Climate factors and gestational diabetes mellitus risk – a systematic review

Background Current and projected increases in global temperatures and extreme climate events have led to heightened interest in the impact of climate factors (i.e. ambient temperature, season/seasonality, and humidity) on human health. There is growing evidence that climate factors may impact metabolic function, including insulin sensitivity. Gestational diabetes mellitus (GDM) is a common pregnancy complication, with an estimated global prevalence of up to 14%. While lifestyle and genetic risk factors for GDM are well established, environmental factors may also contribute to GDM risk. Previous reviews have summarized the growing evidence of environmental risk factors for GDM including endocrine disrupting chemicals and ambient air pollution. However, studies of the effects of climate factors on GDM risk have not been systematically evaluated. Therefore, we conducted a systematic review to summarize and evaluate the current literature on the associations of climate factors with GDM risk. Methods We conducted systematic searches in PubMed and EMBASE databases for original research articles on associations of climate factors (i.e. ambient temperature, season/seasonality, and humidity) with GDM and/or related glycemic outcomes for all publication dates through September 20th, 2020. Results Our search identified 16 articles on the associations of ambient temperature and/or season with GDM and maternal glycemic outcomes during pregnancy, which were included in this review. Despite inconsistencies in exposure and outcome assessment, we found consistent evidence of a seasonal effect on GDM risk, with higher prevalence of GDM and higher pregnancy glucose levels in summer months. We found suggestive evidence of an association between higher ambient temperature and elevated glucose levels from GDM screening tests. Conclusion Climate factors may be associated with GDM risk. However, further research is needed to evaluate these associations and to elucidate the specific mechanisms involved.


Background
Increased awareness of global climate change has led to heightened interest in the impact of climatic factors on human health [1]. Historically, much of the research on the human health effects of climate change focused on extreme temperature events and infectious diseases [2][3][4]. However, there is growing evidence indicating that climate factors (i.e. season, ambient temperature, and humidity) may alter metabolic function, including insulin sensitivity [1,5]. The insulin resistant state of pregnancy may be particularly sensitive to climate factors, which could impact the body's metabolism, increasing gestational diabetes (GDM) risk. Thus, it is important to review the state of the literature on climate factors and GDM.
GDM, defined as glucose intolerance that is less than overt diabetes first occurring during pregnancy, is one of the most common pregnancy complications [6]. The prevalence of GDM has increased over the past 20 years and is currently estimated to affect up to 14% of pregnancies worldwide [7], though estimates vary based on the population and diagnostic criteria [6,[8][9][10]. GDM is associated with both short-and long-term adverse pregnancy, maternal and neonatal outcomes, including preeclampsia, cesarean section, preterm birth, macrosomia and neonatal hypoglycemia [7,11]. Mothers are at increased risk of developing type 2 diabetes [12][13][14] and cardiovascular disease [15,16] in later life. Recent studies demonstrate that offspring may be at increased risk of higher adiposity and abnormal glucose metabolism in mid-childhood [6,11,17].
Lifestyle and genetic factors such as diet, body mass index (BMI), physical activity, parity, age, and family history may not fully account for GDM risk [18][19][20]. Recent reviews have examined the potential role of environmental exposures including endocrine disrupting chemicals [21,22], toxic metals [21], and air pollution [23,24] in the development of GDM. However, climate factors may also play a role in GDM risk [25][26][27]. With the current and projected rise in global surface temperatures and increased frequency of extreme weather events [28], we aim to review the role of climate factors on this significant pregnancy complication.

Rationale for climate factors as a risk factor for gestational diabetes
Previous meta-analyses and primary research studies have found associations between ambient temperature, season, and humidity with type 1 and/or type 2 diabetes [29][30][31]. Potential physiologic explanations for these associations include several different mechanisms, which have also been discussed as possible mechanisms for associations between climate factors and GDM. Cold ambient temperature may cause activation of brown adipose tissue leading to improved insulin sensitivity [32]. On the other hand, high ambient temperatures and relative humidity could cause dehydration and result in hemoconcentration during the summer, leading to spurious increased blood glucose concentrations [33]. Seasonal fluctuations in serum vitamin D levels could also contribute to the observed association between season and type 2 diabetes risk [34]. In fact, vitamin D may aid in glucose regulation by increasing insulin secretion and sensitivity, aiding in beta-cell function, and decreasing systemic inflammation [35]. Alternatively, changes in diet and physical activity levels related to ambient temperature, season, and humidity may contribute to observed seasonal fluctuations in diabetes risk.
A growing number of studies have evaluated climate factors as they relate to GDM; however, these studies have not been systematically reviewed. Therefore, we conducted a systematic review of epidemiological studies evaluating the associations of climate factors with GDM and glycemic outcomes during pregnancy, to assess how climate factors were associated with the continuum of glucose intolerance. We evaluated epidemiological studies identified in PubMed and EMBASE, summarized the state of the literature, identified research gaps, and suggested key next steps for future studies of the influence of climate factors on GDM. To our knowledge, this is the first systematic review of climate factors as they relate to GDM.

Search strategy
We conducted a systematic literature search in PubMed and EMBASE databases for original research articles for all publication dates through September 20th, 2020, based on the guidelines of the PRISMA statement [36]. We considered original epidemiologic studies in pregnant women written in the English language with available full-text. Studies were included in the review if they related one or more climate factors to one or more glucose-related outcomes during pregnancy. Maternal glycemic outcomes included gestational glucose levels, markers of insulin sensitivity, beta cell function, categories of glucose tolerance derived from glucose challenge test (GCT) and/or oral glucose challenge test (OGTT) screenings (e.g. abnormal GCT or OGTT values), or GDM diagnosis.
In PubMed we searched using the following combination of Medical Subject Headings (MeSH) terms and freetext title or abstract terms (tiab): ( Articles were excluded if they were not available in English, were duplicates, conducted in animals, had irrelevant exposures, or irrelevant outcomes, were irrelevant study types (i.e. case-reports, reviews, metaanalyses), were not in pregnant women, or the study outcomes occurred outside of pregnancy (e.g. postpartum glucose levels) (see Fig. 1). In addition to our database searches, we manually checked the listed references of identified articles and relevant reviews for additional articles that we may have missed in our search in order to maximize the likelihood of identifying all relevant articles.

Results
Our systematic search strategy returned 847 articles, 229 from PubMed and 618 from EMBASE (Fig. 1). We identified one additional article by reviewing article reference lists. After excluding duplicate articles (n = 83), we excluded an additional 734 articles through title and abstract screening. We included 31 articles in our full text review, and excluded an additional 15 based on our inclusion/exclusion criteria (non-pregnant population: n = 3, wrong exposure: n = 7, wrong outcome: n = 5). We did not find any articles on humidity and GDM or maternal glycemic outcomes. Additionally, our search did not identify any articles that investigated other maternal or neonatal short and long-term health outcomes as consequences of GDM and/or glycemic outcomes during pregnancy associated with climate factors. In total, we included 16 articles on the associations of ambient temperature and/or season with GDM (Table 2) and maternal glycemic outcomes (Table 3) during pregnancy in this review.

Glucose related study outcomes
There was significant heterogeneity in method of GDM screening/diagnosis across the included studies. Table 1 summarizes the GDM screening methods and diagnostic criteria used by the included studies. The majority of screening methods fall into two categories: (1) a one-step approach, where GDM is diagnosed based on results of a single fasting oral glucose tolerance test (OGTT), or (2) a two-step approach, where women are pre-screened, generally with a non-fasting glucose challenge test (GCT), and only women with abnormal GCT glucose levels (e.g. > 140 mg/dL) receive a subsequent OGTT to diagnose GDM. The International Association of Diabetes in Pregnancy Study Group (IADPSG) criteria follows a one-step approach using a fasting 2-h 75-g OGTT with relatively low glucose level thresholds, requiring only one abnormal value for a positive test. Many countries and organizations, including the WHO, have adopted the IADPSG criteria. Conversely, in the United States, GDM is generally screened and diagnosed using a more conservative twostep approach, consisting of [1] a non-fasting 50-g GCT, followed by [2] a fasting 3-h 100-g OGTT, with higher glucose level thresholds than the IADPSG criteria, requiring two abnormal values for a positive test [8]. Differences in GDM screening and diagnostic criteria are important factors to consider when comparing study results below. In addition to GDM diagnosis, we included studies with maternal glycemic outcomes such as additional categories of glucose intolerance based on GCT and/or OGTT screening results [e.g. abnormal GCT (> 140 mg/ dL), or hyperglycemia in pregnancy]. As with GDM, the definitions and thresholds used in these classifications varied across studies. Multiple studies assessed glucose levels, analyzed as continuous outcomes, usually from GCT and/or OGTT screenings. Two studies also assessed various markers of insulin resistance (IR) [e.g. Matsuda index and homeostasis model assessment of insulin (HOMA-IR, HOMA S)] and beta cell function [e.g. insulin sensitivity index 2 (ISSI-2), insulinogenic index (IGI)/HOMA-IR, and HOMA B].
Timing of outcome assessment also varied by study (Tables 2 & 3), with GDM screening and glycemic outcome measurement typically occurring between 24 and 28 weeks gestation, but as early as 16-18 weeks in some studies [42]. Differences in outcome assessment could also impact observed associations with climate factors as well as variability across studies.

Climate factors & GDM
Seasonality of GDM Twelve studies evaluated associations between season and GDM ( Table 2) [25-27, 37-40, 42, 44-46, 54]. Despite differences in geographical location and seasonal definitions, the majority of studies consistently reported higher incidence or prevalence of GDM diagnosis in the summer and lower incidence or prevalence of GDM diagnosis in the winter [21,25,27,37,38,42,45], while only three studies, two Australian studies (n = 2749 [26]; n = 2120 [40]) and one in the United Kingdom (n = 1074 [39]) reported no association between season of screening and GDM. A populationbased study of 4852 pregnancies located in Plymouth, UK, reported higher prevalence of GDM in the spring (2.3, 95% CI: 1.5, 3.2) rather than the summer but consistently lower GDM prevalence in the winter (1.4, 95% CI: 0.8, 2.3) compared to other seasons, although the differences were not statistically significant [46]. In a large South Australian study (n = 60,306), incidence of GDM was significantly associated with season of estimated date of conception, where adjusted incidence of GDM was highest in pregnancies with estimated conception dates in August (6.6%) (Australian winter), with women entering second trimester-the time period of increasing insulin resistance-during the months of increasing temperature [44]. The lowest prevalence of GDM was among pregnancies with estimated conception dates in January (5.4%) (Australian summer) [44], with women entering second trimester during the months of decreasing temperatures.
Seasonality of glycemic outcomes As with GDM, seasonal variations in gestational glucose levels have been reported as early as 1995 [26]. Eleven studies assessed the relationship between seasonality and maternal glycemic outcomes (Table 3) [25-27, 33, 37-40, 42, 45, 46]. Associations of season with blood glucose levels have been somewhat less consistent across studies compared to those with GDM, but studies have generally reported higher glucose levels in the summer. Two UK-based studies, one population-based study in Plymouth, UK (n = 4852) and one smaller cohort in Cambridge, UK (n = 1074) reported no associations of month or season of screening with glucose levels from fasting 2-h 75-g OGTTs [39,46]. A much larger Israeli retrospective cohort study (n = 59,882) also reported no associations of season of screening with glucose levels from a fasting 3h 100-g OGTT [33]. However, the authors did observe lower glucose levels from a non-fasting 50-g GCT in winter and higher GCT glucose levels in summer, as well as significantly higher odds of elevated GCT glucose levels (> 140 mg/dL) in summer compared to winter (OR 1.58, 95% CI: 1.51, 1.66) [33]. Five studies in Italy (5473) [42], Greece (n = 7618) [27], Spain (n = 2366) [38], and two in Australia (n = 7343, [45]; n = 2120, [40]), observed higher 1 h and 2 h glucose levels from 2-h 75-g (3-h 100-g, [27,38]) OGTTs in the summer and/or lower levels in the winter (autumn, [38]) compared to other seasons. Two studies in Sweden (n = 11,538) [25] and Australia (n = 2749) [26] reported higher 2 h glucose levels from a 75-g OGTT in the summer, but did not see differences in 1 h glucose levels by season [25,26]. However, the majority of these studies did not find variations in fasting glucose by season, except for a cohort in Australia that reported lower fasting glucose levels in summer compared to winter [40], which may reflect different regulation or sensitivity compared to postprandial glucose levels.
Ambient temperature & GDM Eight studies evaluated the association between ambient temperature at varying time points during pregnancy and GDM (Table 2) [21, 25-27, 37, 38, 41, 43]. Three studies found no association between various measures of ambient temperature and GDM [25][26][27]. An older Australian study (n = 2749) [26] and a larger Swedish cohort study (n = 11,538) [25], reported no association between mean monthly temperature during the month of glucose screening and GDM, and a small Greek study (n = 768) reported no association between daily temperature at time of glucose screening and GDM [27]. The remaining five studies reported associations of various ambient temperature variables with increased odds or risk of GDM [21,37,38,41,43].       Three studies reported associations of mean temperature on the day of OGTT screening with increased odds or risk of GDM [21,37,38]. Mean temperature in the days and weeks leading up to the OGTT was also associated with increased odds or risk of GDM in some studies [21,38,43]. For example, a large Canadian registry-based cohort of 555,911 pregnancies from the greater Toronto area, higher ambient temperature averaged over the 30-days preceding routine GDM screening (~27 weeks gestation) was significantly associated with higher odds of GDM [43]. Specifically, each 10-degree increase in mean 30-day temperature was associated with a 6% increased odds of GDM [43]. A separate smaller Toronto-based cohort study (n = 1464), found no association between mean ambient temperature and GDM when outdoor temperature was modeled as mean temperature in the weeks prior to GDM screening (i.e. 7, 14, 21, 28, 35, 42, 49, 56 days pre-screening) [41]. However, researchers did see associations between average daily change in ambient temperature (defined as the difference between the daily minimum and maximum temperatures) over the weeks pre-GDM screening and increased odds of GDM. For example, the odds of GDM were 1.20 (95% CI 1.05, 1.37) per degree increase in average daily change in ambient temperature (°C) over the 14 days pre-GDM screening, with similar results over different time windows. These associations were only seen in the seasons where daily temperatures were increasing (February-July, i.e. Spring-Summer) not in the seasons where daily temperatures were decreasing (August-January, i.e. Fall-Winter) [41]. Similarly, a Spanish cohort reported associations between higher mean temperatures on the day of the OGTT as well as 14-and 28-days pre-OGTT and increased risk of GDM (e.g. mean temp day of OGTT: OR 1.029, 95% CI: 1.005-1.054), but in stratified analyses these associations were present only during seasons where daily temperatures were increasing [38], which may indicate the importance of other seasonal and physiological factors such as acclimatization, beyond ambient temperature alone.
Of note, all three of the studies reporting no association between temperature and GDM used 1-step screening approaches to diagnose GDM (Tables 1 &  2), whereas the five studies that reported positive associations between temperature variables and GDM reported using a 2-step screening approach or were located in countries where a 2-step screening approach is most commonly used [55], although all women underwent both a GCT and 3 h OGTT as part of the study protocol in Retnakaran et al. [41] and both the IADPSG and Carpenter and Coustan criteria are used in Taiwan [21].
In contrast, a recent Canadian study (n = 1464) only found suggestive covariate-adjusted associations of measures of mean temperature in the weeks prior to glucose testing (i.e. 7, 14, 21, 28, 35, 42, 49, 56 days prescreening) with higher glucose levels from a fasting 3-h 100-g OGTT [41]. However, they observed stronger and significant positive associations of mean daily temperature change in the weeks prior to glucose testing (defined as the difference between the daily minimum and maximum temperatures) with both OGTT fasting glucose levels and AUC glucose (fasting, 30, 60, 120, and 180 min) in covariate-adjusted models [41]. Increased mean daily temperature change in the weeks prior to glucose testing was also associated with decreased beta cell function based on measures of ISSI-2 and (IGI)/ HOMA-IR. When stratified by season, they found that these associations were only present in the season where daily temperatures were increasing (February -July, i.e. Spring-Summer) and not in the season where daily temperatures were decreasing (August -January, i.e. Fall-Winter) [41], indicating the potential importance of other seasonal factors, such as magnitude and direction of temperature fluctuations, rather than simple static temperature. Similar to results of the seasonality studies, the majority of the above studies found no association between temperature and fasting glucose levels, however two recent studies found inverse associations between temperature and fasting glucose levels [38,40].

Discussion
In this systematic review, we summarized the current epidemiologic evidence evaluating climate factors and GDM. We found consistent evidence for an association of the summer season with GDM incidence or prevalence [21,25,27,37,38,42,[44][45][46] and 2 h glucose levels on the OGTT [25-27, 38, 40, 42, 45]. Evidence of an association between temperature and GDM was less consistent across studies. However, despite some heterogeneity in study findings, collective results suggest that higher ambient temperatures may be associated with higher glucose levels from GDM screening tests [25-27, 38, 40, 41, 47] and higher odds or risk of GDM [21,37,38,41,43]. Current study findings suggest that climate factors may be important to consider in the study and prevention of GDM, especially in the context of current and projected global climate change.
The consistent association of season with glycemic outcomes is supported by findings that season is associated with diabetes risk outside of pregnancy. Seasonal patterns have been observed for type 1 diabetes incidence [30]. However, unlike GDM incidence, which peaks in the summer, incidence of type 1 diabetes diagnosis generally peaks in the winter months. Type 1 diabetes and GDM have different pathophysiology, which may explain the discrepancy in seasonal patterns between diseases. Glycemic control among individuals with type 2 diabetes also varies by season in a similar pattern as with type 1 diabetes, with winter months showing higher hemoglobin A1c levels [56,57]. Conversely, increased ambient temperature and heat stress have been consistently associated with increased risk of diabetes (type 1 and 2) and glucose intolerance in non-pregnant populations, supporting the association between temperature and increased glucose levels and GDM odds/risk during pregnancy [29]. For example, a large Spanish cohort of non-pregnant adults reported positive associations between higher mean annual ambient temperature and higher prevalence of prediabetes, diabetes, and insulin resistance, as well as higher fasting and 2-h glucose levels and HOMA-IR [58]. The fact that season is associated with the incidence of type 1 diabetes, glycemic control in type 2 diabetes, and GDM, coupled with the relatively consistent findings of effects of ambient temperature on diabetes odds/risk and glucose intolerance in pregnant and non-pregnant populations, suggest the need for future studies of seasonality and temperature related to diabetes risk, with a particular focus on the mechanisms and reasons for the discordant seasonal results across diabetes types.
The studies included in this review varied considerably in terms of exposure assessment, of GDM diagnostic criteria, glucose measurement, methodological approaches, and geographic location, which may explain some of the heterogeneity in study results. Results from the included studies on ambient temperature and GDM were inconsistent, which may partially be due to differences in GDM screening methods across studies (Table 1). Different diagnostic criteria across studies can affect estimated GDM prevalence, and could affect observed associations between climate factors and GDM. While the studies that found no association between ambient temperature and GDM all utilized 1-step diagnostic criteria with 2 h 75-g OGTTs, the studies that reported associations between temperature variables and GDM reported using a 2-step diagnostic approach and/or were located in countries where a 2-step approach is generally used, although one study administered OGTTs to all women, and 3 h 100-g OGTTs were administered. Differences in glucose screening method (e.g. 75-g vs. 100-g OGTT) or timing of testing during pregnancy, could also contribute to the inconsistencies observed between associations of ambient temperature or season with different OGTT glucose levels. Some studies reported associations for certain OGTT glucose levels but not others (e.g. 2 h but not the 1 h values) [25,26], while another study reported associations with the GCT glucose levels, but not with OGTT glucose levels [33]. Differences in ambient temperature patterns and ranges across geographic regions could also have contributed to inconsistencies in study findings. GDM prevalence is highly variable across geographic regions and is highest in the Middle East (median 15.2%) and South-East Asia (15.0%), regions with extreme high temperatures, and noticeably lower in Europe (6.1%) and North America (7.0%), regions with relatively lower temperatures [59]. However, no studies have investigated associations of absolute ambient temperatures and GDM across geographic regions.
Pregnant women may be more susceptible to the adverse health effects of climate related factors including heat and cold stress [60] and may therefore be particularly vulnerable to the development of diabetes and altered glycemic outcomes associated with climate factors in the face of increases in extreme temperatures.
Multiple hypotheses exist for the observed effect of ambient temperature and season on GDM and glycemic outcomes. One possible mechanism is through brown adipose tissue activation, which can induce weight changes and insulin sensitivity [29,61,62]. A recent study reported a positive association between ambient temperature and glycated hemoglobin (HbA1c) levels in 65,535 clinical patients [63]. The researchers hypothesized that these fluctuations could be due to seasonal alterations in brown adipose tissue (BAT) and its activation. BAT is sensitive to temperature fluctuations. At temperatures below the thermoneutral zone (i.e. 27-30°C in unclothed adults), BAT is activated to produce heat [64], consuming large amounts of glucose from the blood in the process [65][66][67][68]. Glucose uptake during non-shivering thermogenesis in BAT occurs through upregulation of mitochondrial uncoupling protein 1 (UCP1) and glucose transporters (GLUT1 and GLUT4) [63,69,70]. Additionally, heat shock protein (HSP) expression in BAT is induced at cold temperatures [71][72][73]. Patients with diabetes and insulin resistance have reduced Hsp70 expression [74]. Reduced Hsp70 has been associated with hyperglycemia during pregnancy in mice [75].
In rodents, BAT may be especially important in regulating glucose metabolism during pregnancy; Qiao et al. showed that fetuses of UCP1 knockout dams had significantly higher blood glucose levels than wild-type dams [76]. At higher temperatures, there is a decrease in temperature-induced BAT activation, which could result in a decrease in glucose uptake. Separately, at higher temperatures beige and brown adipocytes can shift in chromatin structure to resemble white adipose tissue, leading to reduced expression of UPC1 and down regulation of lipid metabolism pathways [75]. In a clinical human population, BAT, detected using positron-emission tomographic and computed tomographic (PET-CT) scans, was inversely correlated with ambient temperature on the day of scan [77].
Alternative hypotheses to explain the positive association between ambient temperature and glucose levels include increased beta-cell dysfunction, insulin resistance, hemoconcentration and increased arterialization of venous blood [5,33,78]. One study in our review looked at associations between ambient temperature and markers of beta-cell function. The authors found that the higher mean daily temperature change in the 3-5 weeks prior to OGTT screening was significantly associated with decreased ISSI-2 and (IGI)/HOMA-IR, implicating beta-cell dysfunction as a potential pathophysiological mechanism behind the parallel associations with higher glucose levels and GDM prevalence, although suggestive associations were also seen with increase insulin resistance (i.e. Matsuda Index and HOMA-IR) [41]. In a large Spanish cohort of nonpregnant adults, higher annual mean temperature was associated with increased insulin resistance (HOMA-IR) [58]. Alternatively, higher ambient temperatures and increased activity in warmer weather could lead to dehydration, and resulting hemoconcentration, which could cause an apparent increase in blood glucose concentrations during glucose screening and resulting GDM diagnoses [33]. Similarly, blood flow distribution is altered at high temperatures, leading to increased arterialization of venous blood, which could result in higher glucose levels measured in venous blood samples leading to increases in failed GDM screening tests and GDM diagnoses. In climate chamber experiments, Moses et al. [5] and Dumke et al. [78] observed significantly increased levels of OGTT glucose levels [5,78] and insulin levels [78] at higher temperatures in healthy male subjects. These physiological changes at high temperatures could cause transient elevations in measured blood glucose levels, leading to potential misclassification of abnormal glucose tolerance and GDM.
Seasonal factors unrelated to temperature may also contribute to the observed seasonal variation in GDM. Circadian and thermogenic networks in BAT are controlled by the nuclear receptor Rev-erbα, which represses UPC1 expression in BAT [79,80]. Consequently, studies have shown that UCP1 expression in BAT follows a circadian rhythm in rodents, peaking during the day [63]. Seasonal changes in circadian rhythms, could contribute to the observed seasonal patterns of GDM risk. Alternatively, seasonal variations in physical activity and dietary patterns, as well as access to green space may also play a role in the observed seasonal variation in GDM and glycemic outcomes. Vitamin D may help regulate glucose homeostasis by increasing insulin sensitivity and beta-cell function, or decreasing systemic inflammation [35] and lower Vitamin D levels and Vitamin D deficiency, have been associated with increased GDM risk [81][82][83][84][85] and higher fasting glucose and insulin resistance during pregnancy [85]. Decreased sun exposure in winter months during early pregnancy could lead to decreased vitamin D levels during early pregnancy, which has been associated with subsequent risk of GDM during later pregnancy, at the time of routine GDM screening [82] In addition to increased GDM risk, lower Vitamin D levels during early pregnancy have been associated with higher HOMA-IR, lower Matsuda index, and lower ISSI-2 during in later pregnancy (24-28 weeks) [82].
Temperature and season also affect other environmental factors known to be associated with GDM, such as air pollution [23,24]. For example, exposure to ambient air pollutants, including nitrous oxides and PM 2.5 (i.e. particulate matter with a diameter of 2.5 μm or less), has been consistently associated with increased GDM risk [84,[86][87][88][89][90][91]. Additionally, potential seasonal changes in gut microbiome could contribute to the observed seasonal variation in glycemic outcomes [92,93]; in GDM complicated pregnancies, altered maternal gut microbiome have been reported [94,95]. Overall, the exact mechanism behind the effect of season and ambient temperature on GDM and glycemic outcomes remains unclear. Further research is needed to investigate the interplay between temperature and additional meteorological factors with glucose regulation in pregnancy using toxicologic and epidemiologic studies.
None of the identified studies assessed the associations of other meteorological-related factors such as precipitation and humidity on GDM risk. Seasonal variations in these factors could also contribute to the observed variation in GDM and glycemic outcomes. For example, a recent study found a positive correlation between diabetes incidence and precipitation in Cameroon [96].
Exposure to ambient air pollution has also been associated with increased risk of GDM [23] and varies by season and meteorological factors. However, further research is needed to understand the role of these additional factors and how they may be related to or interact with temperature to impact risk of GDM.
There is growing evidence that certain subsets of the population (i.e. those with a family history of diabetes or individuals who are overweight/obese) may be more susceptible to the effects of environmental exposures compared to others [97][98][99][100]. However, none of the reviewed studies assessed effect modification of the associations between climate factors and GDM or maternal glycemic outcomes by factors such as family history of diabetes, pre-pregnancy BMI, age, or race/ethnicity. Future studies should assess heterogeneity in associations across different population subgroups.
Due to the ubiquitous nature of environmental exposures, individuals are continuously exposed to complex combinations of environmental factors. While there is increasing awareness for the need to incorporate analyses of exposure mixtures and combinations in epidemiologic studies, none of the current studies have looked at cumulative effects of environmental exposures in the context of multiple climate-related factors such as temperature, humidity, and precipitation. Further research is needed to understand the potential cumulative and interactive effects of these climate factors on GDM risk.
Strategies for Evaluating Climate Factors in Future Studies of GDM: 1. Consider evaluating climate factors and accounting for lag time in modeling procedures. 2. Standardize GDM diagnostic criteria and screening methods. 3. Evaluate possible heterogeneous effects of climate factors across population subgroups by assessing effect modification to identify particularly vulnerable populations. 4. Consider the impact of climate factors on various populations based on region and space and the differential effects in given geographic areas. 5. Evaluate the potential confounding and/or modifying role of season of GDM diagnosis and ambient temperature prior to GDM screening in studies of pregnancy and neonatal outcomes in GDM complicated pregnancies. 6. Evaluate the cumulative impact of multiple climaterelated factors (e.g. temperature, season, humidity, precipitation, and the interplay with air pollution and other environmental factors) on GDM and related outcomes.

Conclusion
In summary, there is mounting evidence that exposure to certain climate factors-ambient temperature and season-during pregnancy is associated with increased risk of developing GDM and adverse glycemic outcomes. The seasonality of GDM was consistent across studies, with higher prevalence of GDM generally observed in the summer months. Furthermore, higher ambient temperature may be associated with elevated glucose levels from GDM screening tests. Associations between ambient temperature and GDM were more inconsistent; however, this could be due to differences in GDM diagnostic criteria. One major limitation of the current literature is the lack of consistency in both exposure and outcome assessment across studies; future studies should work to standardize these methods. Furthermore, future work should include more diverse study populations to allow researchers to identify potential high-risk population subgroups. Finally, future studies should include an emphasis on evaluating effects of exposure to multiple environmental and climate factors. Given the current GDM epidemic coupled with current and projected global climate change, understanding the extent to which climate factors might affect GDM risk is imperative to reducing the risk of this increasingly prevalent and costly pregnancy complication. Authors' contributions TJT, CE, and FMB designed the systematic review. EVP. conducted the systematic search, data extraction, quality assessment of included studies, and wrote the manuscript. TJT, CE, and FMB provided guidance in synthesizing and interpreting the study results and all authors reviewed the manuscript for intellectual content and approved the final manuscript.

Funding
Author support for this systematic review was provided by the National Institute of Environmental Health Sciences of the National Institutes of Health, P30ES000002 and T32ES007069. The content of this review is solely that of the authors and does not necessarily represent the official views of the National Institutes of Health.