Exposure to extreme heat increases preterm birth risk: hypothetical pathophysiological mechanisms

Abstract

Preterm birth (PTB), delivery before 37 weeks gestation, is the leading cause of neonatal mortality globally, accounting for nearly half of all neonatal deaths. While numerous established risk factors for PTB have been identified, ongoing research continues to elucidate additional contributing factors. Epidemiological studies increasingly demonstrate that elevated ambient temperature is an environmental risk factor for PTB, with odds increasing 16% during heat waves and 5% per 1°C temperature rise. This is particularly concerning given escalating global warming trends. While maternal heat susceptibility during pregnancy may be linked to compromised thermoregulation from gestational adaptations, the exact pathophysiological mechanisms leading to heat-associated PTB remain unclear, hindering therapeutic development. This review proposes multitudes potential pathophysiologic mechanisms leading to PTB that can be induced by heat. They include but are not limited to, metabolic derangement, mitochondria dysfunction, inflammation, endothelial dysfunction, oxidative stress, and change in cell fate. These mechanisms are derived from integrated knowledge of pregnancy physiology, parturition processes, and temperature effects on physiological pathways. We also outline future experimental approaches to test these hypotheses.

Introduction

Preterm birth burden and associated risk factors

Preterm birth (PTB), or delivery before 37 weeks gestation, is considered the top direct cause of neonatal mortality worldwide and the leading cause of death for children under five years old.^[1] An estimated 13.4 million PTBs are recorded globally every year.^[2] Alarmingly, nearly one million of these children will die, and a relevant portion of survivors will experience long-term health problems during their life course.^[3] PTB is estimated to occur in one out of every 10 births in the United States.^[4] Since the mother and fetus coexist in one body during pregnancy, the PTB-associated pathophysiological alterations can affect either mother or fetus . Maternal risk exposures during pregnancy can lead to spontaneous preterm birth, which is associated with >60% of all PTBs.^[5] Our review here is focused on spontaneous PTB in response to heat exposure-associated mechanistic pathways that can contribute to PTB.

PTB typically follows a sequence of events even though it can have various initial triggers. Despite limited knowledge of PTB’s etiology, numerous risk factors are known to be contributors. Some of these factors can be categorized as static factors, such as genetics, maternal ethnicity /race, nutrition, behavior, body mass index, and environment, depending on whether they exist regardless of the pregnancy.^[6,7] Another category consists of dynamic factors that develop during pregnancy, notably fetal membrane rupture, endocrine dysfunction, infection, autoimmune, physiological stress, allergies, and bleeding.^[6,8] These factors differentially trigger dynamic change at the cellular and molecular levels, affecting the biological pathways leading to delivery in preterm labor.^[8] It is believed that PTB and full-term follow the same final physiological pathways, which include myometrial contraction, decidual activation, membrane extracellular matrix degradation, membrane weakening and rupture, and cervical ripening, ultimately resulting in labor and delivery.^[9-12] However, in the case of PTB, these pathways are initiated prematurely. Despite limited understanding of the physiological triggers that activate these final pathways, several pathophysiological mechanisms have been proposed to contribute to the onset of PTB.

Placental dysfunction, characterized by inflammation, endocrine disturbances, and uteroplacental insufficiency, can initiate inflammatory signaling and promote the spread of inflammatory mediators to maternal and fetal gestational tissues, ultimately leading to PTB.^[8] Another contributing mechanism is premature senescence of the fetal membranes, primarily triggered by oxidative stress (OS). This process induces early activation of inflammatory pathways and compromises membrane integrity through telomere shortening, p38 MAPK activation, and the release of senescence-associated secretory phenotypes (SASPs) and damage-associated molecular patterns (DAMPs), thereby increasing the risk of rupture and PTB.^[13] Furthermore, the accumulation of OS within the myometrium is thought to contribute to PTB by promoting inflammation, disrupting hormonal signaling, and altering intercellular communication through exosome release.^[14,15] However, a knowledge gap remains regarding the mechanisms through which PTB-contributing factors activate these pathophysiological pathways. This is a barrier to identifying novel PTB risk factors. One new PTB risk factor that has increasingly garnered attention in epidemiological studies is climate change-associated elevated environment temperature.^[16-19] Emerging epidemiological data increasingly links exposure to elevated ambient temperatures with pregnancy complications, including PTB.^[2,20,21] The next section of this review details the epidemiological relevance of high-temperature exposure as a PTB risk factor.

Epidemiology evidence of heat association with preterm birth

Climate change is predicted to increase global temperature by 1.5°C in the next decade^[22]. It is an emerging concern as extreme heat is frequently expected, impacting human health and, most importantly, pregnancy as a vulnerable period.^[23] Mounting epidemiological evidence associates an increase in environmental temperature with a high PTB prevalence, along with other adverse pregnancy outcomes, including stillbirth and low birth weight.^[24] A 2023 United Nations International Children’s Emergency Fund report estimated that the rate of PTB increases by 5% for every 1°C rise above region temperature norms and by 16% during a heat wave. While this report primarily focuses on low- and middle-income countries, the link between heat exposure and PTB is also evident in high-income nations. For instance, a Swedish study found that 5.1% of 560,615 single live births were preterm due to short-term high ambient temperature exposure.^[25] In the USA, a 5.6°C increase in weekly average temperature was associated with an 8.6% rise in PTB ^[26]. Similar associations have been observed in Canada, France, Germany^[17], and Australia.^[27] The impact of heat exposure on PTB has been evidenced to be significant when exposure occurs during the entire pregnancy or pregnancy’s third trimester.^[24] Notably, the vulnerability to extreme temperatures is not equally distributed across racial groups; non-Hispanic black women are most vulnerable, followed by non-Hispanic white women, while Hispanic women are least vulnerable.^[28] Furthermore, the study that evaluated seasonality association with PTB demonstrated that the hot seasons, summer and autumn, were associated with extreme PTB prevalence.^[29] Despite the availability of epidemiological data linking heat exposure and PTB, there is still a lack of knowledge about the biological mechanisms through which this occurs; this knowledge could facilitate clinical intervention. Under normal circumstances, pregnant women can successfully control their body temperature. However, they also undergo multiple physiological changes^[30] that may disrupt their thermoregulatory abilities, resulting in susceptibility to increased environmental temperatures.

Fetal-maternal thermoregulation adaptation

Pregnancy is often compared to stress, where multiple physiological changes must occur for adaptation (Figure 1). One of the critical adaptations accompanied by these changes is thermoregulation alteration.^[31] During pregnancy, fetal metabolism increases due to the rapid growth and development of organ systems, producing heat per kilogram of body mass assessed as about twice that of the mother. This establishes a fetal-maternal temperature gradient, allowing the fetus to dissipate heat to the mother.^[32] As the fetus relies on the mother for heat dissipation, the mother’s temperature must remain stable and maintained within a narrow margin^[33], a crucial role of the hypothalamus.^[34] Although it is not known when the fetal-maternal temperature gradient is established during gestation, it has been proven in mammals that the fetus’s temperature is approximately 0.5°C higher than that of the mother. ^[32,35] Thus, it is apparent that a situation where maternal core temperature increases (e.g., heat exposure) will result in fetal heat transfer reduction. The fetal heat transfer to the mother occurs through placental circulation, accounting for 85% of fetal heat loss, and the remaining 15% occurs through the fetal membrane-decidual-uterine wall. Indeed, the temperature of amniotic fluid surrounding the fetus is estimated to be 0.3°C lower than that of the fetus, making amniotic fluid a means of intermediate heat loss from the fetus to the uterine cavity.^[32] The molecular mechanism governing fetal-maternal heat transfer is unclear but likely involves the interplay of multiple processes. Fetal heat production may potentially induce the activation of heat shock proteins (HSPs), particularly those in the HSP70 family, which function as molecular chaperones involved in thermotolerance.^[36,37] These proteins may help maintain protein stability and facilitate heat transfer across the placental and fetal membrane barriers. In addition, the placenta and the amnion epithelial cells of the fetal membranes^[38] express specialized membrane proteins, specifically aquaporins (AQPs)^[39], whose critical function in transmembrane water transport^[40] may contribute to heat transfer through the convection mechanism. On the maternal side, the pregnancy induces the development of various heat dissipation adaptive mechanisms, including an increase in plasma volume and skin blood flow, a reduction in core temperature, an increase in sweat production, and an increase in thermal heat capacity due to rising body mass.^[31,41,42] Despite the existence of the maternal heat dissipation adaptive system, it will weaken when exposed to extremely high temperatures, impacting pregnancy outcomes. Pregnant women’s socioeconomic status can also play a role in their vulnerability to heat exposure. For example, some pregnant women in certain geographical regions (e.g., in some low- and middle-income countries) must be exposed to heat that exceeds their tolerance limits due to a lack of cooling infrastructure and the need to participate in outdoor activities such as work; they continue to work until late in their pregnancies due to financial constraints.^[43]

Figure 1: Depiction of thermoregulation adaptation during pregnancy.

The increase in fetal metabolism generates internal heat as gestation progresses, creating a temperature gradient between the mother and fetus. This causes the fetus to dissipate heat to the mother, primarily through the amniotic fluid/amniochorionic membranes and placenta. In the mother, heat dissipation occurs through various mechanisms, including increased skin blood flow, a reduction in core temperature, increased sweat production, and a higher thermal heat capacity (figure created with BioRender.com).

Hypothetical pathophysiological mechanisms

1. Metabolic derangement

Maternal metabolic adaptation is an important physiological state during pregnancy, considering the growing fetus’s critical need for nutrient supply. Maternal metabolic adaptation is dictated by the mother’s metabolic and nutrient status and the placenta and amniochorion’s release of endocrine factors that exert metabolic effects. Available evidence associates pregnancy with several metabolic pathways, including glucose, fatty acids, lipoproteins, amino acids, inflammatory markers, and hormones.^[44] It is also evident that inappropriate metabolic adaptation results in pregnancy complications, notably as an impact on fetal growth and PTB.^[45] Several animal studies have previously demonstrated a link between heat exposure during pregnancy and metabolic disruption. In sheep, chronic maternal heat stress from mid to late gestation was found to impair placental function by reducing cellularity and Na⁺/K⁺-ATPase-dependent oxygen consumption.^[46] Heat exposure during late gestation also caused a shift in fetal metabolism from anabolic to catabolic pathways, contributing to fetal growth restriction.^[47] In mice, late-gestation heat stress was shown to disrupt placental barriers, elevate fetal corticosterone levels, and decrease the expression of genes involved in nutrient transport and lipid metabolism.^[48] Another study in mice reported that maternal heat stress altered maternal metabolism, impaired placental vascular development, and ultimately limited fetal growth due to reduced nutrient supply.^[49] We hypothesize that heat exposure may trigger PTB via metabolic disruptions involving activation of downstream pathophysiological processes such as energy metabolism dysregulation, oxidative stress (OS), and inflammation. In fact, various metabolic-associated disorders are known to implicate these processes. The defect in glucose metabolism, particularly in the case of hyperglycemia, leads to the accumulation of advanced glycation end products, which trigger inflammatory cascades via interaction with their downstream signaling receptors termed receptor for advanced glycation end products (RAGE).^[50] It is also evident that metabolic stress also activates the hypothalamic-pituitary-adrenal axis, increasing placental corticotropin-releasing hormone production.^[51], which is identified as a key trigger for early labor onset.^[52,53] In addition, the alteration of lipid metabolism can trigger disruption in trophoblastic progesterone production^[54], potentially compromising pregnancy maintenance pathways. Moreover, the pivotal role of immune activation in the PTB pathophysiological process is well-established, with multiple metabolic pathways playing essential roles in immune cell activation, including glycolysis, the tricarboxylic acid (TCA) cycle, mitochondrial oxidative phosphorylation, fatty acid metabolism, and glutaminolysis.^[55] In the study where lipopolysaccharide was used to induce metabolic change by stimulating an increase in succinate, a key TCA cycle intermediate, resulted in macrophage-enhanced production of pro-inflammatory IL-1β via HIF-1α.^[56] The involvement of metabolic change in the increased production of reactive oxygen species (ROS) is also evident. As shown in animal experimentation high glucose levels trigger ROS production through NADPH oxidase in cardiomyocytes.^[57] Specific metabolic change is undoubtedly dictated by a specific stimulus, which also applies to heat exposure, where we predict it will stimulate specific metabolic pathways that trigger downstream pathways associated with PTB activation.

2. Mitochondria dysfunction

Mitochondria play an important role in cellular energy metabolism, as most of the intracellular adenosine triphosphate (ATP) is generated by mitochondrial respiration^[58]. Heat stress has been previously reported to increase mitochondrial superoxide radical (O₂^•−), a precursor of most ROS.^[59,60] Indeed, through their respiratory chain, mitochondria are the major source of intracellular ROS generation and, simultaneously, are an important target for ROS’ damaging effects.^[59] Most importantly, mitochondria possess antioxidant defense systems that intervene to detoxify excessive ROS and repair ROS-induced damage.^[60] The main components of the mitochondrial antioxidant defense system responsible for thermotolerance comprise manganese superoxide dismutase and glutathione peroxidase, which are involved in O₂^•− radical and hydrogen peroxide (H₂0₂) detoxification, respectively.^[61] Heat exposure may cause an impaired mitochondria antioxidant system, leading to failure to maintain free radicals’ steady-state level, which causes OS. Consequently, multiple physiological changes associated with mitochondria dysfunction, such as loss of mitochondria membrane potential, induced mitochondria DNA damage, impaired ATP synthesis, and uncoupling respiration, are known to be triggered by OS.^[59]. There has been increasing recognition that loss of mitochondrial integrity and its compartmentalization can release mitochondrial content into the cytoplasm, resulting in the activation of inflammation.^[62] Thus, heat exposure-induced mitochondrial dysfunction may participate in PTB through the activation of inflammatory cascades. Furthermore, given the central role of mitochondria in cellular metabolism, impaired metabolic function represents an additional mechanism through which mitochondrial dysfunction may contribute to the PTB pathophysiological process.

3. Oxidative stress

The implication of OS in the initiation of onset labor is well established, and it occurs in several ways.^[63-65] OS promotes placental aging via the activation of pregnancy-termination signaling factors, thereby contributing to the onset of labor.^[66] Furthermore, excessive OS can precipitate placental and fetal membrane dysfunctions, ultimately leading to PTB^[67]. Additionally, OS modulates fetal maturation processes and telomere reduction, which are critically involved in determining the timing of labor initiation^[68]. Another crucial mechanism by which OS influences labor timing is through uterine activation, mediated via inflammatory pathway activation. This process is orchestrated through the activation of nuclear factor-kappa B (NF-κB), a transcription factor that induces the production of inflammatory mediators, predominantly cytokines and chemokines downstream labor cascade.^[69-71] The precise inflammatory pathways that may be triggered by heat-induced OS are not known; however, some OS-associated pathways have been documented. For example, OS has been shown to trigger activation of the Nod-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome. NLRP3 is a multiprotein complex that activates caspase 1, leading to the processing and secretion of pro-inflammatory cytokines, including interleukin-1β (IL-1β) and IL-18.^[72] We anticipate heat to induce ROS accumulation, triggering OS that activates the specific inflammatory pathway in fetal-maternal signaling, leading to the onset of preterm labor.

4. Inflammatory activation

The onset of inflammation is a common underlying mechanism in full-term and PTB. The growth of the feto-placental unit is facilitated by regulated inflammation, which is primarily maintained through mechanisms of progressive cell senescence (aging) and cyclic cellular transition.^[73] A stimulus that triggers inflammatory balance disruption can result in PTB. We believe that heat exposure may stimulate inflammatory signals exchanged between the mother and fetus, leading to PTB. This response may reflect a compromised ability of both fetal (placenta, fetal membrane, umbilical cord) and maternal (decidua, myometrium, cervix) reproductive tissues to maintain immune homeostasis. Indeed, heat stress is known to promote inflammation. A recent study reported by the American Heart Association (2024) investigated the immune response to various heat levels. It demonstrated an increase in inflammatory markers for every 5°C increase in the Thermal Climate Index.^[74] Identified upregulated markers included inflammatory-associated immune cells, including eosinophils, monocytes, and natural killer T-cells, as well as a rise in pro-inflammatory cytokines, notably TNF-α. In addition, heat-induced inflammatory signaling in skeletal muscle through NF-κB activation has been reported in a pig model.^[75] Supporting this, a recent study in dairy cows showed that heat stress during late gestation upregulated key inflammatory genes in placental tissue, including IL6 and MMP12, and enriched pathways linked to cytokine regulation and immune response. In addition, this study also showed that DNA methylation in inflammation-related genes was affected by heat exposure, highlighting lasting epigenetic impacts.^[76] Based on these studies, it is evident that there is an overlap between heat-activated inflammatory pathways and inflammatory pathways leading to PTB. As documented in different studies^[73,77-79], the inflammatory immune response leading to normal labor and PTB occurs in subsequent events initiated by toll-like receptors (TLRs) engagement expressed on immune cells and endothelial cells at the fetal-maternal interface. TLR activation triggers a cascade of intracellular signaling events leading to inflammasome activation and the release of pro-inflammatory cytokines and chemokines such as IL1β, IL6, IL8, and CCL2. This is followed by immune cells’ recruitment and activation, which release inflammatory mediators, notably NF-κb in macrophages, which induce uterine contraction and cervical ripening, leading to labor. ^[80] Whether heat-induced inflammation is mediated through NF-κB activation in fetal-maternal tissue is yet to be addressed.

5. Endothelial dysfunction and impaired angiogenesis

During pregnancy, coordination of vascular development and adaptations at both sides of the maternal-fetal interface is key to the success of implantation, placentation, and subsequent pregnancy evolution.^[81] The angiogenesis process (the sprouting of new blood vessels from pre-existing vasculature)^[82] is responsible for both uterine and placenta vasculature for pregnancy adaptation. Angiogenesis is a tightly regulated process that involves endothelial cell growth, migration, and proliferation. This process is mainly regulated by endothelial growth factors (VEGFs) via interaction with their cognate receptors VEGF receptors^[83] and subsequent activation of mitogen-activated kinase (MAPK) pathways leading to endothelial cell proliferation.^[84] Endothelial dysfunction and subsequent abnormal placental vasculature development lead to placental insufficiencies, which can decrease nutrient and waste exchanges between maternal and fetal circulations. Those changes may result in adverse uterine conditions, inducing preterm delivery, and various other pregnancy complications for both the mother and the fetus, such as gestational hypertension, intrauterine growth restriction, and preeclampsia.^[85-87] We hypothesize that heat exposure can induce endothelial dysfunction, which may cause disruption of uterine and placenta angiogenesis and consequently trigger PTB. Endothelial dysfunction may arise from impaired endothelial-derived nitric oxide (NO) synthesis or oxidative degradation. This substance is associated with a wide range of biological properties that maintain vascular homeostasis and play a critical role in triggering angiogenesis via endothelial-constitutive NO synthase (ec-NOS) activation, cyclic GMP elevation, MAPK activation, and fibroblast growth factor-2 expression.^[88] Thus, heat exposure may cause imbalanced endothelial NO, resulting in endothelial dysfunction.

6. Cell fate: senescence and cellular transitions

Birth timing is a coordinated event mediated by various physiological changes where cell fate-associated alterations such as cell senescence and cellular transitions occur.^[89-91] Heat exposure is expected to accelerate those changes, leading to premature delivery. Senescence is a form of biological aging where cells under the senescence process lose their proliferative ability. It is marked by reduced functionality accompanied by secretion of a senescence-associated secretory phenotype.^[92] It is common for cellular senescence to occur in both fetal and maternal tissues and accumulates as pregnancy approaches delivery. Research has suggested that labor signaling can be initiated by the fetal membranes through increased membrane senescence.^[93] This process is believed to induce the activation of maternal decidua to secrete pro-inflammatory cytokine, triggering signaling pathways leading to parturition. The initiation factor remains unexplored, but some factors, including telomere shortening, OS build-up in the amniotic cavity, activation of p38MAPK, and soluble HMGB1, have been proposed to contribute.^[67,94] RAGE, as mentioned above, is a receptor for HMGB1 and these factors can initiate a vicious cascade of events to enhance inflammation. Heat exposure can be expected to influence the accumulation of these factors. Indeed, heat-induced cell senescence has previously been reported in vitro using human-derived skin and cancer cells.^[95] In addition to senescence, cellular transition, notably epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET), is another cell fate-associated event crucial for fetal membrane maintenance and inflammatory signals’ secretion that promotes parturition.^[96] Cyclic EMT-MET maintains membrane integrity during gestation, and a terminal state of EMT at term increases inflammation. In this regard, available data suggest that, at term, increased OS promotes EMT via increasing levels of TGF-β levels; differently, such an OS increase induces a lack of MET through reduced progesterone. This mechanism will trigger localized inflammation and fetal membrane disruption toward parturition.^[73] EMT markers and inflammation are evident in PTB. Thus, we expect heat to induce PTB by accelerating the EMT state.

Conclusion and recommendation for future studies

Epidemiological evidence increasingly recognizes pregnant women as a population group highly vulnerable to environmental heat effects, and heat exposure has proven to be associated with PTB. Despite epidemiological evidence, little progress has been made to address the pathophysiological mechanisms that underpin heat-induced PTB and facilitate the development of a treatment approach to mitigate heat’s impact on PTB. We provide hypothetical pathophysiological mechanisms (Figure 2) that may mediate heat exposure’s effect on PTB. Experimental testing of the proposed hypothesis must be conducted to address which predominant mechanisms mediate heat exposure and PTB and whether these mechanisms are independent or are together activated and synergically trigger downstream signaling leading to PTB. It is also crucial to address how maternal-fetal heat transfer takes place. However, clinical in-vivo studies addressing these mechanisms would be challenging mainly due to ethical concerns regarding direct exposure of pregnant women to high temperatures for experimental purposes, which may harm both mother and fetus. An alternative experimental approach could involve in vitro studies that integrate 2D and 3D models using maternal- and fetal-derived cells. Though in vitro testing doesn’t recapitulate the thermoregulation system, it is a more relevant model because it allows the assessment response of each feto-maternal derived cell independently upon heat exposure in a 2D model. 3D model assessment employing recently developed pregnancy organ-on-chip technology^[97] representing the structure, functions, and responses of feto-maternal interfaces could allow simulation of heat transfer from the mother to the fetus and assessment of how heat-induced downstream signals are transferred between both. Mechanistic pathways could lead to biomarker identification and provide an approach for developing diagnostic and targeted therapy for temperature-associated PTB risk.

Figure 2: Illustration of hypothesized pathophysiological mechanisms mediating heat exposure and preterm birth.

We propose that heat may trigger preterm birth via alterations in cell fate, inflammatory induction, metabolic changes, endothelial dysfunction, mitochondrial dysfunction, and oxidative stress (figure created with BioRender.com).

Data availability statement

No datasets were generated or analyzed in this article; therefore, data sharing is not applicable.