Ian Hough
email: ian.hough@univ-grenoble-alpes.fr

Matthieu Rolland

Ariane Guilbert

Emie Seyve

Barbara Heude

Rémy Slama

Sarah Lyon-Caen

Isabelle Pin

Cécile Chevrier

Itai Kloog

Johanna Lepeule

Early delivery following chronic and acute ambient temperature exposure: a comprehensive survival approach

Keywords: preterm birth, heat, cold, exposure windows

BACKGROUND: Ambient temperature, particularly heat, is increasingly acknowledged as a trigger of preterm delivery, but study designs have been limited and results mixed. We aimed to comprehensively evaluate the association between ambient temperature throughout pregnancy and preterm delivery.

METHODS:

We estimated daily temperature throughout pregnancy using a cutting-edge spatiotemporal model for 5,347 live singleton births from three prospective cohorts in France, 2002-2018. We performed Cox regression (survival analysis) with distributed lags to evaluate time-varying associations with preterm birth simultaneously controlling for exposure during the first 26 weeks and last 30 days of pregnancy. We examined weekly mean, daytime, nighttime, and variability of temperature, and heatwaves accounting for adaptation to location and season.

RESULTS: Preterm birth risk was higher following cold (5 th vs 50 th percentile of mean temperature) 7-9 weeks after conception [relative risk (RR) 1.3, 95% confidence interval (CI) 1.0-1.6 for 2°C vs 11.6°C] and 10-4 days before delivery (1.6 [1.1-2.1] for 1.2°C vs 12.1°C).

Night-time heat (95 th vs 50 th percentile of minimum temperature; 15.7°C vs 7.4°C) increased risk when exposure occurred within five weeks of conception (2.0 [1.05-3.8]) or 20-26 weeks after conception (2.9 [1.2-6.8]). Overall and daytime heat (high mean and maximum temperature) showed consistent effects. We found no clear associations with temperature variability or heatwave indicators, suggesting they may be less relevant for preterm birth.

CONCLUSION:

In a temperate climate, night-time heat and chronic and acute cold exposures were associated with increased risk of preterm birth. These results suggest night-time heat as a relevant indicator. In the context of rising temperatures and more frequent weather hazards, these results should inform public health policies to reduce the growing burden of preterm births.

Introduction

Climate change already affects human health, and continued increases in mean temperature and the frequency and intensity of extreme weather events will magnify morbidity and mortality impacts. [START_REF] Atwoli | Call for emergency action to limit global temperature increases, restore biodiversity and protect health[END_REF] A growing body of research suggests that extreme ambient temperatures can increase the risk of adverse birth outcomes such as preterm birth. [START_REF] Zhang | Temperature exposure during pregnancy and birth outcomes: An updated systematic review of epidemiological evidence[END_REF][START_REF] Chersich | Associations between high temperatures in pregnancy and risk of preterm birth, low birth weight, and stillbirths: Systematic review and meta-analysis[END_REF] Preterm birth (delivery at <37 weeks amenorrhea) is the leading cause of under-5 mortality worldwide [START_REF] Liu | Global, regional, and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the Sustainable Development Goals[END_REF] and increases the risk of adverse health outcomes throughout childhood and into adulthood. [START_REF] Mccormick | Prematurity: An Overview and Public Health Implications[END_REF] Globally, about 11% of births are preterm, and the rate is increasing in many countries. [START_REF] Chawanpaiboon | Global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis[END_REF] In France, the rate of preterm birth increased from 5.4% in 1995 to 7.5% in 2016. [START_REF] Blondel | Trends in perinatal health in metropolitan France from 1995 to 2016: Results from the French National Perinatal Surveys[END_REF] The drivers of these trends remain unclear, [START_REF] Vogel | The global epidemiology of preterm birth[END_REF] but exposure to extreme and variable temperatures may contribute and is expected to increase as climate change progresses. [START_REF]Impacts, Adaptation, and Vulnerability. Contribution of Working Group II to the Sixth Assessment Report of the Intergovernmental Panel on Climate Change[END_REF] The biological pathways underlying associations between temperature and preterm birth remain unclear. Chronic exposure throughout pregnancy could increase the risk of preterm delivery and acute exposure could trigger preterm delivery. Pregnant women have increased fat deposition, decreased surface area to mass ratio, weight gain, and higher metabolic heat production (as the foetus contributes), which could make them more susceptible to heat. Heat may cause the release of cytokines involved in labour induction such as prostaglandin and oxytocin, [START_REF] Dadvand | Climate extremes and the length of gestation[END_REF] and their concentration in the blood might be increased by heat-induced dehydration. [START_REF] Schifano | Effect of ambient temperature and air pollutants on the risk of preterm birth, Rome 2001-2010[END_REF] Dehydration and shifting of blood flow to the skin to dissipate heat could limit oxygen supply to the foetus, [START_REF] Sun | Ambient temperature and preterm birth: A retrospective study of 32 million US singleton births[END_REF] and heat shock proteins might cause inflammation. [START_REF] Basu | The impact of maternal factors on the association between temperature and preterm delivery[END_REF] Heat may also be linked to preeclampsia. [START_REF] Shashar | Temperature and preeclampsia: Epidemiological evidence that perturbation in maternal heat homeostasis affects pregnancy outcome[END_REF] Fewer mechanisms have been proposed for cold, but thermoregulatory responses can cause peripheral vasoconstriction and increase blood pressure and viscosity, which might restrict blood flow to the placenta or contribute to gestational hypertension. [START_REF] Basu | The impact of maternal factors on the association between temperature and preterm delivery[END_REF] Many previous studies of temperature and preterm birth focused only on the last days of pregnancy (acute exposure), and most reported that high temperatures or heatwaves were associated with decreased gestational duration or increased risk of preterm or early term birth. [START_REF] Sun | Ambient temperature and preterm birth: A retrospective study of 32 million US singleton births[END_REF][START_REF] Vicedo-Cabrera | Exposure to elevated temperatures and risk of preterm birth in Valencia, Spain[END_REF][START_REF] Cox | Ambient temperature as a trigger of preterm delivery in a temperate climate[END_REF][START_REF] Schifano | Heat and air pollution exposure as triggers of delivery: A survival analysis of population-based pregnancy cohorts in Rome and Barcelona[END_REF] Fewer studies have examined chronic exposure earlier in pregnancy, and results have been less consistent: chronic heat and cold may increase the risk of preterm birth in some populations, [START_REF] He | Ambient Temperature and the Risk of Preterm Birth in Guangzhou, China (2001-2011)[END_REF][START_REF] Wang | Ambient temperature and the risk of preterm birth: A national birth cohort study in the mainland China[END_REF][START_REF] Guo | The association between ambient temperature and the risk of preterm birth in China[END_REF][START_REF] Li | Temporal change in the impacts of ambient temperature on preterm birth and stillbirth: Brisbane, 1994-2013[END_REF][START_REF] Kloog | Using Satellite-Based Spatiotemporal Resolved Air Temperature Exposure to Study the Association between Ambient Air Temperature and Birth Outcomes in Massachusetts[END_REF] but may protect or have no effect in others. [START_REF] Wang | Ambient temperature and the risk of preterm birth: A national birth cohort study in the mainland China[END_REF][START_REF] Guo | The association between ambient temperature and the risk of preterm birth in China[END_REF][START_REF] Giorgis-Allemand | The influence of meteorological factors and atmospheric pollutants on the risk of preterm birth[END_REF][START_REF] Ha | Ambient temperature and early delivery of Singleton Pregnancies[END_REF] These mixed findings could in part be due to misidentification of critical windows in studies that did not fully account for correlation in exposure between trimesters. [START_REF] Wilson | Potential for Bias When Estimating Critical Windows for Air Pollution in Children's Health[END_REF] Since windows of susceptibility may not align with trimesters, 24 some recent studies have examined narrower exposure windows such as months or weeks, [START_REF] Guo | The association between ambient temperature and the risk of preterm birth in China[END_REF][START_REF] Ha | Ambient temperature and early delivery of Singleton Pregnancies[END_REF][START_REF] Liu | Associations of maternal ambient temperature exposures during pregnancy with the risk of preterm birth and the effect modification of birth order during the new baby boom: A birth cohort study in Guangzhou, China[END_REF] but the timing of critical windows remains unclear. Previous studies mostly estimated temperature exposure for all inhabitants of a city or region based on one or a few monitoring stations. This can lead to exposure error that biases associations towards the null, 27 particularly for rural populations, which may live far from monitors, and for urban residents, who may be affected by urban heat islands. To address this, a few recent studies estimated exposure with spatiotemporally resolved models coupled to home addresses. [START_REF] Wang | Ambient temperature and the risk of preterm birth: A national birth cohort study in the mainland China[END_REF][START_REF] Kloog | Using Satellite-Based Spatiotemporal Resolved Air Temperature Exposure to Study the Association between Ambient Air Temperature and Birth Outcomes in Massachusetts[END_REF][START_REF] Liu | Associations of maternal ambient temperature exposures during pregnancy with the risk of preterm birth and the effect modification of birth order during the new baby boom: A birth cohort study in Guangzhou, China[END_REF][START_REF] Spolter | Prenatal exposure to ambient air temperature and risk of early delivery[END_REF] Previous studies also considered various exposure indicators such as mean, minimum, maximum, and apparent temperature. Some reported stronger associations for certain indicators [START_REF] Cox | Ambient temperature as a trigger of preterm delivery in a temperate climate[END_REF][START_REF] Avalos | The impact of high apparent temperature on spontaneous preterm delivery: a case-crossover study[END_REF] while others found that all indicators gave similar results. [START_REF] Huang | Acute associations between heatwaves and preterm and early-term birth in 50 US metropolitan areas: a matched case-control study[END_REF] Mortality studies suggest that temperature variability may have health impacts [START_REF] Shi | Impacts of temperature and its variability on mortality in New England[END_REF] and that acclimation to location and season may modify associations, [START_REF] Nordio | Changing patterns of the temperature-mortality association by time and location in the US, and implications for climate change[END_REF] but few studies have examined these in relation to preterm birth.

A recent review highlighted these methodological disparities and recommended that future studies consider cold as well as heat, focus on identifying windows of susceptibility using more accurate exposure data, and use methods such as survival analysis that account for time-varying associations with birth outcomes. [START_REF] Zhang | Temperature exposure during pregnancy and birth outcomes: An updated systematic review of epidemiological evidence[END_REF] In this study, we estimated daily temperature exposure throughout pregnancy for three French prospective mother-child cohorts using a cutting-edge spatiotemporal model (spatial unit 200 m to 1 km) coupled to participants' exact home addresses. We performed a survival analysis using Cox proportional hazards models with distributed lags to evaluate the time-varying nonlinear association between temperature and preterm birth. We simultaneously considered chronic and acute exposures by exploring gestational-week specific temperatures and daily temperatures preceding delivery. We further examined several exposure indicators: overall (mean), daytime (maximum), and night-time (minimum) temperature, temperature variability, and a heatwave index that accounts for acclimation to location and season.

Methods

Study population

We obtained data from three French prospective mother-child cohorts that were designed to study the effects of prenatal environmental exposures on child development and health: EDEN (Étude des Déterminants pré et post natals du développement et de la santé de l'Enfant), [START_REF] Heude | Cohort Profile: The EDEN mother-child cohort on the prenatal and early postnatal determinants of child health and development[END_REF] PELAGIE (Perturbateurs Endocriniens : étude Longitudinale sur les Anomalies de la Grossesse, l'Infertilité, et l'Enfance), [START_REF] Petit | Impact on fetal growth of prenatal exposure to pesticides due to agricultural activities: a prospective cohort study in Brittany, France[END_REF] and SEPAGES (Suivi de l'Exposition à la Pollution Atmosphérique durant la Grossesse et Effets sur la Santé). [START_REF] Lyon-Caen | Deciphering the impact of early-life exposures to highly variable environmental factors on foetal and child health: Design of SEPAGES couple-child cohort[END_REF] S1).

All three cohorts collected medical and sociodemographic information via clinical examinations and questionnaires during and after pregnancy. Exact home addresses (including any changes during pregnancy) were geocoded. For 43% of PELAGIE participants, only the municipality or neighbourhood of residence at inclusion (on average 10.4 weeks after conception) was available; we assumed these women did not move during pregnancy.

We excluded multiple gestation, non-livebirths, pre-existing diabetes or hypertension, and participants lost to follow-up before delivery. To ensure complete equal-length exposure histories, we further excluded participants missing covariates (described below) or missing exposure for more than one day in any of the 26 weeks following conception (among these were five extremely preterm births at <28 weeks amenorrhea; all remaining participants had exposure for the 30 days ending at delivery). This left 5,347 mother-child pairs (Figure 1).

Outcome definition

Duration of pregnancy (conception to birth) was assessed in days using both the reported date of the last menstrual period (LMP) and the estimate from the first trimester ultrasound (when LMP was not reported or when the two differed by more than 30 days). When neither of these were available (n = 3 in EDEN; n = 84 in PELAGIE), we used the obstetrician's estimate of gestational age at delivery. We defined preterm birth as delivery at <37.0 weeks amenorrhea (<35.0 weeks since conception). 36

Exposure assessment

We estimated daily ambient temperature at women's home address using a multi-resolution hybrid spatiotemporal model. [START_REF] Hough | A multi-resolution air temperature model for France from MODIS and Landsat thermal data[END_REF] The model estimates daily minimum, maximum, and mean air temperature from 2000 to 2018 at a 1 km spatial resolution across France and at a 200 m spatial resolution over urban areas with >50,000 inhabitants. Briefly, it uses a multi-stage ensemble approach combining linear mixed models, random forests, and gradient boosting to calibrate air temperature measured at meteorological stations with satellite-derived land surface temperature, elevation, and other spatiotemporal predictors. The model performs well, with cross-validated R 2 better than 0.9 and mean absolute error of about 1°C. We used 200 m temperature for women in urban areas covered by the model (n = 1,741; 33%) and 1 km temperature otherwise.

We calculated five indicators of exposure based on each woman's daily temperature profile from conception to delivery: 1) weekly mean temperature (Tmean), a marker of overall exposure; 2) weekly average of daily maximum temperature (Tmax), a marker of daytime exposure because temperature is usually highest in the afternoon; 3) weekly average of daily minimum temperature (Tmin), a marker of night-time exposure because temperature is typically lowest before sunrise; 4) weekly temperature variability (TSD, the standard deviation of daily mean temperature), a marker of exposure to temperature swings; and 5) daily Excess Heat Factor (EHF), a marker of exposure to extreme heat that accounts for both spatial and seasonal acclimation. [START_REF] Nairn | The excess heat factor: A metric for heatwave intensity and its use in classifying heatwave severity[END_REF] Supplementary Material Part A details the EHF calculation.

Main analysis

We used Cox proportional hazards models with duration of pregnancy (weeks since conception) as the time variable and birth as the outcome (censored at 35 weeks after conception). We fit a separate model for each of the five exposure indicators (Tmean, Tmin, Tmax, TSD, EHF). We accounted for the time-varying effects of exposure using a distributed lag nonlinear model (DLNM) [START_REF] Gasparrini | Distributed lag non-linear models[END_REF] with two exposure matrices: the 26 weeks following conception (weekly chronic exposure) and the 30 days ending at delivery (daily acute exposure). We censored chronic exposure at 26 weeks to avoid excluding a substantial fraction of preterm births. We modelled both the exposure-response and the lag-response relationship using natural cubic splines with equally spaced knots and three degrees of freedom (chosen by testing 3-6 degrees of freedom for the lowest value that minimized the Akaike information criterion). The reference temperatures for each model were the median exposure (50 th percentile) of the study population during each of the chronic and acute periods. We adjusted all models for possible confounders or predictors of the outcome selected a priori based on the literature and our reasoning: cohort recruitment area (Nancy / Poitiers / Côtesd'Armor / Finistère / Ille-et-Vilaine / Grenoble), season of conception (Winter / Spring / Summer / Fall), urbanicity (city centre / suburban / rural), normalized difference vegetation index (NDVI; a measure of vegetation density), child sex, and maternal characteristics (age at conception, height, pre-pregnancy body mass index [BMI], parity, education, and smoking during pregnancy [none / active smoker]). Table 1 lists the levels of the covariates. We did not adjust for gestational hypertension or preeclampsia as these may mediate the association between temperature and preterm birth. Nor did we adjust for air pollution, as it is on the causal pathway between temperature and preterm birth. [START_REF] Buckley | Does air pollution confound studies of temperature?[END_REF] Urbanicity was based on data from the French National Institute of Statistics and Economics for the home address at birth. We calculated mean NDVI from Landsat satellite data 41 in a 500 m buffer around the home address during summer (June-August) of the year of birth. Our intent was to capture total vegetated area (rather than temporal changes in vegetation extent and greenness) and to minimize the influence of missing data due to snow and cloud cover during colder seasons. Previous studies of preterm birth estimated NDVI on a single summer day, [START_REF] Asta | The modifying role of socioeconomic position and greenness on the short-term effect of heat and air pollution on preterm births in Rome, 2001-2013[END_REF][START_REF] Glazer | Residential green space and birth outcomes in a coastal setting[END_REF][START_REF] Abelt | Green streets: Urban green and birth outcomes[END_REF][START_REF] Grazuleviciene | Surrounding greenness, proximity to city parks and pregnancy outcomes in Kaunas cohort study[END_REF][START_REF] Agay-Shay | Green spaces and adverse pregnancy outcomes[END_REF][START_REF] Laurent | Green spaces and pregnancy outcomes in Southern California[END_REF] reported very high correlation between seasonal and annual NDVI, [START_REF] Hystad | Residential Greenness and Birth Outcomes: Evaluating the Influence of Spatially Correlated Built-Environment Factors[END_REF] or reported consistent effects for every month. [START_REF] Sun | Associations between green space and preterm birth: Windows of susceptibility and interaction with air pollution[END_REF] We considered NDVI missing if it was unavailable over more than 25% of the buffer.

205

e Coded as a continuous variable.

206

To better understand the associations with temperature and evaluate the robustness of our findings, we repeated our analyses 1) including the 309 participants (of which 16 preterm births) that were missing covariates, which we imputed using the cohort recruitment area-specific median or mode; 2) using temperature estimated at a 1 km spatial resolution for all participants (rather than using 200 m temperature for the 33% of participants that lived in large urban areas);

3) adjusting for year of conception in addition to the main covariates; and 4) including TSD as a simultaneous exposure along with each of Tmin, Tmean, Tmax, and EHF (TSD was the only uncorrelated exposure indicator).

We used the fitted models to estimate the relative risk (RR) of preterm birth and 95% confidence interval (CI) associated with moderate (10 th , 90 th percentiles), severe (5 th , 95 th percentiles), and extreme (1 st , 99 th percentiles) exposure compared to the median exposure (50 th percentile)

during the chronic and acute periods. We report both the cumulative risk associated with exposure throughout the entire duration of a critical window and the mean risk associated with exposure on only a single week or day during each window. We calculated mean risk by averaging the risk of all individual weeks or days in each window. We conducted all statistical analyses using R version 4.1.0 50 with the packages survival v3.2-11 [START_REF] Therneau | A Package for Survival Analysis in R [Internet[END_REF] and dlnm v2.4.6. 52

Results

Over half (58%) of the women lived in Brittany; 18% lived in Nancy, 16% in Poitiers, and 8%

in Grenoble (Table 1). Almost half (45%) lived in a rural area. Most women (72%) were 25 to 34 years old at conception, had completed at least one year of post-secondary education (63%), and were multiparous (56%). A quarter (25%) of women smoked during pregnancy.

Mean duration of pregnancy (conception to delivery) was 37.9 weeks and 4.3% of births were preterm. Mean temperature ± standard deviation during the 26 weeks following conception was 11.8 ± 3.6°C; the standard deviation of weekly temperature averaged 2.0 ± 0.3°C. Mean EHF was 0.7 ± 1.1 over days 30 to 181 since conception. Supplementary Figure S2 shows the distribution of mean temperature and EHF over time for each cohort and Supplementary Table S1 summarizes the distribution of the exposure indicators.

Cold

Severe cold (5 th vs 50 th percentile of Tmean) during weeks 7-9 after conception and days 10-4 before delivery increased the risk of preterm birth (Figure 2). A mean temperature of 2°C throughout weeks 7-9 after conception was associated with RR for preterm birth of 1.29 (95% Tmean, daily mean temperature; Tmin, daily minimum temperature.

CI: 1.02-1.64) compared to the reference temperature of 11.6°C (Figure 3). A mean temperature of 1.2°C throughout days 10-4 before delivery had RR of 1.55 (95% CI: 1.14-2.11) compared to 12.1°C. Considering a single week or day during each critical window, the mean RR for preterm birth was about 1.09 (95% CI: 1.01-1.18) following severe cold on one of weeks 7-9 after conception; the mean RR for preterm birth was about 1.06 (95% CI: 1.01-1.12)

following severe cold on one of days 10-4 before delivery (Supplementary Figure S3). For extreme cold (1 st percentile of Tmean), the critical windows were 4-9 weeks after conception and 10-4 days before delivery; the only critical window for moderate cold (10 th percentile of Tmean) was 10-5 days before delivery (Figure 3). Chronic daytime cold (low Tmax) showed a longer critical window than chronic overall cold (low Tmean) (Figure 2), while night-time cold (low Tmin) was only significant when it was extreme (1 st percentile) 7-6 days before delivery (Figure 3). Imputing missing covariates did not substantially change the associations; nor did adjusting for year of conception or including TSD as a simultaneous exposure. Using only 1 km temperature made the critical windows shorter or widened the confidence intervals. Maternal education was the only variable that did not satisfy the proportional hazards assumption; stratifying the Cox models on education did not substantially alter our results.

Heat

Heat (high Tmean) during the first weeks following conception, the second half of the second trimester, and the last days before delivery seemed to correspond with an increased risk of preterm birth (Figure 4). We identified critical windows for severe night-time heat (95 th vs 50 th percentile of Tmin; 15.7°C vs 7.4°C) during weeks 1-5 after conception (RR: 2.00; 95% CI:1.05-3.84) and 20-26 weeks after conception (RR: 2.87; 95% CI: 1.21-6.79) (Figure 3, Figure 4). Focusing on a single week during each critical window, an average minimum temperature of 15.7°C during any one of weeks 1-5 or weeks 21-26 after conception was associated with mean RR of about 1.16 (95% CI: 1.02-1.34) (Supplementary Figure S3). Moderate (90 th percentile) night-time heat showed a somewhat smaller effect during the same windows, while extreme (99 th percentile) night-time heat showed a larger effect but only 21-26 weeks after conception (Figure 3). Sensitivity analyses did not substantially alter the results.

Temperature variability and Excess Heat Factor

There was no clear association between temperature variability and risk of preterm birth.

Moderately variable temperature (90 th vs 50 th percentile of TSD; 3.3°C vs 1.8°C) 7-8 weeks after conception may have had a protective effect (Supplementary Figure S4), but the association did not clearly differ from null (RR: 0.85; 95% CI: 0.73-1.00). There were no critical windows for other exposure levels, and sensitivity analyses showed similar results.

There was no association between EHF and preterm birth (Supplementary Figure S5).

Discussion

Our results are based on a state-of-the-art approach combining survival analysis with daily residence-based temperature exposure, controlling for both chronic (weekly for the 26 weeks following conception) and acute (daily for the 30 days ending at delivery) exposure, and accounting for lagged nonlinear effects. Pregnant women were susceptible to cold from the middle of the first to the middle of the second trimester and about one week before delivery.

Women were susceptible to heat during the five weeks following conception and the end of the second trimester. Night-time heat (high Tmin) seemed to increase preterm birth risk more than daytime (high Tmax) or overall (high Tmean) heat, while night-time cold seemed less harmful than daytime or overall cold.

Cold

We found a critical window for chronic cold 4-9 weeks after conception. Women were more sensitive to daytime cold: the critical window continued until 18 weeks after conception. We found no critical window for chronic night-time cold. Women may have been less exposed to night-time cold as they were likely inside a heated home.

Few previous studies examined cold early during pregnancy in temperate climates, with most finding protective effects. [START_REF] Wang | Ambient temperature and the risk of preterm birth: A national birth cohort study in the mainland China[END_REF][START_REF] Guo | The association between ambient temperature and the risk of preterm birth in China[END_REF][START_REF] Giorgis-Allemand | The influence of meteorological factors and atmospheric pollutants on the risk of preterm birth[END_REF][START_REF] Ha | Ambient temperature and early delivery of Singleton Pregnancies[END_REF] Consistent with our results, a study in the USA found that cold during the two weeks before or five weeks after conception increased the risk of preterm birth, and studies in China reported increased risk from entire-pregnancy cold in temperate [START_REF] Wang | Ambient temperature and the risk of preterm birth: A national birth cohort study in the mainland China[END_REF] and cold areas. [START_REF] Guo | The association between ambient temperature and the risk of preterm birth in China[END_REF] Compared to previous studies, we examined narrower windows (single weeks during the first two trimesters), estimated residence-based temperature (rather than using citywide or regional temperature), and adjusted for temperature later in pregnancy, which may have improved our ability to detect critical windows.

We also found a critical window for acute cold 10-4 days before delivery. Previous studies of acute cold in temperate climates have reported conflicting results of no association with preterm birth, [START_REF] Guo | The association between ambient temperature and the risk of preterm birth in China[END_REF][START_REF] Kloog | Using Satellite-Based Spatiotemporal Resolved Air Temperature Exposure to Study the Association between Ambient Air Temperature and Birth Outcomes in Massachusetts[END_REF][START_REF] Vicedo-Cabrera | Exposure to seasonal temperatures during the last month of gestation and the risk of preterm birth in stockholm[END_REF][START_REF] Lee | Mortality burden of diurnal temperature range and its temporal changes: A multi-country study[END_REF] a decreased risk, [START_REF] Ha | Ambient temperature and early delivery of Singleton Pregnancies[END_REF] or oscillating positive and negative associations. [START_REF] Sun | Ambient temperature and preterm birth: A retrospective study of 32 million US singleton births[END_REF][START_REF] Cox | Ambient temperature as a trigger of preterm delivery in a temperate climate[END_REF] Most of these studies considered only the last seven days or four weeks of pregnancy, which may have limited their ability to detect a critical window starting about 10 days before delivery, and most did not adjust for temperature earlier in pregnancy as we did.

Heat

We found critical windows for chronic heat during the five weeks after conception and 20-26 weeks after conception. The association was clearest for night-time heat, but the shape of the lag-response curve was similar for overall and daytime heat. Heatwave mortality studies have suggested that hot nights following hot days may be particularly dangerous because they limit the ability to recover from daytime exposure, [START_REF] Laaidi | The impact of heat islands on mortality in Paris during the August 2003 heat wave[END_REF][START_REF] Murage | Effect of night-time temperatures on cause and agespecific mortality in London[END_REF] and recent studies in California and Belgium found a clearer association with preterm birth for night-time than daytime heat. [START_REF] Cox | Ambient temperature as a trigger of preterm delivery in a temperate climate[END_REF][START_REF] Avalos | The impact of high apparent temperature on spontaneous preterm delivery: a case-crossover study[END_REF] Our study may have been particularly suited to examining night-time heat because we estimated residence-based exposure using a model that captures the higher night-time temperatures of urban heat islands. [START_REF] Hough | A multi-resolution air temperature model for France from MODIS and Landsat thermal data[END_REF] Taken together, these results suggest that future studies should consider night-time heat indicators in order to clarify the effects of heat during pregnancy, particularly in countries such as France where only about 13% of homes have air conditioning. [START_REF] Randazzo | Air conditioning and electricity expenditure: The role of climate in temperate countries[END_REF] Many studies have reported that heat in the last days of pregnancy may trigger preterm delivery, 2,3 although a few have reported no effect in cold or cool climates. [START_REF] Sun | Ambient temperature and preterm birth: A retrospective study of 32 million US singleton births[END_REF][START_REF] Guo | The association between ambient temperature and the risk of preterm birth in China[END_REF][START_REF] Kloog | Using Satellite-Based Spatiotemporal Resolved Air Temperature Exposure to Study the Association between Ambient Air Temperature and Birth Outcomes in Massachusetts[END_REF][START_REF] Vicedo-Cabrera | Exposure to seasonal temperatures during the last month of gestation and the risk of preterm birth in stockholm[END_REF] In our study, heat during the last five days of pregnancy may have increased risk of preterm birth, but the association was unclear. This might be because we adjusted for temperatures earlier in pregnancy whereas most previous studies did not. Our residence-based exposure estimates may also be less accurate during the final days of pregnancy for some women who may have been admitted to maternity units before the day of delivery.

Temperature variability and acclimation

Temperature variability and acclimation to location and season have been shown to affect the risk of mortality, [START_REF] Shi | Impacts of temperature and its variability on mortality in New England[END_REF][START_REF] Nordio | Changing patterns of the temperature-mortality association by time and location in the US, and implications for climate change[END_REF] but few studies have examined them in relation to birth outcomes. A recent study in the Andes associated more variable temperature with lower birth weight, [START_REF] Molina | The perils of climate change: In utero exposure to temperature variability and birth outcomes in the Andean region[END_REF] and a study in France using a subset of our study population associated more variable temperature during weeks 4-18 after conception with lower term birth weight. [START_REF] Jakpor | Term birthweight and critical windows of prenatal exposure to average meteorological conditions and meteorological variability[END_REF] We did not find an association between preterm birth and the variability of temperature. Nor did we find an association with EHF, a heatwave index that accounts for acclimation to both location and season. This might be related to the fact that we only found critical windows for night-time heat (high Tmin) whereas EHF is based on Tmean. Our sample size may also have limited our ability to examine an infrequent acute exposure such as EHF. We also adjusted for EHF earlier in pregnancy, which may have reduced the effect of EHF shortly before delivery;

previous heatwave studies only examined exposure during the last week of pregnancy. [START_REF] Huang | Acute associations between heatwaves and preterm and early-term birth in 50 US metropolitan areas: a matched case-control study[END_REF][START_REF] Sun | Examining the joint effects of heatwaves, air pollution, and green space on the risk of preterm birth in California[END_REF] Overall, our findings suggest that daily mean, minimum, and maximum temperature may be more relevant for preterm birth than temperature variability or heatwaves.

Strengths and limitations

We estimated outdoor temperature at women's home address, but women likely spent time indoors (particularly at night) and at other locations (particularly early in pregnancy). We also lacked complete address history for a quarter of participants (all from the PELAGIE cohort);

for these women we used municipality or neighbourhood of residence at inclusion (mean 10. Although we adjusted for major confounders including maternal smoking, age, parity, and prepregnancy BMI, we were unable to adjust for some possible confounders such as household income (although we used education as a proxy), noise, and light at night. We also did not account for humidity, which may modify the physiological effects of heat. [START_REF] Davis | Humidity: A review and primer on atmospheric moisture and human health[END_REF] However, the evidence for humidity is mixed: some studies found it did not substantially modify the association between temperature and mortality [START_REF] Armstrong | The Role of Humidity in Associations of High Temperature with Mortality: A Multicountry, Multicity Study[END_REF][START_REF] Barnett | What measure of temperature is the best predictor of mortality?[END_REF] or birth outcomes 30 while others suggested a significant role [START_REF] Jakpor | Term birthweight and critical windows of prenatal exposure to average meteorological conditions and meteorological variability[END_REF] or that humidity's importance varies between locations. [START_REF] Bobb | A Bayesian model averaging approach for estimating the relative risk of mortality associated with heat waves in 105 U.S. cities[END_REF] Despite these limitations, our study has several strengths. Pooling three cohorts from different regions of France allowed us to increase the study population and capture greater climatic variability while maintaining detailed health data and similar lifestyles across participants. We estimated exposure at participants' home address with a spatiotemporally resolved temperature model. This likely reduced exposure error for the 45% of women that lived in rural areas, which often have few weather monitors, and the 33% of women that lived in large urban areas, where we were able to use 200 m temperature estimates that better capture urban heat islands and finescale spatial patterns. One previous study of temperature and birth weight found that associations disappeared when using coarser monitor-based exposure rather than residencebased exposure. [START_REF] Kloog | Using Satellite-Based Spatiotemporal Resolved Air Temperature Exposure to Study the Association between Ambient Air Temperature and Birth Outcomes in Massachusetts[END_REF] Consistently, our sensitivity analyses using 1 km rather than 200 m temperature for urban women showed similar trends as the main analysis but the associations were weakened and critical windows shortened.

We performed a survival analysis with pregnancy duration as the time variable, which is the most effective method to study time-varying exposures in cohorts. [START_REF] Lepeule | Survival analysis to estimate association between short-term mortality and air pollution[END_REF][START_REF] Suh | Different effects of PM10 exposure on preterm birth by gestational period estimated from time-dependent survival analyses[END_REF] It also avoids possible confounding by temporal trends in conception rates and accounts for the fact that the risk of preterm birth increases exponentially later in pregnancy. [START_REF] Strand | Methodological challenges when estimating the effects of season and seasonal exposures on birth outcomes[END_REF] To avoid underestimating gestational age in the case that temperature affects foetal growth during the first trimester, we preferred gestational duration calculated from the last menstrual period rather than from measurements performed at the first ultrasound. We accounted for lags in the effect of exposure, examined narrow windows, and adjusted our estimates of chronic effects (during the 26 weeks following conception) for acute effects (during the 30 days preceding delivery) and vice versa. We further adjusted for potential confounders such as season of conception, maternal age, education, and smoking, but did not adjust for air pollution because it may be on the causal pathway from temperature to preterm birth. [START_REF] Buckley | Does air pollution confound studies of temperature?[END_REF] Future research may investigate the possible synergistic effects of air pollution and temperature. [START_REF] Sun | Examining the joint effects of heatwaves, air pollution, and green space on the risk of preterm birth in California[END_REF][START_REF] Wang | Independent and combined effects of heatwaves and PM2:5 on preterm birth in Guangzhou, China: A survival analysis[END_REF][START_REF] Qiu | Prenatal exposure to particulate air pollution and gestational age at delivery in Massachusetts neonates 2001-2015[END_REF]

Conclusion

Our results indicate that, in a temperate climate, cold between the middle of the first and second trimesters may increase the risk of preterm birth and cold late in pregnancy may trigger preterm birth with a lag time of about one week. Night-time heat may be harmful during the five weeks following conception and the 6 th month of pregnancy. We found inconclusive evidence for heat as a short-term trigger of preterm birth. In the context of the demonstrated and increasing risks of climate change and preterm birth's association with poorer health in childhood and adulthood, health professionals and policy makers should use these findings to increase awareness of the risks of extreme temperature for pregnant women.

Figure 1 .

 1 Figure 1. Flow chart of the study population.

201abcd

  From conception to delivery. 202 Mean during the 26 weeks following conception. 203 Mean weekly standard deviation during the 26 weeks following conception.204 Mean during days 30-181 after conception (up to 26 weeks following conception).

Figure 2 .

 2 Figure 2. Adjusted relative risk (solid line) and 95% confidence interval (shaded area) for preterm birth associated with severe cold during the 26 weeks following conception (left) and the 30 days ending at delivery (right). Top: overall cold (5th percentile of Tmean); middle: daytime cold (5th percentile of Tmax); bottom: night-time cold (5th percentile of Tmin). Reference is 50th percentile of temperature. Models included exposure throughout pregnancy, area, season of conception, urbanicity, NDVI, child sex, and maternal characteristics (age at conception, height, pre-pregnancy BMI, parity, education, smoking during pregnancy). BMI, body mass index; NDVI, normalized difference vegetation index; Tmax, daily maximum temperature;

Figure 3 .

 3 Figure 3. Cumulative adjusted relative risk (RR) for preterm birth associated with ambient temperature exposure throughout an entire critical window. Bars show timing of critical windows; bar labels show cumulative RR (95% confidence interval). Models included exposure throughout pregnancy, area, season of conception, urbanicity, NDVI, child sex, and maternal characteristics (age at conception, height, pre-pregnancy BMI, parity, education, smoking during pregnancy). BMI, body mass index; NDVI, normalized difference vegetation index; Tmax, daily maximum temperature; Tmean, daily mean temperature; Tmin, daily minimum temperature.

Figure 4 .

 4 Figure 4. Adjusted relative risk (solid line) and 95% confidence interval (shaded area) for preterm birth associated with severe heat during the 26 weeks following conception (left) and the 30 days ending at delivery (right). Top: overall heat (95th percentile of Tmean); middle: daytime heat (95th percentile of Tmax); bottom: night-time heat (95th percentile of Tmin). Reference is 50th percentile of temperature. Models included exposure throughout pregnancy, area, season of conception, urbanicity, NDVI, child sex, and maternal characteristics (age at conception, height, pre-pregnancy BMI, parity, education, smoking during pregnancy). BMI, body mass index; NDVI, normalized difference vegetation index; Tmax, daily maximum temperature; Tmean, daily mean temperature; Tmin, daily minimum temperature.

Table 1 .

 1 Characteristics of the study population by cohort (n = 5347).

	200
		Consortium	EDEN	PELAGIE	SEPAGES
		n (%) or	n (%) or	n (%) or	n (%) or
		mean (sd)	mean (sd)	mean (sd)	mean (sd)
	Participants	5347 (100%) 1806 (33.8%) 3116 (58.3%)	425 (7.8%)
	Preterm births	232 (4.3%)	103 (5.7%)	110 (3.5%)	19 (4.5%)
	Duration of pregnancy a (weeks)	37.9 (1.7)	37.7 (1.8)	38.1 (1.6)	37.7 (1.5)
	Temperature b (°C)	11.8 (3.6)	11.3 (4.1)	12.1 (3.2)	12 (4.4)
	Temperature variability c (°C)	2.0 (0.3)	2.2 (0.2)	1.9 (0.3)	2.1 (0.2)
	Excess Heat Factor d	0.7 (1.1)	0.8 (1.3)	0.6 (0.9)	0.7 (1.0)
	Child sex
	Boy	2737 (51.2%)	940 (52%) 1572 (50.4%) 225 (52.9%)
	Girl	2610 (48.8%)	866 (48%) 1544 (49.6%) 200 (47.1%)
	Parity
	0	2374 (44.4%)	794 (44.0%) 1386 (44.5%) 194 (45.6%)
	1	2021 (37.8%)	670 (37.1%) 1166 (37.4%) 185 (43.5%)
	>=2	952 (17.8%)	342 (18.9%)	564 (18.1%)	46 (10.8%)
	Maternal age at conception (years) e	30 (4.5)	29.4 (4.9)	29.9 (4.3)	32.5 (3.9)
	Maternal height
	135-175 cm	4612 (86.3%) 1561 (86.4%) 2719 (87.3%) 332 (78.1%)
	170-190 cm	735 (13.7%)	245 (13.6%)	397 (12.7%)	93 (21.9%)
	Maternal pre-pregnancy BMI
	<18.5 kg/m 2	412 (7.7%)	157 (8.7%)	229 (7.3%)	26 (6.1%)
	18.5 -25 kg/m 2	3844 (71.9%) 1177 (65.2%) 2346 (75.3%) 321 (75.5%)
	>25 kg/m 2	1091 (20.4%)	472 (26.1%)	541 (17.4%)	78 (18.4%)
	Maternal education
	Baccalaureate or less	1987 (37.2%)	840 (46.5%) 1125 (36.1%)	22 (5.2%)
	Baccalaureate +1 or +2 years	1373 (25.7%)	415 (23.0%)	906 (29.1%)	52 (12.2%)
	>= Baccalaureate +3 years	1987 (37.2%)	551 (30.5%) 1085 (34.8%) 351 (82.6%)
	Smoking status during pregnancy
	None	4006 (74.9%) 1347 (74.6%) 2257 (72.4%) 402 (94.6%)
	Active smoker	1341 (25.1%)	459 (25.4%)	859 (27.6%)	23 (5.4%)
	NDVI e	0.50 (0.11)	0.46 (0.10)	0.52 (0.10)	0.49 (0.16)
	Urbanicity
	City-centre	896 (16.8%)	191 (10.6%)	547 (17.6%) 158 (37.2%)
	Small city-centre or suburban	2021 (37.8%)	879 (48.7%)	918 (29.5%) 224 (52.7%)
	Rural	2430 (45.4%)	736 (40.8%)	1651 (53%)	43 (10.1%)
	Season of conception
	Winter	1321 (24.7%)	431 (23.9%)	762 (24.5%) 128 (30.1%)
	Spring	1211 (22.6%)	371 (20.5%)	751 (24.1%)	89 (20.9%)
	Summer	1477 (27.6%)	527 (29.2%)	860 (27.6%)	90 (21.2%)
	Autumn	1338 (25.0%)	477 (26.4%)	743 (23.8%) 118 (27.8%)
	Cohort recruitment area
	Nancy	940 (17.6%)	940 (52%)	0 (0%)	0 (0%)
	Poitiers	866 (16.2%)	866 (48%)	0 (0%)	0 (0%)
	Côtes-d'Armor	898 (16.8%)	0 (0%)	898 (28.8%)	0 (0%)
	Finistère	157 (2.9%)	0 (0%)	157 (5.0%)	0 (0%)
	Ille-et-Vilaine	2061 (38.5%)	0 (0%) 2061 (66.1%)	0 (0%)
	Grenoble	425 (7.9%)	0 (0%)	0 (0%) 425 (100%)
	BMI, body mass index; NDVI, normalized difference vegetation index.

  4 weeks after conception), which may have increased exposure measurement error and biased our associations towards null. DLNM requires complete equal-length exposure histories, so we only considered exposure during the 26 weeks following conception and the 30 days ending at delivery. This could have led us to miss critical windows early in the third trimester (e.g. weeks 27-30 after conception).

A recent study in Rome and Barcelona found that acute heat was more harmful earlier in the third trimester, 17 so future studies should investigate critical windows in the first half of the third trimester. Such studies might stratify preterm birth by gestational age,

[START_REF] Schifano | Heat and air pollution exposure as triggers of delivery: A survival analysis of population-based pregnancy cohorts in Rome and Barcelona[END_REF]

or use alternate designs such as natural experiments.

[START_REF] Rich | Differences in birth weight associated with the 2008 Beijing olympics air pollution reduction: Results from a natural experiment[END_REF]

Our study's relatively small population precluded stratification and is another limitation.

Acknowledgements

We thank the two anonymous reviewers who helped improve the manuscript. We acknowledge the commitment of the EDEN mother-child cohort study group: I. Annesi-Maesano, JY. Bernard, J. Botton, MA. Charles, P. Dargent-Molina, B. de Lauzon-Guillain, P. Ducimeti.re, M. de Agostini, B. Foliguet, A. Forhan, X. Fritel, A. Germa, V. Goua, R. Hankard, B. Heude, M. Kaminski, B. Larroque, N. Lelong, J. Lepeule, G. Magnin, L. Marchand, C. Nabet, F. Pierre, R. Slama, MJ. Saurel-Cubizolles, M. Schweitzer, O. Thiebaugeorges. We also acknowledge the commitment of the SEPAGES study group: E. Eyriey, A. Licinia, A. Vellement (Groupe Hospitalier Mutualiste, Grenoble), I. Pin, P. Hoffmann, E. Hullo, C. Llerena (Grenoble Alpes University Hospital, La Tronche), X. Morin (Clinique des Cèdres, Echirolles), A. Morlot (Clinique Belledonne, Saint-Martin d'Hères), J. Lepeule, S. Lyon-Caen, C. Philippat, I. Pin, J.

Funding

This work was supported by the Fondation de France (CLIMATHES grant 00081169), the French Centre National de la Recherche Scientifique and Israel Ministry of Science and Technology (PRC 2018-2020). Ian Hough is supported by a grant from the French National Agency for Research in the framework of the "Investissements d'avenir" program (ANR-15-IDEX-02) and Ben Gurion University of the Negev. The EDEN cohort was supported by the Foundation for Medical Research, the National Agency for Research, the National Institute for Research in Public Health (IRESP: TGIR cohorte sant. 2008 program), the French Ministry of Health, the French Ministry of Research, the Inserm Bone and Joint Diseases National Research and Human Nutrition National Research Programs, Paris-Sud University, Nestlé, the French National Institute for Population Health Surveillance, the French National Institute for Health Education, the European Union FP7 programmes (FP7/2007-2013, HELIX, ESCAPE, ENRIECO, Medall projects), the Diabetes National

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author with permission of the EDEN, PELAGIE, and SEPAGES steering committees.

Ethics approval

All participating women gave informed written consent for themselves and their children.

Supplementary data

Supplementary data are available at IJE online.

Author contributions

IH helped design the study, prepared data, performed analyses, interpreted the results, and wrote the manuscript. MR helped design the study, prepared data, performed analyses, helped interpret the results, and edited the manuscript. AG helped design the study, prepared data, Quentin, V. Siroux, R. Slama (Grenoble Alpes University, Inserm, CNRS, IAB). We thank the many people that assisted with the cohorts, especially the participants.

Conflict of interest

None declared.