Abstract
The incidence and severity of heatwaves are increasing globally with concomitant health complications. Pregnancy is a critical time in the life course at risk of adverse health outcomes due to heat exposure. Dynamic physiological adaptations, which include altered thermoregulatory pathways, occur in pregnancy. If heat dissipation is ineffective, maternal and neonate health outcomes can be compromised. Indeed, epidemiological studies and animal models reveal that exposure to heat in pregnancy likely elicits an array of health complications including miscarriage, congenital anomalies, low birth weight, stillbirth, and preterm birth. Despite these associations, the reasons for why these complications occur are unclear. An array of physiological and endocrine changes in response to heat exposure in pregnancy likely underpin the adverse health outcomes, but currently, conclusive evidence is sparse. Accompanying these fundamental gaps in knowledge is a poor understanding of what exact climatic conditions challenge pregnant physiology. Moreover, the overlay of thermoregulatory-associated behaviours such as physical activity needs to be taken into consideration when assessing the risks to human health and identifying critical populations at risk. While the health impacts from heat are largely preventable through strategic interventions, for the related clinical practice, public health, and policy approaches to be effective, the gaps in basic science understanding urgently need to be addressed.
Invited Author’s profile
Caitlin Wyrwoll is Associate Professor in the School of Human Sciences, The University of Western Australia. Her research background is on the impact of stress on placental and fetal development and the ramifications for offspring health in later life. Her recent research focuses on the environmental change (particularly heat exposure and drinking water quality) on maternal adaptations to pregnancy and child health outcomes. This work is becoming increasingly transdisciplinary with integration of discovery science with lived experience and environmental epidemiology. She is a research theme lead within The NHMRC Healthy Environments and Lives (HEAL) Network.
Introduction
The effects of climate change on health are an emerging public health crisis. The pathways between climate change and human health are myriad and include both direct and indirect effects. Global warming is driving extreme weather events (heatwaves, floods, drought, and fire), air quality is declining, and ecosystems and biodiversity are under threat. This rapid environmental change is leading to health issues such as undernutrition, mental health complications, cardiovascular and respiratory disease, with disproportionate complications in marginalised communities, outdoor workers, and people at critical life stages.
A key critical life stage is pregnancy; a time of striking physiological and behavioural adaptations, orchestrated by maternal, placental, and fetal endocrine signals. These adaptations are crucial to support the embryo and fetus, and alterations to established adaptations can compromise development. Thus, environmental stressors related to climate change have ramifications not only for short-term maternal, fetal, and infant health but also for the long-term consequences, as the early life environment is a powerful determinant of adult health.
This narrative review predominantly focuses on the health impact and underlying physiological and endocrine considerations of increased heatwave exposure during pregnancy. While there is evidence that heat exposure causes pregnancy complications, the evidence for the underlying biological changes that elicit these adverse effects is surprisingly sparse. Given the potential adverse maternal and fetal health impacts and the projected increase in higher seasonal temperatures and severity and frequency of heatwaves, more research in this area is urgently required.
Thermoregulation in pregnancy
As global average temperatures increase, the frequency and duration of heatwaves are intensifying (IPCC 2022). Heatwaves have significant social, health, and economic impacts globally, with heatwave events increasing morbidity and mortality (IPCC 2022). A recent global overview of the mortality burden due to non-optimal temperatures highlighted that Europe, particularly Eastern Europe, and Oceania have increased heat-related deaths in comparison to other regions (Zhao et al. 2021). Further delineation into the effects of short-term (days) temperature variability on mortality reveals that much of Asia, Australia, and New Zealand have a higher mortality burden than the global mean, highlighting that acute physiological response to temperature change challenges health (Wu et al. 2022). Indeed, in Australia, heatwaves contribute to 55% of excess mortality due to natural hazards, which is more than all other natural hazards combined (Coates et al. 2014), with recent evidence that official records underestimate heat-related mortality by at least 50-fold (Longden 2019). Further, global studies are limited by the available health data, and the paucity of data from some countries will affect outcomes. This highlights that the ramification of heat not only for mortality but also morbidity is likely grossly underappreciated and further compounded when considering the health of pregnant and newborn people, a frequently neglected research and policy area.
A range of physiological and behavioural adaptations must occur in pregnancy, with one crucial adaptation being an alteration of thermoregulatory pathways. During gestation, heat production is increased due to metabolic heat from the developing placenta and fetus. The fetus is entirely dependent on maternal heat dissipation and temperature stability, which needs to be maintained within a narrow margin (Laburn et al. 1992, Schroder & Power 1997, Laburn et al. 2002, Hartgill et al. 2011). For successful fetal heat dissipation, a feto–maternal temperature gradient is established. This occurs as the fetus produces high metabolic heat relative to its mass and placental blood flow then determines fetal heat dissipation (Laburn et al. 1992). When in gestation the temperature gradient is established is unclear due to experimental and ethical constraints; this gap in knowledge could be overcome using modelling approaches. However, it is clear that by late gestation in mammals, the fetal temperature is approximately 0.5℃ (±0.1℃) higher than the maternal core temperature (Laburn et al. 1992, Faurie et al. 2004). The vast majority of the heat produced by the fetus is transferred to the mother via the placental circulation, and the remaining heat is transferred through the amniotic fluid to the uterine wall (Laburn 1996). Thus, in situations when the maternal core temperature is elevated, fetal heat transfer is reduced.
Heat dissipation mechanisms in pregnancy include reduction of core temperature, vasodilation of cutaneous blood vessels, increased sweat production, increased plasma volume, and heightened thermal heat capacity due to increased body mass (Abrams et al. 1970, Clapp 1991, Lindqvist et al. 2003, Dervis et al. 2021, Samuels et al. 2022). Altered behaviours are also crucial for effective thermoregulation. In the context of human pregnancy, the capacity for thermoregulatory behaviours is an important consideration for considering at-risk populations. Access to cooling may be limited in climate zones with increasing atypical ambient temperatures and in low socioeconomic populations. Physical activity can further exacerbate heat exposure, a particular concern for outdoor labour when pregnant; females make up a significant proportion of the global agricultural workforce, particularly in low-income countries (Spencer et al. 2022). Physiological processes, including endocrine regulation, become compromised if effective heat dissipation does not occur. Therefore, if the capacity to transfer heat to the external environment is limited, maternal health, placental development and function, and child health outcomes can be compromised.
Heat exposure in pregnancy causes health complications: epidemiological and experimental model evidence
Epidemiological investigations associate heatwave events with an array of health complications in pregnancy. These complications vary by gestational stage – with heightened vulnerability in the first trimester proposed to elicit an increased risk of miscarriage and congenital anomalies. While there is some evidence for chronic heat exposure and congenital anomalies in humans (Haghighi et al. 2021), there is currently no clear evidence for increased miscarriage incidence. In other mammals such as sheep, these complications tend to occur in severe acute heat stress; once maternal core temperature is elevated from 1.5℃ to 2℃ above baseline (Gericke et al. 1989, Graham et al. 1998, Miller et al. 2002).
The evidence for heat exposure associating with pregnancy complications is stronger in later gestation when physiological and endocrine processes are accommodating substantial maternal adaptation, placental function, and fetal demand. Chronic heat exposure in later gestation, particularly in the third trimester, is associated with preterm birth, stillbirth, low birth weight, preeclampsia, pregnancy-associated hypertension, gestational diabetes, neonatal stress, and emergency hospital admissions (Cil & Cameron 2017, Chersich et al. 2020, Haghighi et al. 2021). A recent systematic review has highlighted that a consistent outcome variable in epidemiological studies of chronic heat exposure in pregnancy is preterm birth and stillbirth (Chersich et al. 2020). With every 1°C increase in temperature, preterm birth and stillbirth rates purportedly rise by 5%, suggesting a dose response (Chersich et al. 2020). Preterm birth rates increase by 16% during heatwaves, with exposure at 37–39 weeks a likely critical window, although this may be earlier for at-risk populations (Chersich et al. 2020). In comparison to preterm birth, associations of heat exposure with fetal growth restriction or low birth weight in human populations are less consistent (Chersich et al. 2020, Syed et al. 2022). Further, while evidence for heat increasing maternal mortality is limited, it has been highlighted as a potential strong predictor of pregnancy-related mortality in the United States of America (Harville et al. 2022), but further work is required to address this gap in knowledge. Associations of heat exposure with preterm birth and reduced fetal weight are further pronounced in populations already at risk of these complications including low socioeconomic groups (Son et al. 2019), black and Hispanic women in the US (Carmichael et al. 2014, Ngo & Horton 2016, Basu et al. 2017, 2018), First Nations Australians (Wang et al. 2013), and those with chronic conditions (Schifano et al. 2013, Basu et al. 2017). The adverse health impact of heat exposure in pregnancy also extends to negative implications for mental health (Lin et al. 2017) and challenges for physical activity and outdoor work (Spencer et al. 2022). These factors likely contribute to an increased risk of pregnancy complications.
While there is epidemiological evidence, there is little fundamental understanding of why heat exposure in pregnancy places maternal and neonate health at risk. It remains unclear whether the increasing prevalence of health complications is due to heat stress or the physiological consequences associated with extreme ambient temperature. Potential critical windows of exposure are difficult to identify from epidemiological studies due to the overlay of other environmental exposures, limitations in health and climate data, and the long gestational period of humans. Moreover, there is limited definitive evidence for human health implications due to ethical considerations. There is utility in animal models for overcoming these limitations in understanding, but they need to be approached carefully.
Rodents, particularly rats and mice, are commonly used for assessing the consequences of environmental exposures on pregnancy outcomes and offspring health. Intermittent heat exposure of mice in late gestation results in effective maternal thermoregulatory adaptations at the expense of restricted placental and fetal development (Olivier et al. 2021). In rats, chronic high-temperature housing during pregnancy delays the offspring’s neurodevelopmental milestones (Adebiyi et al. 2022). Rodent models of heat exposure have caveats in their application to human health; standard laboratory housing conditions of rodents are frequently below their thermoneutral zone which makes the comparison of experimental to control animals challenging (Olivier et al. 2021). Further, rodents have effective thermoregulatory behaviours that increase heat loss including altered nest building and grooming saliva onto fur (Gordon 1990).
Exposure of sheep, a common experimental model, to high temperatures restricts fertility (including early embryo loss), decreases birthweight, and reduces live births (for review see van Wettere et al. 2021), but to date, there is no clear evidence for preterm birth. Similar outcomes are also observed in cattle with a reduction in fertility (for a review see Roth 2020). The effects of heat on sheep and cattle reproduction is a growing area due to the agricultural based concerns for animal welfare and economic impact. Utilisation of sheep as an experimental model enables elegant maternal and fetal physiological assessments that are not possible in humans. However, the different thermoregulatory responses of different species (Mitchell et al. 2018) in comparison to humans need to be taken into consideration. Further, in human pregnancy, the limited capacity of the placenta to accommodate/compensate for environmental stressors in late gestation and the increased physiological demand of a long gestation may pronounce adverse consequences of heat exposure in comparison to animal models. Implementation of further experimental approaches and the research synergy between the agricultural and human health sectors will hopefully add substantially to understanding in the next few years.
Physiological and endocrine changes due to heat exposure in pregnancy
Numerous biological processes in pregnancy affected by heat exposure have been posited. They include reduced placental function, dehydration, and altered uterine contractility and increased inflammation. These, other considerations, and the associated endocrine milieu are outlined below.
Placental function
During heat exposure, placental perfusion may decline to facilitate increased blood flow to the skin and thus heat loss. If restricted placental perfusion does occur, it would be likely a critical mechanism underlying the epidemiological observations of fetal growth restriction and stillbirth. However, evidence for this is variable and limited. In ruminants, chronic heat exposure has been shown to reduce placental diffusion capacity and result in fetal hypoxia (Thureen et al. 1992, Galan et al. 1998, Regnault et al. 2003), while others have shown increased flow during acute heat stress (Laburn 1996). Recent elegant work has shown that exposure of pregnant subsistence farmers to heat while doing manual labour increased maternal and fetal strain (defined by fetal heart rate changes or increased umbilical resistance index) (Bonell et al. 2022). As discussed further below, this highlights that exposure to acute heat events in pregnancy has different health implications in comparison to more prolonged periods, and the overlay of behaviour such as activity levels during heat events is an important consideration when assessing risk.
Heat exposure may also alter placental morphology and function. Chronic heat exposure in ruminants and rodents decreases placental size and vascularisation (Collier et al. 1982, Bell et al. 1989, Olivier et al. 2021). Accompanying reduced vascularisation is decreased expression of placental growth factor, vascular endothelial growth factor, and associated receptors (Regnault et al. 2002, Olivier et al. 2021), as well as reduced amino acid transfer and reduced glucose transport capacity (Thureen et al. 1992). These alterations likely contribute to placental dysfunction, therefore contributing to fetal growth restriction.
Uterine contractility
Modification of pathways associated with uterine contractility is frequently, but not conclusively, implicated in heat exposure. However, given that preterm birth is a frequent outcome in epidemiological studies highlights the need for a comprehensive understanding of how uterine contractility may be altered by heat exposure. Initiation of labour is complex but involves the interplay of factors from the fetus, fetal membranes, placenta, and mother. Acute heat exposure has been reported to increase maternal glucocorticoid levels (Leon et al. 2006, McMorris et al. 2006, Wang et al. 2015). In contrast, chronic exposure of pregnant mice to heat in the final days of gestation did not clearly elevate maternal corticosterone concentrations when blood was analysed at the end of the heat exposure regime (Olivier et al. 2021). Elevations in cortisol during heat exposure could potentially stimulate uterine contractions via alteration in oxytocin/prostaglandin pathways (Chersich et al. 2020, Samuels et al. 2022). Further, acute heat exposure in animals near term, when the elevated oestrogenic milieu prime uterine contractility response, increases oxytocin and prostaglandin levels (Dreiling et al. 1991, Wolfenson et al. 1993). Hyperthermia also elevates arginine vasopressin which can also induce oxytocin-mediated uterine contractility (Åkerlund 2002, Sharif-Naeini et al. 2008). Implications for elevated glucocorticoids also extend to their potent effects on fetal tissue development, with overexposure in the fetal period, particularly in late gestation, leading to adverse cardiometabolic and neuropsychiatric outcomes in adult life (Shearer et al. 2019).
Dehydration
Maternal dehydration due to limited fluid intake and sweating in late gestation is an additional component of the health complications that arise from elevated ambient temperature. Indeed, reduced amniotic fluid (which is impacted by the maternal hydration as well as renal function and placental perfusion) has been noted during heatwaves (Sciscione et al. 1997, Luton et al. 2004) and is a marker for fetal complications. Dehydration will reduce vascular volume and uterine blood flow and may increase antidiuretic hormone and oxytocin (Theobald 1959). This may have consequent effects on preterm birth. However, if this hypothesis extends to a therapeutic context is unclear, in a randomised clinical trial, improving hydration status does not improve outcomes for threatened preterm birth (Guinn et al. 1997). However, this study was not done in the context of improving the hydration status of heat-exposed pregnancies.
Inflammation and infection
Little consideration has been placed on the effect of heatwaves on inflammation and infection in pregnancy, leading causes of preterm birth. Gestational age at delivery is inversely associated with the prevalence of intrauterine inflammation and/or infection (Stinson & Payne 2019). Heat exposure can increase inflammatory-related pathways including cytokines in animals and non-pregnant people but if this is also the case in pregnancy is not clear. This gap in knowledge needs to be addressed as cytokine balance is crucial for pregnancy progression. Acute exposure to high ambient temperatures may initiate the cell stress response and subsequently induce changes in gene expression and protein activity in cells (Horowitz 2002, Sonna et al. 2002). To reduce the negative impacts of thermal stress on cells, genes associated with increased thermotolerance such as heat shock proteins are temporarily upregulated in numerous tissues and organs (Kregel 2002, Sonna et al. 2002) and can cause the release of proinflammatory cytokines. The degree to which these genes are upregulated depends on the severity of the stressor (Kregel 2002). Whether this applies to heat exposure in pregnancy is unclear but elevated heat shock proteins are associated with fetal growth restriction, stillbirth, preterm birth, preeclampsia, and uterine contractility (Samuels et al. 2022). Heat shock proteins are critical for decidualisation and implantation (Jee et al. 2021), and as such changes may be implicated in miscarriage. However, as discussed above, there is no clear evidence that chronic heat exposure associates with miscarriage in humans.
How heat alters infection status in pregnancy has also not been addressed. Infection of the amniotic cavity occurs due to bacteria in the cervicovaginal mucosal layer breaching the cervical barrier and colonising the decidua and fetal membranes, referred to as chorioamnionitis (Stinson & Payne 2019). Chorioamnionitis instigates preterm birth via the activation of inflammatory processes that promote the onset of labour, rupture of membranes and dilation of the cervix (Stinson & Payne 2019). Of interest, vaginal Lactobacillus sp. depletion is strongly associated with preterm birth (Brown et al. 2019, Payne et al. 2021) and is reduced by heat exposure (Song et al. 2020, Shi et al. 2022). Thus, ascertaining whether existing infection in pregnancy is exacerbated by heat exposure is of interest.
Other considerations
Much of the evidence to date points to the heat exposure in late pregnancy, when maternal adaptations and fetal demand are maximal, as the critical period that alters endocrine and physiological responses, leading to pregnancy complications. Heat-related complications in early pregnancy could also be driven by a perturbed endocrine response although the evidence from this is predominantly from ruminant-based studies. Thus, sheep and cattle fertility declines with heat exposure, which may be mediated in part by alterations in the hyplothalamic–pituitary–gonadal axis. Oestrous cycle length becomes reduced in response to heat, with an underlying decrease in luteinising hormone (LH) secretion, reduced LH pulsatility, perturbed circulating oestradiol and progesterone, and impaired follicular growth and development (Roth 2020, van Wettere et al. 2021).
For pregnancies with existing gestational complications (i.e. diabetes, pre-eclampsia, and hypertension), heat exposure may further challenge physiology and exacerbate adverse outcomes. Following from this, the current associations of heatwave exposure and preterm birth need further delineation to determine whether spontaneous or iatrogenic preterm birth rates are increasing. Approximately 30% of preterm births are iatrogenic with pre-eclampsia and fetal growth restriction leading causes (Valencia et al. 2021). If heat exposure is exacerbating pregnancy complications for people with these conditions, then this may be increasing early labour induction and caesarean delivery. A further important consideration for neonatal health is the effect of heat exposure on lactation, which is a highly metabolic, heat-producing process. There is limited information on this in humans although in dairy cows (Monteiro et al. 2016) and mice (Bao et al. 2020), heat exposure decreases milk production but the implications for milk composition are unclear.
How hot is too hot?
Underpinning the lack of understanding of altered biological pathways from heat exposure in pregnancy, there is also a lack of knowledge on how effectively pregnant females adapt in different climate contexts and what specific environmental conditions (temperature, humidity, and wind) present the greatest thermoregulatory challenge. The definition of what constitutes a heatwave is variable, but the general principle is that it involves a sequence of days with air temperature higher than the average for the season and geographical area. Acclimation to a particular climate zone may confer different risks in pregnancy when heatwaves or atypical elevated ambient temperature for that climate zone occurs, but currently evidence is limited for this.
Pregnant thermoregulatory physiology seems robust in response to acute heat exposure. Thus, short-term exposure (under an hour) to elevated temperature through exercise, sauna, or hot bath does not substantially alter maternal core temperature (Ravanelli et al. 2019, Smallcombe et al. 2021). However, prolonged high ambient temperature (including at night which will disrupt normal circadian rhythm), the overlay of prolonged physical activity, and climatic factors other than temperature all need to be taken into consideration when assessing health risks in pregnancy. The ability of a human to maintain core body temperature depends on factors aside from the temperature of the air, especially humidity, wind speed, and solar radiation. If human thermoregulation is the underlying mechanism of pregnancy complications due to heatwaves, then indices of human thermoregulation (Maloney & Forbes 2011) should provide a more accurate prediction of what aspects of heat are responsible for which adverse pregnancy outcome. If pregnancy has a heightened vulnerability to certain climatic conditions in comparison to non-pregnant health has yet to be determined. Increasingly, studies such asBonell et al. (2022) are utilising different indices to assess the role of human thermal balance in health complications.
Broader perspectives
Unfortunately, exposure to heatwaves does not occur in isolation from other environmental changes. Exposure to air pollution increases the risk of adverse antenatal health outcomes and, when coupled with extreme heat events, pregnancy complications are exacerbated (Bekkar et al. 2020). Climate change affects crop yields and crop nutritional composition (Soares et al. 2019), which places a disproportionate burden on those pregnant or lactating as they have greater nutritional requirements. Climate change exacerbates inequities in access to sufficient and safe drinking water, with water contaminants such as nitrate placing a further burden on the pregnant health (Sherris et al. 2022). Increases in vector-borne disease (Colón-González et al. 2021) and the physiological and psychological stresses caused by extreme weather events and forced migration will also complicate short- and long-term health (Cianconi et al. 2020).
Concurrent with consideration of multiple environmental exposures is low- and middle-income countries (LMIC) context where heat exposure in pregnancy will convey greater health risks. Rates of preterm birth in LMIC are already higher than the global average, and there are more likely to be subgroups of populations who have reduced physiological capacity to respond to heat variability due to factors such as malaria, multiple pregnancies, HIV infection, and other chronic conditions (Basu et al. 2017, Chersich et al. 2020). This, accompanied by challenges in accessing adequate healthcare and cool spaces, highlights an urgent need for evidence-informed community-based health education and promotion.
Further, the long-term health implications of heat exposure in pregnancy are unclear. Drawing on the comprehensive field of ‘developmental origins of adult disease’, it is clear that the environmental perturbations in utero that result from climate change, including heatwave exposure, will have enduring adverse effects on the offspring health. Moreover, the physiological challenges directly experienced during pregnancy may predicate health complications in older age. The specific effects of heat exposure in pregnancy on later health will be difficult to ascertain in human populations, again highlighting the utility of animal models.
Conclusions
Globally, pregnant people will be increasingly exposed to heatwaves, and with this comes significant adverse individual and societal impact. The consideration of pregnancy as a time in the life course more at risk of the adverse effects of heat is relatively recent, and general knowledge on health protective behaviours during heatwaves when pregnant is limited. The populations most likely at risk of heat exposure already have high rates of pregnancy-related complications and chronic conditions and as global temperatures increase, the health risks during pregnancy will likely compound. Health impacts from heat in pregnancy are largely preventable through strategic interventions to facilitate cooling behaviours (improved housing and workplaces, fluid availability, and activity guidelines). However, for clinical practice, public health, and policy to be effective, addressing the gaps in evidence and understanding urgently needs to be prioritised.
Declaration of interest
The author has no conflict of interest.
Funding
This work is related to funding from the National Health and Medical Research Council Special Initiative in Human Health and Environmental Change (Grant no. 2008937).
Acknowledgements
Many thanks to numerous colleagues for various discussions on this topic over the years, particularly Professor Shane Maloney. The author acknowledges the Healthy Environments and Lives (HEAL) National Research Network, of which they are a research theme lead.
References
Abrams R, Caton D, Clapp J & & Barron DH 1970 Thermal and metabolic features of life in utero. Clinical Obstetrics and Gynecology 13 549–564. (https://doi.org/10.1097/00003081-197009000-00005)
Adebiyi OE, Adigun KO, Adebiyi AI & & Odenibi BS 2022 High environmental temperature: insights into behavioural, neurodevelopmental and gut microbiome changes following gestational exposure in rats. Neuroscience 488 60–76. (https://doi.org/10.1016/j.neuroscience.2022.02.026)
Åkerlund M 2002 Chapter 28 involvement of oxytocin and vasopressin in the pathophysiology of preterm labor and primary dysmenorrhea. Progress in Brain Research 139 359–365. (https://doi.org/10.1016/s0079-6123(0239030-7)
Bao MH, Chen LB, Hambly C, Speakman JR & & Zhao ZJ 2020 Exposure to hot temperatures during lactation in Swiss mice stunts offspring growth and decreases future reproductive performance of female offspring. Journal of Experimental Biology 223. (https://doi.org/10.1242/jeb.223560)
Basu R, Chen H, Li DK & & Avalos LA 2017 The impact of maternal factors on the association between temperature and preterm delivery. Environmental Research 154 109–114. (https://doi.org/10.1016/j.envres.2016.12.017)
Basu R, Rau R, Pearson D & & Malig B 2018 Temperature and term low birth weight in California. American Journal of Epidemiology 187 2306–2314. (https://doi.org/10.1093/aje/kwy116)
Bekkar B, Pacheco S, Basu R & & DeNicola N 2020 Association of air pollution and heat exposure with preterm birth, low birth weight, and stillbirth in the US: a systematic review. JAMA Network Open 3 e208243. (https://doi.org/10.1001/jamanetworkopen.2020.8243)
Bell AW, McBride BW, Slepetis R, Early RJ & & Currie WB 1989 Chronic heat stress and prenatal development in sheep: I. Conceptus growth and maternal plasma hormones and Metabolites2. Journal of Animal Science 67 3289–3299. (https://doi.org/10.2527/jas1989.67123289x)
Bonell A, Sonko B, Badjie J, Samateh T, Saidy T, Sosseh F, Sallah Y, Bajo K, Murray KA, Hirst J, et al.2022 Environmental heat stress on maternal physiology and fetal blood flow in pregnant subsistence farmers in the Gambia, west Africa: an observational cohort study. Lancet. Planetary Health 6 e968–e976. (https://doi.org/10.1016/S2542-5196(2200242-X)
Brown RG, Al-Memar M, Marchesi JR, Lee YS, Smith A, Chan D, Lewis H, Kindinger L, Terzidou V, Bourne T, et al.2019 Establishment of vaginal microbiota composition in early pregnancy and its association with subsequent preterm prelabor rupture of the fetal membranes. Translational Research 207 30–43. (https://doi.org/10.1016/j.trsl.2018.12.005)
Carmichael SL, Cullen MR, Mayo JA, Gould JB, Loftus P, Stevenson DK, Wise PH & & Shaw GM 2014 Population-level correlates of preterm delivery among black and white women in the U.S. PLoS One 9 e94153. (https://doi.org/10.1371/journal.pone.0094153)
Chersich MF, Pham MD, Areal A, Haghighi MM, Manyuchi A, Swift CP, Wernecke B, Robinson M, Hetem R, Boeckmann M, et al.2020 Associations between high temperatures in pregnancy and risk of preterm birth, low birth weight, and stillbirths: systematic review and meta-analysis. BMJ 371 m3811. (https://doi.org/10.1136/bmj.m3811)
Cianconi P, Betrò S & & Janiri L 2020 The impact of climate change on mental health: a systematic descriptive review. Frontiers in Psychiatry 11 74. (https://doi.org/10.3389/fpsyt.2020.00074)
Cil G & & Cameron TA 2017 Potential climate change health risks from increases in heat waves: abnormal birth outcomes and adverse maternal health conditions. Risk Analysis 37 2066–2079. (https://doi.org/10.1111/risa.12767)
Clapp JF 3rd 1991 The changing thermal response to endurance exercise during pregnancy. American Journal of Obstetrics and Gynecology 165 1684–1689. (https://doi.org/10.1016/0002-9378(9190015-j)
Coates L, Haynes K, O’Brien J, McAneney J & & de Oliveira FD 2014 Exploring 167 years of vulnerability: an examination of extreme heat events in Australia 1844–2010. Environmental Science and Policy 42 33–44. (https://doi.org/10.1016/j.envsci.2014.05.003)
Collier RJ, Doelger SG, Head HH, Thatcher WW & & Wilcox CJ 1982 Effects of heat stress during pregnancy on maternal hormone concentrations, calf birth weight and postpartum milk yield of Holstein cows. Journal of Animal Science 54 309–319. (https://doi.org/10.2527/jas1982.542309x)
Colón-González FJ, Sewe MO, Tompkins AM, Sjödin H, Casallas A, Rocklöv J, Caminade C & & Lowe R 2021 Projecting the risk of mosquito-borne diseases in a warmer and more populated world: a multi-model, multi-scenario intercomparison modelling study. Lancet. Planetary Health 5 e404–e414. (https://doi.org/10.1016/S2542-5196(2100132-7)
Dervis S, Dobson KL, Nagpal TS, Geurts C, Haman F & & Adamo KB 2021 Heat loss responses at rest and during exercise in pregnancy: a scoping review. Journal of Thermal Biology 99 103011. (https://doi.org/10.1016/j.jtherbio.2021.103011)
Dreiling CE, Carman FS & & Brown DE 1991 Maternal endocrine and fetal metabolic responses to heat stress. Journal of Dairy Science 74 312–327. (https://doi.org/10.3168/jds.S0022-0302(9178175-7)
Faurie AS, Mitchell D & & Laburn HP 2004 Peripartum body temperatures in free-ranging ewes (Ovis aries) and their lambs. Journal of Thermal Biology 29 115–122. (https://doi.org/10.1016/j.jtherbio.2003.12.004)
Galan HL, Hussey MJ, Chung M, Chyu JK, Hobbins JC & & Battaglia FC 1998 Doppler velocimetry of growth-restricted fetuses in an ovine model of placental insufficiency. American Journal of Obstetrics and Gynecology 178 451–456. (https://doi.org/10.1016/s0002-9378(9870419-3)
Gericke GS, Hofmeyr GJ, Laburn H & & Isaacs H 1989 Does heat damage fetuses? Medical Hypotheses 29 275–278. (https://doi.org/10.1016/0306-9877(8990111-4)
Gordon CJ 1990 Thermal biology of the laboratory rat. Physiology and Behavior 47 963–991. (https://doi.org/10.1016/0031-9384(9090025-y)
Graham JM Jr, , Edwards MJ, & Edwards MJ1998 Teratogen update: gestational effects of maternal hyperthermia due to febrile illnesses and resultant patterns of defects in humans. Teratology 58 209–221. (https://doi.org/10.1002/(SICI)1096-9926(199811)58:5<209::AID-TERA8>3.0.CO;2-Q)
Guinn DA, Goepfert AR, Owen J, Brumfield C & & Hauth JC 1997 Management options in women with preterm uterine contractions: a randomized clinical trial. American Journal of Obstetrics and Gynecology 177 814–818. (https://doi.org/10.1016/s0002-9378(9770274-6)
Haghighi MM, Wright CY, Ayer J, Urban MF, Pham MD, Boeckmann M, Areal A, Wernecke B, Swift CP, Robinson M, et al.2021 Impacts of high environmental temperatures on congenital anomalies: a systematic review. International Journal of Environmental Research and Public Health 18 4910. (https://doi.org/10.3390/ijerph18094910)
Hartgill TW, Bergersen TK & & Pirhonen J 2011 Core body temperature and the thermoneutral zone: a longitudinal study of normal human pregnancy. Acta Physiologica 201 467–474. (https://doi.org/10.1111/j.1748-1716.2010.02228.x)
Harville EW, Grady SK, Langston MA, Juarez PJ, Vilda D & & Wallace ME 2022 The public health exposome and pregnancy-related mortality in the United States: a high-dimensional computational analysis. BMC Public Health 22 2097. (https://doi.org/10.1186/s12889-022-14397-x)
Horowitz M 2002 From molecular and cellular to integrative heat defense during exposure to chronic heat. Comparative Biochemistry and Physiology. Part A, Molecular and Integrative Physiology 131 475–483. (https://doi.org/10.1016/s1095-6433(0100500-1)
IPCC 2022 Climate Change 2022: Impacts, Adaptation and Vulnerability. Contribution of Working Group II to the Sixth Assessment Report of the Intergovernmental Panel on Climate Change. H-O Pörtner et al. (eds.). Cambridge UK and New York, NY, USA: Cambridge University Press. (https://doi.org/10.1017/9781009325844)
Jee B, Dhar R, Singh S & & Karmakar S 2021 Heat shock proteins and their role in pregnancy: redefining the function of “old rum in a new bottle”. Frontiers in Cell and Developmental Biology 9 648463. (https://doi.org/10.3389/fcell.2021.648463)
Kregel KC 2002 Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance. Journal of Applied Physiology 92 2177–2186. (https://doi.org/10.1152/japplphysiol.01267.2001)
Laburn HP 1996 How does the fetus cope with thermal challenges? Physiology 11 96–100. (https://doi.org/10.1152/physiologyonline.1996.11.2.96)
Laburn HP, Faurie A, Goelst K & & Mitchell D 2002 Effects on fetal and maternal body temperatures of exposure of pregnant ewes to heat, cold, and exercise. Journal of Applied Physiology 92 802–808. (https://doi.org/10.1152/japplphysiol.00109.2001)
Laburn HP, Mitchell D & & Goelst K 1992 Fetal and maternal body temperatures measured by radiotelemetry in near-term sheep during thermal stress. Journal of Applied Physiology 72 894–900. (https://doi.org/10.1152/jappl.1992.72.3.894)
Leon LR, Blaha MD & & DuBose DA 2006 Time course of cytokine, corticosterone, and tissue injury responses in mice during heat strain recovery. Journal of Applied Physiology 100 1400–1409. (https://doi.org/10.1152/japplphysiol.01040.2005)
Lin Y, Hu W, Xu J, Luo Z, Ye X, Yan C, Liu Z & & Tong S 2017 Association between temperature and maternal stress during pregnancy. Environmental Research 158 421–430. (https://doi.org/10.1016/j.envres.2017.06.034)
Lindqvist PG, Marsal K, Merlo J & & Pirhonen JP 2003 Thermal response to submaximal exercise before, during and after pregnancy: a longitudinal study. Journal of Maternal-Fetal and Neonatal Medicine 13 152–156. (https://doi.org/10.1080/jmf.13.3.152.156)
Longden T 2019 The impact of temperature on mortality across different climate zones. Climatic Change 157 221–242. (https://doi.org/10.1007/s10584-019-02519-1)
Luton D, Alran S, Fourchotte V, Sibony O & & Oury JF 2004 Paris heat wave and oligohydramnios. American Journal of Obstetrics and Gynecology 191 2103–2105. (https://doi.org/10.1016/j.ajog.2004.05.090)
Maloney SK & & Forbes CF 2011 What effect will a few degrees of climate change have on human heat balance? Implications for human activity. International Journal of Biometeorology 55 147–160. (https://doi.org/10.1007/s00484-010-0320-6)
McMorris T, Swain J, Smith M, Corbett J, Delves S, Sale C, Harris RC & & Potter J 2006 Heat stress, plasma concentrations of adrenaline, noradrenaline, 5-hydroxytryptamine and cortisol, mood state and cognitive performance. International Journal of Psychophysiology 61 204–215. (https://doi.org/10.1016/j.ijpsycho.2005.10.002)
Miller MW, Nyborg WL, Dewey WC, Edwards MJ, Abramowicz JS & & Brayman AA 2002 Hyperthermic teratogenicity, thermal dose and diagnostic ultrasound during pregnancy: implications of new standards on tissue heating. International Journal of Hyperthermia 18 361–384. (https://doi.org/10.1080/02656730210146890)
Mitchell D, Snelling EP, Hetem RS, Maloney SK, Strauss WM & & Fuller A 2018 Revisiting concepts of thermal physiology: predicting responses of mammals to climate change. Journal of Animal Ecology 87 956–973. (https://doi.org/10.1111/1365-2656.12818)
Monteiro APA, Tao S, Thompson IMT & & Dahl GE 2016 In utero heat stress decreases calf survival and performance through the first lactation. Journal of Dairy Science 99 8443–8450. (https://doi.org/10.3168/jds.2016-11072)
Ngo NS & & Horton RM 2016 Climate change and fetal health: the impacts of exposure to extreme temperatures in New York City. Environmental Research 144 158–164. (https://doi.org/10.1016/j.envres.2015.11.016)
Olivier K, Reinders LA, Clarke MW, Crew RC, Pereira G, Maloney SK & & Wyrwoll CS 2021 Maternal, placental, and fetal responses to intermittent heat exposure during late gestation in mice. Reproductive Sciences 28 416–425. (https://doi.org/10.1007/s43032-020-00291-7)
Payne MS, Newnham JP, Doherty DA, Furfaro LL, Pendal NL, Loh DE & & Keelan JA 2021 A specific bacterial DNA signature in the vagina of Australian women in midpregnancy predicts high risk of spontaneous preterm birth (the Predict1000 study). American Journal of Obstetrics and Gynecology 224 206.e201–206.e223. (https://doi.org/10.1016/j.ajog.2020.08.034)
Ravanelli N, Casasola W, English T, Edwards KM & & Jay O 2019 Heat stress and fetal risk. Environmental limits for exercise and passive heat stress during pregnancy: a systematic review with best evidence synthesis. British Journal of Sports Medicine 53 799–805. (https://doi.org/10.1136/bjsports-2017-097914)
Regnault TRH, de Vrijer B, Galan HL, Davidsen ML, Trembler KA, Battaglia FC, Wilkening RB & & Anthony RV 2003 The relationship between transplacental O2 diffusion and placental expression of PlGF, VEGF and their receptors in a placental insufficiency model of fetal growth restriction. Journal of Physiology 550 641–656. (https://doi.org/10.1113/jphysiol.2003.039511)
Regnault TRH, Orbus RJ, de Vrijer B, Davidsen ML, Galan HL, Wilkening RB & & Anthony RV 2002 Placental expression of VEGF, PlGF and their receptors in a model of placental insufficiency—intrauterine growth restriction (PI-IUGR). Placenta 23 132–144. (https://doi.org/10.1053/plac.2001.0757)
Roth Z 2020 Reproductive physiology and endocrinology responses of cows exposed to environmental heat stress - Experiences from the past and lessons for the present. Theriogenology 155 150–156. (https://doi.org/10.1016/j.theriogenology.2020.05.040)
Samuels L, Nakstad B, Roos N, Bonell A, Chersich M, Havenith G, Luchters S, Day LT, Hirst JE, Singh T, et al.2022 Physiological mechanisms of the impact of heat during pregnancy and the clinical implications: review of the evidence from an expert group meeting. International Journal of Biometeorology 66 1505–1513. (https://doi.org/10.1007/s00484-022-02301-6)
Schifano P, Lallo A, Asta F, De Sario M, Davoli M & & Michelozzi P 2013 Effect of ambient temperature and air pollutants on the risk of preterm birth, Rome 2001–2010. Environment International 61 77–87. (https://doi.org/10.1016/j.envint.2013.09.005)
Schroder HJ & & Power GG 1997 Engine and radiator: fetal and placental interactions for heat dissipation. Experimental Physiology 82 403–414. (https://doi.org/10.1113/expphysiol.1997.sp004035)
Sciscione AC, Costigan KA & & Johnson TRB 1997 Increase in ambient temperature may explain decrease in amniotic fluid index. American Journal of Perinatology 14 249–251. (https://doi.org/10.1055/s-2007-994137)
Sharif-Naeini R, Ciura S & & Bourque CW 2008 TRPV1 gene required for thermosensory transduction and anticipatory secretion from vasopressin neurons during hyperthermia. Neuron 58 179–185. (https://doi.org/10.1016/j.neuron.2008.02.013)
Shearer FJG, Wyrwoll CS & & Holmes MC 2019 The role of 11β-hydroxy steroid dehydrogenase Type 2 in glucocorticoid programming of affective and cognitive behaviours. Neuroendocrinology 109 257–265. (https://doi.org/10.1159/000499660)
Sherris AR, Baiocchi M, Fendorf S, Luby SP, Yang W & & Shaw GM 2022 Nitrate in drinking water during pregnancy and spontaneous preterm birth: a retrospective within-mother analysis in California. Environmental Health Perspectives 129 057001.
Shi Y, Tang L, Bai X, Du K, Wang H, Jia X & & Lai S 2022 Heat stress altered the vaginal microbiome and metabolome in rabbits. Frontiers in Microbiology 13 813622. (https://doi.org/10.3389/fmicb.2022.813622)
Smallcombe JW, Puhenthirar A, Casasola W, Inoue DS, Chaseling GK, Ravanelli N, Edwards KM & & Jay O 2021 Thermoregulation during pregnancy: a controlled trial investigating the risk of maternal hyperthermia during exercise in the heat. Sports Medicine 51 2655–2664. (https://doi.org/10.1007/s40279-021-01504-y)
Soares JC, Santos CS, Carvalho SMP, Pintado MM & & Vasconcelos MW 2019 Preserving the nutritional quality of crop plants under a changing climate: importance and strategies. Plant and Soil 443 1–26. (https://doi.org/10.1007/s11104-019-04229-0)
Son JY, Lee JT, Lane KJ & & Bell ML 2019 Impacts of high temperature on adverse birth outcomes in Seoul, Korea: disparities by individual- and community-level characteristics. Environmental Research 168 460–466. (https://doi.org/10.1016/j.envres.2018.10.032)
Song SD, Acharya KD, Zhu JE, Deveney CM, Walther-Antonio MRS, Tetel MJ & & Chia N 2020 Daily vaginal microbiota fluctuations associated with natural hormonal cycle, contraceptives, diet, and exercise. mSphere 5. (https://doi.org/10.1128/mSphere.00593-20)
Sonna LA, Fujita J, Gaffin SL & & Lilly CM 2002 Invited review: effects of heat and cold stress on mammalian gene expression. Journal of Applied Physiology 92 1725–1742. (https://doi.org/10.1152/japplphysiol.01143.2001)
Spencer S, Samateh T, Wabnitz K, Mayhew S, Allen H & & Bonell A 2022 The challenges of working in the heat whilst pregnant: insights from Gambian women farmers in the face of climate change. Frontiers in Public Health 10 785254. (https://doi.org/10.3389/fpubh.2022.785254)
Stinson LF & & Payne MS 2019 Infection-mediated preterm birth: bacterial origins and avenues for intervention. Australian and New Zealand Journal of Obstetrics and Gynaecology 59 781–790. (https://doi.org/10.1111/ajo.13078)
Syed S, O’Sullivan TL & & Phillips KP 2022 Extreme heat and pregnancy outcomes: a scoping review of the epidemiological evidence. International Journal of Environmental Research and Public Health 19 2412. (https://doi.org/10.3390/ijerph19042412)
Theobald GW 1959 The separate release of oxytocin and antidiuretic hormone. Journal of Physiology 149 443–461. (https://doi.org/10.1113/jphysiol.1959.sp006351)
Thureen PJ, Trembler KA, Meschia G, Makowski EL & & Wilkening RB 1992 Placental glucose transport in heat-induced fetal growth retardation. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 263 R578–R585. (https://doi.org/10.1152/ajpregu.1992.263.3.R578)
Valencia CM, Mol BW & & Jacobsson B 2021 FIGO good practice recommendations on modifiable causes of iatrogenic preterm birth. International Journal of Gynecology & Obstetrics 155 8–12. (https://doi.org/10.1002/ijgo.13857)
van Wettere WHEJ, Kind KL, Gatford KL, Swinbourne AM, Leu ST, Hayman PT, Kelly JM, Weaver AC, Kleemann DO & & Walker SK 2021 Review of the impact of heat stress on reproductive performance of sheep. Journal of Animal Science and Biotechnology 12 26. (https://doi.org/10.1186/s40104-020-00537-z)
Wang J, Williams G, Guo Y, Pan X & & Tong S 2013 Maternal exposure to heatwave and preterm birth in Brisbane, Australia. BJOG 120 1631–1641. (https://doi.org/10.1111/1471-0528.12397)
Wang LI, Liu F, Luo Y, Zhu L & & Li G 2015 Effect of acute heat stress on adrenocorticotropic hormone, cortisol, interleukin2, interleukin12 and apoptosis gene expression in rats. Biomedical Reports 3 425–429. (https://doi.org/10.3892/br.2015.445)
Wolfenson D, Bartol FF, Badinga L, Barros CM, Marple DN, Cummins K, Wolfe D, Lucy MC, Spencer TE & & Thatcher WW 1993 Secretion of PGF2α and oxytocin during hyperthermia in cyclic and pregnant heifers. Theriogenology 39 1129–1141. (https://doi.org/10.1016/0093-691x(9390012-t)
Wu Y, Li S, Zhao Q, Wen B, Gasparrini A, Tong S, Overcenco A, Urban A, Schneider A, Entezari A, et al.2022 Global, regional, and national burden of mortality associated with short-term temperature variability from 2000-19: a three-stage modelling study. The Lancet Planetary Health 6 e410–e421. (https://doi.org/10.1016/s2542-5196(2200073-0)
Zhao Q, Guo Y, Ye T, Gasparrini A, Tong S, Overcenco A, Urban A, Schneider A, Entezari A, Vicedo-Cabrera AM, et al.2021 Global, regional, and national burden of mortality associated with non-optimal ambient temperatures from 2000 to 2019: a three-stage modelling study. The Lancet Planetary Health 5 e415–e425. (https://doi.org/10.1016/S2542-5196(2100081-4)
