and Rajput48} and Palladino et al. ^{Reference Palladino, Moccia and De Pascale49} studies. The sample sizes in most studies aimed at investigating seasonality of birth in AD and PD were, however, small, so findings from these studies are rather inconclusive.

Evidence for seasonality of birth was also obtained for the amyotrophic lateral sclerosis (ALS), a neurodegenerative disease predominantly affecting upper and lower motor neurons, resulting in progressive paralysis and death from respiratory failure. The peak age of onset of this disease is 55–70 years.^{Reference Martin, Al Khleifat and Al-Chalabi50} Among the Swiss ALS patients, an excess of births was found in the spring months (March–May).^{Reference Ajdacic-Gross, Wang and Gutzwiller51} In Sweden, individuals born from October through December were at 11% increased risk of ALS compared to those born from April to June.^{Reference Fang, Valdimarsdóttir and Bellocco52} In Australia, ALS birth rates were shown to increase between late summer and early winter, and to decrease between midwinter and early summer.^{Reference Pamphlett and Fang53}

Cardiometabolic disorders

Skewed season-of-birth patterns have been found for various cardiometabolic pathological conditions. Prevalence of obesity was found to be greater among those men who were born in Hertfordshire (UK) in January–June than among those born in July–December.^{Reference Phillips and Young54} In Canada, the proportion of class III obese persons was higher among adult individuals who were born throughout winter/spring.^{Reference Wattie, Ardern and Baker55}

Seasonality of birth for patients with type 1 diabetes has been reported repeatedly around the world.^{Reference Laron, Lewy and Wilderman56} In contrast to the well-established seasonality of birth in childhood diabetes persons, the birth seasonality in adult type 2 diabetic patients has been detected in a few studies only. Most of these studies were small sample sized and findings were inconsistent. For example, seasonal birth patterns were found for 155 type 2 diabetic adolescent African-Americans^{Reference Grover, Lipton and Sclove57} and for 282 adult patients in the Netherlands.^{Reference Jongbloet, van Soestbergen and van der Veen58} By now, the most convincing evidence for seasonality of birth in type 2 diabetes patients was obtained in the Ukrainian population.^{Reference Vaiserman, Khalangot and Carstensen59} The peak prevalence of type 2 diabetes has been revealed in both men and women born in April and the lowest one was observed in women born in December and in men born in November. Remarkably, in the cohort born during 1930–1939 years, the highest monthly prevalence of type 2 diabetes was observed among individuals born in April 1934, i.e. about 9 months after mortality caused by the Ukraine famine of 1932–1933 peaked^{Reference Lumey, Khalangot and Vaiserman60} (see also Fig. 3 based on our unpublished data). This suggests that the long-term effects of early life seasonal factors may be more pronounced if early human development occurs in severe conditions such as natural or man-made disasters. In another large prospective study conducted in China, both male and female participants born in summer had a lower risk of type 2 diabetes in comparison with those born during other seasons.^{Reference Si, Yu and Guo61} No evidence for seasonality of birth, however, was obtained in adult patients with type 2 diabetes in Denmark.^{Reference Jensen, Zimmermann and Gamborg62}

Fig. 3. Prevalence of type 2 diabetes in Ukraine cohort born during 1930–1939 years, according to month and year of birth. Points indicate monthly prevalence estimates.

Seasonal variations in mean systolic blood pressure, with a minimum level in adults born in spring and summer and maximum level in those born in autumn and winter, have been observed in Spanish men aged 45–64 years.^{Reference Banegas, Rodríguez-Artalejo and de la Cruz63} In China, those persons who were born in winter were shown to have an increased risk of coronary artery disease in adult life compared to those born in spring.^{Reference Zhang, Zhao and Yang64} In a large US sample (n = 1,169,599), strong season-of-birth patterns were found for lifelong risks of the cardiovascular condition such as essential hypertension, coronary arteriosclerosis, cardiomyopathy, atrial fibrillation, chronic myocardial ischemia, and pre-infarction syndrome.^{Reference Li, Boland, Miotto, Tatonetti and Dudley65} The risks for these cardiovascular adverse events were shown to be highest in those individuals who are born during the late winter/early spring. In a Canadian province, Ontario, higher risks of hypertension and coronary heart disease were found in those persons who were born in January and April.^{Reference Poltavskiy, Spence, Kim and Bang66} In the UK, women born during the winter had a significantly higher prevalence of coronary heart disease, dyslipidemia, insulin resistance, and poor lung function than those born during other seasons.^{Reference Lawlor, Davey Smith, Mitchell and Ebrahim67}

Cancer

Seasonality of birth has been repeatedly reported for different types of tumors. In Northern England, significant sinusoidal variation in month of birth was observed for childhood acute lymphoblastic leukemia (peak in March), acute non-lymphocytic leukemia (peak in September), and also astrocytoma and osteosarcoma (for both, peaks in October). Such sinusoidal month-of-birth patterns were found for all lymphomas (peak in March) and Hodgkin’s lymphoma (peak in January) in girls.^{Reference Basta, James, Craft and McNally68} In a subsequent UK study, birth peaks for patients with gliomas (except for astrocytoma and ependymoma) were observed in May and November.^{Reference van Laar, Kinsey, Picton and Feltbower69} A significant February month-of-birth peak was also shown for childhood leukemia in another UK study.^{Reference Higgins, dos-Santos-Silva, Stiller and Swerdlow70} In Sweden, an increased risk of non-Hodgkin (but not Hodgkin) lymphoma was revealed in children and young adults born in spring or summer.^{Reference Crump, Sundquist, Sieh, Winkleby and Sundquist71}

In a meta-analysis by Georgakis et al.,^{Reference Georgakis, Ntinopoulou, Chatzopoulou and Petridou72} the risk for occurrence of central nervous system tumors or tumor subtypes was significantly associated with birth season in 8 of the 10 included studies in children and in 4 of the 8 studies in adults, with a clustering of births mainly in autumn and winter months. Seasonality of birth was also observed for other cancer types such as skin cancer,^{Reference La Rosa, Liso, Bianconi, Duca and Stracci73} colorectal cancer,^{Reference Francis, Curtis, Noble, Cortina-Borja and Salib74} lung cancer,^{Reference Hao, Yan, Ke, Wang and He75} and breast cancer.^{Reference Yuen, Ekbom, Trichopoulos, Hsieh and Adami76} Most of these studies, however, were conducted with small size samples, so, these findings are rather inconclusive and show only correlation but no causal relationships.

Nutrition

Nutrition is one of the most important factors that influence these processes.^{Reference Vaiserman2} Currently, the impact of this factor is rather low in developed countries depending only slightly on seasonal factors owing to the year-round availability of fresh produce from a global market, but it is certainly high in low-income and primarily agricultural societies. In these populations, babies born during periods of seasonal malnutrition can develop adaptive metabolic responses aimed at maximizing the metabolic efficiency in order to optimize the use and storage of nutrients.^{Reference Zhu, Cao and Li99} Such developmental adaptation can lead to a reallocation of resources aimed at better protection of brain at the expense of other fetal organs, such as adipose tissue, liver, muscles, and pancreas.^{Reference Kim100} These processes may be mediated by impaired development of hypothalamic appetite-regulating circuits and feeding behavior.^{Reference Zeltser101} As a consequence, long-lasting alterations can arise in glucose–insulin metabolism. Such metabolic changes, including lowered insulin secretion and insulin resistance, may result in an improved capacity to store fat throughout adult life. If the prenatal development occurs under poor climatic conditions and seasonal malnutrition, while postnatal development occurs during the abundant seasonal supply of nutrition, such a developmental scenario can lead to catch-up postnatal growth, and consequently, to long-term adverse health outcomes.

Infection exposure

Infection exposure can be one more factor potentially influencing processes involved in developmental programming. It is firmly established that adult immune responses can be programmed by neonatal exposure to certain immune-modulating stimuli throughout the process of priming of the antibody-forming system.^{Reference Spencer, Galic and Pittman102} The process of neonatal maturation of the immune system seems to be very important in determining lifelong health status since chronic inflammation is well known to contribute to most chronic pathologies such as cardiometabolic disorders, neurodegeneration, and cancer.^{Reference Rajendran, Chen and Chen103} It seems to be important in the context discussed because patterns of infectious exposures are definitely different in various seasons. Indeed, in the Northern Hemisphere, late summer or early autumn seasonality exists in enteroviral infections and predominantly wintertime seasonality exists in viral respiratory infections.^{Reference Fisman104} So, neonatal exposure to differing seasonal infectious patterns may likely result in differing disease profiles in adult life.

Gut microbiota profile

Environmental factors acting during early life development also contribute to establishment of the gut microbiota profile (the totality of microorganisms inhabiting the intestine).^{Reference Vandenplas, Carnielli and Ksiazyk105} It is certainly an important point to consider with respect to the early life seasonal programming, since microbiota composition is known to establish early in life (a “microbial programming” phenomenon^{Reference Koleva, Kim, Scott and Kozyrskyj106}) and then remains fairly unchanged and determines health status throughout the whole life course.^{Reference Codagnone, Spichak and O’Mahony107,Reference Stinson108} Remarkably, the establishment of the adult-like profile of the gut microbiota is known to continue from the periconception period up to 2 years of age^{Reference Butel, Waligora-Dupriet and Wydau-Dematteis109} and thus, it largely coincides with a critical period of human developmental plasticity. Nutritional factors certainly play a crucial role in these processes,^{Reference Dahl and Rivero Mendoza110} although other environmental exposures (day length, infections, environmental toxicants and pollutants, etc.),^{Reference Karl, Hatch and Arcidiacono111} perinatal vitamin D levels^{Reference McGrath112} and lifestyle factors (alcohol and drug intake, smoking, physical activity, etc.)^{Reference Flandroy, Poutahidis and Berg113} can be also of great importance. All these factors significantly fluctuate with the season changes, especially in regions with strong climatic seasonality. Substantial seasonal differences in the human microbiota composition have been observed in some studies. Most evidence for such differences was obtained in autochthonous hunter-gatherer communities like the Hadza hunter-gatherers of Tanzania^{Reference Smits, Leach and Sonnenburg114} or in isolated ethnoreligious groups such as Hutterites.^{Reference Davenport, Mizrahi-Man and Michelini115} Evidence for seasonal microbiome shifts was also found on the population level in the US,^{Reference Korownyk, Liu and Garrison116} and also in samples from general populations in Mongolia^{Reference Zhang, Guo and Lim117} and Ukraine.^{Reference Koliada, Moseiko and Romanenko118}

Epigenetic processes

The effects of all the above factors can be mediated by epigenetic processes (including DNA methylation, histone modifications, chromatin remodeling, and noncoding regulatory RNAs) known to play a central role in the Developmental Origins of Health and Disease (DOHaD) phenomenon.^{Reference Safi-Stibler and Gabory119} The persistent epigenetic alterations triggered by certain seasonal cues during early development may, due to predictive adaptive response, have adaptive significance in postnatal development, but they might predispose to chronic disorders later in life. The evidence for an association among season of birth and profiles of DNA methylation in adult life has been obtained in the study by Lockett et al. ^{Reference Lockett, Soto-Ramírez and Ray120} In this epigenome-wide association study (EWAS) conducted in 367 participants aged 18 from the UK, methylation at 92 CpG dinucleotides has been found to be associated with the season of birth. Four of the associations observed have been replicated in an independent series of 207 children aged 8 from the Netherlands. Season-of-birth-associated methylation patterns were enriched in gene pathways involved in cell cycle, development, and apoptosis. Remarkably, these season-related methylation profiles were nearly absent in newborns, but they were evident in 18-year-old participants. These findings, however, have not been confirmed in a subsequent study by Dugué et al. ^{Reference Dugué, Geurts and Milne121} attempted to replicate 92 associations revealed by Lockett et al. ^{Reference Lockett, Soto-Ramírez and Ray120} using 2774 adults aged 40–70 residing in Southern Hemisphere (Australia). The difference between analytical approaches applied was proposed as a potential explanation for the inconsistency between these studies.^{Reference Lockett, Zhang, Karmaus and Holloway122} The authors agreed that more in-depth research is required to determine the role of epigenetic mechanisms in season-of-birth programming of adult-life disease.