Understanding the Causal Impact of Elevated Maternal Stress During Pregnancy: A Systematic Literature Review of Guinea Pig Models

Understanding the Causal Impact of Elevated Maternal Stress During Pregnancy: A Systematic Literature Review of Guinea Pig Models | bioRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-M677548'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search New Results Understanding the Causal Impact of Elevated Maternal Stress During Pregnancy: A Systematic Literature Review of Guinea Pig Models View ORCID Profile Rebecca L. Wilson , Caitlin Messiah , Adetola F. Louis-Jacques doi: https://doi.org/10.1101/2025.07.30.667555 Rebecca L. Wilson 1 Center for Research in Perinatal Outcomes, University of Florida College of Medicine , Gainesville, Florida, USA 32610 2 Department of Obstetrics and Gynecology, University of Florida College of Medicine , Gainesville, Florida, USA 32610 Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Rebecca L. Wilson For correspondence: rebecca.wilson{at}ufl.edu Caitlin Messiah 2 Department of Obstetrics and Gynecology, University of Florida College of Medicine , Gainesville, Florida, USA 32610 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Adetola F. Louis-Jacques 1 Center for Research in Perinatal Outcomes, University of Florida College of Medicine , Gainesville, Florida, USA 32610 2 Department of Obstetrics and Gynecology, University of Florida College of Medicine , Gainesville, Florida, USA 32610 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abstract Full Text Info/History Metrics Preview PDF Abstract Increased maternal stress during pregnancy has been linked to numerous adverse pregnancy outcomes, including preterm birth and impaired fetal development. While clinical studies have established strong associations between maternal stress and adverse pregnancy outcomes, understanding the biological mechanisms is crucial for developing effective preventive intervention. Rodent models have provided valuable insights, however physiological differences from humans limit translational relevance. This systematic review evaluated and synthesized experimental models of increased maternal stress during pregnancy in guinea pigs. Guinea pigs share key pregnancy characteristics with humans, including relevant placental structure, maternal hormonal recognition of pregnancy and precocial offspring development. We identified 43 studies using various experimental approaches categorized into three main types: behavioral models, drug/substance exposure models, and physiological challenge models. These studies demonstrated significant fetal and offspring effects, particularly sex-specific neurodevelopmental outcomes. However, maternal physiological adaptations were often superficially characterized, focusing primarily on weight gain and occasional stress hormone measurements. Most studies began interventions during established pregnancy, potentially missing critical pre-pregnancy and early pregnancy periods. Overall, this review highlights the need for future studies to consider pre-conception interventions to better model human conditions and more comprehensively examine maternal adaptations. Introduction Increased maternal stress, including psychological stress (example, anxiety or depression) and physical stressors (example, malnutrition or infection), during pregnancy has been linked to numerous adverse pregnancy outcomes in humans. Clinical studies have demonstrated associations between maternal stress and increased risk of preterm birth (Dole et al., 2003; Copper et al., 1996), low birth weight (Wadhwa et al., 2004) and preeclampsia (Zhang et al., 2013). Additionally, the impact of high maternal stress during pregnancy has been shown to have extensive effects on fetus and offspring health and development [ 1 , 2 ]. The biological mechanisms underlying the associations between high maternal stress and adverse pregnancy outcome are complex but likely involve a number of key physiological mechanisms. Activation of the maternal hypothalamic-pituitary-adrenal (HPA) axis, resulting in elevated cortisol levels can affect placental function and fetal development [ 3 , 4 ]. Maternal stress can trigger inflammatory responses and alter immune function, potentially compromising pregnancy maintenance [ 5 ]. Additionally, the timing of stress exposure appears particularly important, with different gestational periods showing varying susceptibility to stress-induced complications [ 6 , 7 ]. While human studies have provided valuable insights into these relationships, animal models are essential for understanding the causal relationships between increased maternal stress, pregnancy outcome and long-term offspring health. Rodent models are a cost-effective option for studying causal relationships and have been valuable in investigating potential mechanisms linking maternal stress to adverse pregnancy outcomes. Most consistent findings across rodent models are those relating to fetal growth and placental function [ 8 – 10 ]. Outcomes often reported include reduced litter size and litter weight and activation of the maternal HPA-axis that is associated with reduced circulating progesterone and alterations in placenta structure and functions. However, while human studies consistently show associations between maternal stress and increased risk of preterm birth [ 11 ], rodent models have produced variable results regarding gestational length [ 12 ]. In those that did report early delivery, gestational length was only minimally premature [ 13 , 14 ]. The variability in pregnancy outcomes might reflect differences in stress protocols, timing of exposure, or species-specific responses to maternal stress [ 15 ]. The guinea pig (Cavia porcellus) has emerged as a particularly valuable model species for studying maternal-fetal interactions due to its similarities to human pregnancy, including comparable placental structure, relatively long gestation period, and advanced fetal development [ 16 – 18 ]. Guinea pigs, unlike rats and mice, exhibit similar hormonal profiles to humans during pregnancy, particularly in their production and regulation of progesterone, estrogen, and stress hormones [ 19 , 20 ]. The maternal hypothalamic-pituitary-adrenal (HPA) axis undergoes comparable adaptations during pregnancy, including increased basal cortisol levels and altered stress responsiveness [ 21 ]. Importantly, like humans, but unlike most rodents, guinea pigs primarily produce cortisol as their main glucocorticoid, rather than corticosterone [ 22 ]. This is significant because cortisol plays a crucial role in maternal metabolic adaptation to pregnancy and the timing of parturition in both species [ 23 , 24 ]. Additionally, the guinea pig’s relatively long gestation period (∼65-70 days) allows for detailed study of temporal changes in maternal physiology across pregnancy, more closely matching the timeline of human gestational adaptation than shorter-gestation rodent models. Over the past two decades, researchers have developed various experimental approaches to investigate the causal connections between increased prenatal maternal stress, pregnancy outcome and offspring developmental outcomes using guinea pig models (see references summarized in this review). These studies have encompassed a wide range of interventions, from psychological stressors to physiological challenges, providing insights into both the immediate and long-term consequences of prenatal stress exposure, particularly in offspring. The diversity of experimental approaches means multiple aspects of fetal and offspring development, including neurodevelopmental outcomes, cardiovascular function, and metabolic programming have been examined. This systematic review aimed to evaluate and synthesize the available literature on maternal stress during pregnancy using guinea pig models, focusing on experimental manipulations published between 2000 and present. We specifically examine the types of interventions employed, the timing of these interventions during pregnancy, and their effects on both maternal and offspring outcomes. This analysis will provide a critical overview of current knowledge in the field and identify gaps that require further investigation. Materials and Methods Eligibility Criteria Studies included only those utilizing guinea pigs as a model species and focused on maternal experimental manipulation during pregnancy. There were no restrictions imposed on type of experimental manipulation but was specifically targeted to increased maternal stress, either psychologically or physiologically, during pregnancy. Given the heterogeneity of the observational strategies, a meta-analysis was not possible. Information Sources and Search The search strategy and procedure was guided by the PRISMA statement [ 25 ]. Potential studies were located through electronic databases (Web of Science, Academic Search Premier and Scopus), as well as manual searches of references in review articles and relevant articles known by the authors. Limits included full text articles written in English and published in academic journals between 2000-present. The last search was performed in June 2025. Search terms and MeSH headings in the title, abstract, and index terms, were initially identified in Scopus and subsequent key words were used for the remaining databases (Appendix A). The search included the following: Maternal Stress or Stress; Pregnancy or Prenatal; Guinea Pig or Guinea Pigs. Data Collection An independent search of the literature was performed in April 2025 and again in July 2025. Titles and abstracts were examined independently by two of the authors who documented reasons for excluding full text articles. Any differences between the two reviewers were clarified; a third reviewer resolved any disagreements. If an article appeared in duplicate from two or three of the databases, only the search containing the most relevant and useful information was included. For each eligible study, the following data was extracted: author, year; aim/hypothesis; study design; study outcome and preterm birth phenotype. Results Figure 1 outlines the literature search and selection of studies. We identified 172 citations (10 duplicates) after searching Web of Science, Academic Search Premier and Scopus databases. A further 16 were added by authors after handsearching. After screening the title and abstract, 55 full text papers were read. Overall, 43 studies met the inclusion criteria and were included in the review ( Table 1 ). Download figure Open in new tab Figure 1. Flow diagram of the search strategy used in this review including the relevant number of papers at each point. View this table: View inline View popup Table 1. Summary of studies systematically reviewed. Most studies utilized timed pregnant guinea pigs with interventions occurring at specific gestational ages, typically between days 45-65 of pregnancy (term 65-70 days) [ 26 ]. One study began experimental manipulations from gestational day 1 [ 27 ] while only four studies [ 28 – 31 ] utilized a pre-conception experimental manipulation. The experimental designs generally included relatively small sample sizes, ranging from 4-16 animals per group, with most studies examining fetal and/or offspring outcomes. The majority of studies aimed to assess near-term fetal brain development [ 32 – 35 ] or neurodevelopmental outcomes in offspring [ 27 , 36 – 53 ]. Additional aims included understanding fetal and/or offspring vascular function [ 54 – 56 ], fetal and/or neonatal lung development and function [ 57 , 58 ], fetal liver damage [ 59 ], offspring auditory outcomes [ 60 ] and maternal impacts [ 61 , 62 ]. Regarding pregnancy outcomes, most interventions did not significantly affect gestational length, though several models showed reduced fetal/offspring weights [ 31 , 33 , 50 , 54 , 56 , 58 , 59 ]. Fetal survival was often demonstrated except in cases of severe interventions such as infection models [ 63 , 64 ]. Impacts to offspring were routinely sex-specific in nature [ 31 , 34 – 36 , 38 , 39 , 41 – 43 , 46 , 49 ]. For example, Crombie et al., [ 39 ] found that following maternal psychosomatic stress via strobe light in pregnancy, female offspring showed increased anxiety, decreased locomotion and increased freezing while male offspring showed hyperactivity behavior, increased locomotion and decreased fear behavior. When reported, maternal responses to experimental manipulations were generally well-tolerated with dams maintaining appropriate weight gain throughout pregnancy [ 34 , 40 , 41 , 61 , 62 , 65 ] except with iron deficiency [ 29 ] and methadone treatment [ 47 ] where maternal weight gain was reduced. Increased maternal cortisol and stress responses were observed with strobe light [ 37 , 45 ] and combined environmental stressors [ 34 ] but not with hyperthermia [ 62 ], chronic ethanol exposure [ 27 , 33 ], iron deficiency [ 29 ] or endotoxin administration [ 40 ]. Adverse maternal outcomes were relatively rare, primarily occurring in infection models [ 64 , 66 ]. The experimental manipulations to increase maternal stress used in these studies can be categorized into three main types. Stress and behavioral models [ 34 – 39 , 41 , 42 , 49 , 51 , 60 , 67 ]: maternal stress induced via strobe light exposure, maternal separation protocols, novel environment exposure, and social stress paradigms. Drug and substance exposure models: betamethasone or dexamethasone administration [ 43 , 44 , 46 , 52 , 53 ], ethanol exposure [ 27 , 32 , 33 , 57 , 58 ], methadone [ 47 ] and pharmacological intervention [ 65 , 67 ]. Physiological models: uterine artery occlusion for growth restriction [ 45 , 54 ], maternal nutrition manipulation [ 29 – 31 , 61 , 68 ], hypoxia exposure [ 50 , 55 , 56 , 59 ], carbon monoxide [ 48 ], temperature [ 62 ] and infection/inflammation challenges [ 40 , 63 , 64 , 66 , 69 ]. Stress and behavioral models Stress and behavioral models in pregnant guinea pigs have been particularly well-characterized, with several research groups establishing reproducible protocols that demonstrate clear offspring effects. The most commonly used protocol involved exposure to strobe light stress, typically administered for 2-hour periods during specific gestational windows [ 36 , 41 ]. This model induced a reliable maternal stress response, evidenced by elevated salivary cortisol levels, without causing pregnancy loss or significantly altering gestational length [ 37 ]. The timing of stress exposure appears critical, with different windows of exposure producing distinct offspring phenotypes, particularly in behavioral and neuroendocrine outcomes [ 41 , 51 ]. The physiological basis for these behavioral changes has been extensively investigated, with studies revealing alterations in offspring HPA axis function [ 28 , 37 ] and modifications in neurotransmitter systems [ 43 ]. More complex stress paradigms have also been developed, including chronic unpredictable stress protocols that better mirror human psychological stress [ 34 , 35 ] and social environment manipulations [ 28 , 49 , 67 ]. [ 34 ] demonstrated that combining multiple stressors, including novel environment exposure, social stress, and intermittent food availability, created a more comprehensive model of chronic maternal stress. This approach showed that maternal HPA axis activation persisted throughout gestation, with increased basal cortisol levels evident by mid-gestation. The offspring effects of these various stress protocols were sex-specific, with males generally displaying increased anxiety-like behaviors and hyperactivity, while females showed more subtle behavioral alterations [ 39 , 42 , 49 ]. Importantly, these behavioral changes persisted into juvenile periods, suggesting permanent programming effects [ 37 ]. Some studies have attempted to ameliorate these stress-induced changes through postnatal interventions or environmental enrichment, though with varying success [ 35 , 38 ]. Drug and substance exposure models Drug and substance exposure models primarily focused on glucocorticoids and ethanol. Betamethasone and dexamethasone were studied because of their use to accelerate fetal lung maturation in cases of premature delivery [ 70 , 71 ]. Early work by Dean et al., [ 46 ] showed that dexamethasone exposure during rapid brain growth altered offspring HPA function in a sex-specific manner, with increased resting cortisol in males but not females. Multiple studies examined both single and repeated courses of betamethasone, also administered at critical windows of brain development [ 43 , 44 ]. Studies showed that maternal betamethasone administration affects offspring brain development, particularly myelination patterns and GABA receptor expression, with effects that persist into juvenile periods [ 43 ]. Additionally, the effects of single or repeated betamethasone exposure have been shown to affect HPA-axis function in both first and second-generation [ 52 , 53 ]. These transgenerational effects show distinct sex-specific patterns and suggest that clinical use of antenatal steroids may have longer-lasting consequences than previously recognized. Ethanol exposure models were also well-characterized, providing important insights into fetal alcohol spectrum disorders. These studies typically utilized chronic exposure protocols, with ethanol administered either through drinking water or direct administration [ 27 , 33 ]. Key findings demonstrated that prenatal ethanol exposure affected multiple systems, including altered HPA axis function, modified glutamate signaling, and immune system development, particularly alveolar macrophage function [ 57 ]. Several other pharmacological interventions were studied and provided insights into programming effects of modulating the maternal HPA axis. Vartazarmian et al., [ 65 ] investigated prenatal selective serotonin reuptake inhibitor (fluoxetine) exposure and demonstrated altered pain thresholds in adult offspring despite no effects on pregnancy outcomes while Kaiser et al., [ 72 ] examined the effects of adrenocorticotropic hormone administration during pregnancy, finding increased aggressive behaviors and elevated cortisol levels in female offspring. Physiological models Physiological models focused primarily on three key areas: growth restriction (uterine artery ligation), hypoxia exposure, and infection/inflammation challenges. Growth restriction models produced fetal growth restriction while maintaining pregnancy viability, allowing investigation of both immediate and long-term consequences of restricted fetal growth [ 29 , 30 , 54 ]. Cumberland et al., [ 45 ] demonstrated that the combination of growth restriction and prenatal stress increased the risk of preterm labor, while growth restriction alone did not affect gestation length. These models have also shown impacts on fetal endocrine function, with growth restriction combined with prenatal stress resulting in decreased fetal circulating cortisol levels and altered allopregnanolone concentrations. Some studies have explored potential therapeutic interventions, such as N-acetylcysteine supplementation, showing promising results in ameliorating some adverse effects of growth restriction, particularly regarding vascular function and oxidative stress markers [ 54 , 56 ]. Nutritional models have demonstrated diverse impacts of maternal dietary deficiencies and restrictions on fetal/offspring development. Models specifically targeting a particular nutrient deprivation (maternal vitamin C or iron deficiencies) indicated particular gestational or postnatal age effects. For example, maternal vitamin C deficiency caused transient intrauterine growth restriction at gestational day 45 which resolved by gestational day 56 [ 61 ]. Iron deficiency implemented from pre-conception through lactation resulted in elevated cortisol in offspring at postnatal day 24 that normalized by day 84, suggesting developmental programming effects on stress responsiveness that were correctable with postnatal nutritional rehabilitation [ 29 ]. Global nutritional restrictions provided insights into placental adaptations and fetal growth programming including placental transcriptome changes relating to DNA repair, apoptosis regulation, nutrient transport and IGF1 regulation [ 30 ] and sex-specific effects on hypoxia and oxidative stress markers in the fetal brain [ 31 ]. Collectively, these nutritional models demonstrate that different types and severities of maternal dietary restrictions produce distinct patterns of fetal adaptation, from transient growth effects with micronutrient deficiencies to more profound metabolic and transcriptional changes with global caloric restriction. Infection and inflammation models provided crucial insights into mechanisms of preterm birth and fetal inflammatory responses. Studies using various pathogens, including E. coli [ 63 ], Brucella [ 64 ], and cytomegalovirus [ 66 ], have increased understanding of maternal-fetal transmission and fetal immune responses. These models showed that timing and severity of infection significantly impact outcomes, with early gestation infections often leading to pregnancy loss [ 64 , 66 ], while later infections resulted in fetal inflammation without pregnancy termination [ 63 ]. The work by Hensel et al., [ 64 ] particularly demonstrated how maternal infection can lead to placental inflammation and fetal compromise, with specific patterns of inflammatory markers that parallel human responses. Hypoxia models were used to understand fetal adaptations to reduced oxygen availability, with protocols ranging from chronic moderate hypoxia to more severe intermittent exposures and carbon monoxide exposure [ 48 , 50 , 55 , 56 , 59 ]. These studies revealed important insights into fetal cardiovascular adaptations, including changes in endothelial nitric oxide synthase expression and vascular remodeling, and redox imbalances in the neonatal brain. Fetal organs respond differently to hypoxic challenges, with tissue-specific alterations in oxidative stress markers and cellular adaptation mechanisms [ 59 ]. Whilst studies that extended the understanding of hypoxia effects beyond the fetal period and demonstrated long-term cardiovascular programming in female offspring [ 55 ] and mechanistic understanding of how prenatal hypoxia may predispose neuronal dysfunction in adulthood [ 50 ]. Discussion This systematic review aimed to evaluate and synthesize the available literature on maternal stress during pregnancy using translational guinea pig models: Summarized in Figure 2 . Overall, analysis of the available literature revealed a predominant focus on fetal and offspring outcomes, with relatively limited examination of maternal physiological adaptations to various stressors. While experimental designs successfully demonstrated diverse methods of increasing maternal stress, from acute psychosocial stressors to chronic physiological challenges, maternal responses were often only superficially characterized through basic measures such as weight gain and occasional cortisol sampling. Even when maternal stress was confirmed through elevated cortisol levels or behavioral changes, the underlying maternal adaptations and potential compensatory mechanisms remained largely unexplored. This knowledge gap is particularly notable given that maternal physiological responses likely play a crucial role in mediating the well-documented offspring effects, which frequently showed sex-specific patterns in behavioral, endocrine, and developmental outcomes. Download figure Open in new tab Figure 2. Summary of systematic review of the literature aimed to evaluate and synthesize the available literature on maternal stress during pregnancy using translational guinea pig models. Of the studies that examined maternal responses, most focused on basic physiological markers such as weight gain and stress hormones. Maternal weight gain was generally maintained during stress interventions [ 34 , 40 , 41 , 62 ], with reductions only observed in specific challenges like iron deficiency [ 29 ] and methadone treatment [ 47 ]. These findings parallel human studies where severe nutritional deficiencies or substance use affect maternal health [ 73 , 74 ]. Maternal HPA axis activation was primarily assessed through cortisol measurements in blood or saliva. Elevated cortisol levels were observed following acute stressors such as strobe light exposure [ 37 , 45 ] and combined environmental stressors [ 34 ]. Interestingly, several interventions including chronic ethanol exposure [ 27 , 33 ] and iron deficiency [ 29 ] did not elicit increased cortisol responses, suggesting a possible adaptation of the maternal stress response system to chronic stress. Maternal adaptations to chronic maternal stress have also been observed in human pregnancies with chronic stress exposure [ 75 ]. These adaptations include changes in the HPA-axis function and cortisol patterns that attenuate stress reactivity and blood pressure responses [ 76 ]. Cardiovascular and metabolic adaptations have also been studied revealing differential hemodynamic responses and neuroendocrine reactivity [ 75 ]. Based on the literature reviewed here, the most severe maternal outcomes were observed in infection models [ 64 , 66 ], particularly with high pathogen doses, mirroring the significant maternal morbidity associated with severe infections during human pregnancy [ 77 , 78 ]. However, detailed characterization of maternal immune responses, cardiovascular adaptations, metabolic changes and behavioral modifications were largely absent from these studies. Overall leaving critical gaps in our understanding of how maternal systems adapt to maintain pregnancy despite significant stressors. Despite extensive evidence linking maternal stress to preterm birth in human populations, the experimental models reviewed here showed little impact on gestational length, even with significant maternal stress manipulations. Cumberland et al., [ 45 ] demonstrated increased preterm labor and specifically when intrauterine growth restriction was combined with prenatal stress, whilst Maki et al., [ 31 ] reported preterm delivery in 3 of 18 nutrient restricted dams. These finding suggest that multiple ’hits’ may be necessary to initiate mechanisms resulting in spontaneous preterm delivery and highlights a critical gap in our understanding of the mechanisms linking maternal stress to pregnancy termination. Studies identified in the literature search that did result in spontaneous preterm birth but were subsequently excluded because no maternal stress experimentation was utilized, were artificially induced through pharmacological means (aglepristone and oxytocin)[ 79 – 81 ]. Pharmacological induction of parturition was used as a tool to study prematurity effects on fetal and offspring development rather than to understand spontaneous preterm birth mechanisms. Even in infection models, which showed the highest rates of pregnancy loss [ 63 , 64 , 66 ], the focus remained primarily on fetal outcomes rather than examining the maternal inflammatory and endocrine pathways leading to pregnancy termination. This gap in mechanistic understanding may partly explain why current clinical interventions for preventing preterm birth remain largely ineffective [ 82 , 83 ], as they target downstream processes rather than the fundamental response pathways that initiate premature labor. On of the goals of this systematic review was to synthesize the available literature on maternal stress during pregnancy using guinea pig models because of the translational potential guinea pigs offer. Traditionally, rodent models (particularly rats and mice) have been extensively used to study pregnancy and parturition. However, their fundamental differences in maternal adaptation to pregnancy responses and parturition initiation mechanisms limit their translational relevance for understanding human pregnancy physiology. Unlike humans and guinea pigs, where progesterone remains elevated throughout gestation and labor occurs without systemic progesterone withdrawal [ 19 , 84 , 85 ], mice and rats require a sharp decline in circulating progesterone to initiate parturition [ 19 ]. This distinct endocrine profile means that stress-induced or inflammation-mediated preterm birth in these species may operate through mechanisms that are not necessarily relevant to human pregnancy. Additionally, humans and guinea pigs shift progesterone production from the ovary to the placenta during pregnancy [ 86 ] so that pregnancy maintenance is independent of the ovary [ 87 ]; this mechanism is not observed in mice and rats [ 88 ]. Placental establishment and micro-structure in the guinea pigs more closely mirrors humans than mice and rats and guinea pigs deliver precocial young making which offers advantages in studying fetal and offspring responses to various experimental approaches. Maternal stress and glucocorticoid responses are also similar between humans and guinea pigs with cortisol, as opposed to corticosterone in mice and rats, being the primary glucocorticoid [ 22 ]. However, despite the similarities between humans and guinea pigs, the studies reviewed here demonstrate that even guinea pig models have not fully replicated the stress-induced preterm birth phenomenon observed in human populations. This suggests that additional factors, perhaps related to the complexity of human psychosocial stress or the interaction of multiple physiological systems, may be necessary to fully model the pathways leading to stress-induced preterm birth. Another limitation in guinea pig models included in this review is that experimental approaches often began during established pregnancy rather than before conception or during early pregnancy. In humans, many risk factors for adverse pregnancy outcome are present before pregnancy, including chronic medical conditions (diabetes, hypertension), previous reproductive history, and social determinants of health (poverty, stress, racism) [ 89 – 92 ]. Human studies demonstrate that chronic maternal stress and inflammation present before conception significantly increase preterm birth risk, with one systematic review showing a 2-3 fold increased risk in women with pre-pregnancy anxiety or depression [ 93 ]. For many of the studies presented here, various maternal insults - including stress [ 36 , 41 ], infection [ 63 , 64 ], growth restriction [ 54 ], and drug exposures [ 27 , 33 ] - created significant fetal effects, however, maternal physiology and health outcomes were often not reported. It is possible that the lack of reports on maternal health outcomes was because there was no significant effect to report. Hence furthering our hypothesis that experimental protocols that begin during pregnancy fail to capture the complex interplay of pre-pregnancy and early pregnancy factors that epidemiological studies have shown contribute to adverse pregnancy outcomes in humans [ 94 , 95 ]. It is our belief that to develop more clinically relevant models, experimental manipulations likely need to begin prior to conception to better reflect human conditions where pre-existing maternal conditions or early pregnancy events contribute to adverse pregnancy outcome risk. This represents an important gap in the current literature and an opportunity for future research directions that could better align animal models with human clinical presentations. Author Contributions RLW: Conceptualization, Methodology, Validation, Investigation, Formal Analysis and Writing. CM: Methodology, Validation, Investigation, Editing. AFL-J Methodology, Validation, Investigation, Editing. All authors approve final manuscript. Funding RLW is supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) award R00HD109458. Competing Interests The authors have declared that no competing interest exists Funder Information Declared Eunice Kennedy Shriver National Institute of Child Health and Human Development , K99HD109458 , R00HD109458 Footnotes Paper revised to include newly published literature References [1]. ↵ Van den Bergh BRH , van den Heuvel MI , Lahti M , Braeken M , de Rooij SR , Entringer S , et al. Prenatal developmental origins of behavior and mental health: The influence of maternal stress in pregnancy . Neurosci Biobehav Rev . 2020 ; 117 : 26 – 64 . OpenUrl CrossRef PubMed [2]. ↵ Fowden AL , Giussani DA , Forhead AJ . Intrauterine programming of physiological systems: causes and consequences . Physiology (Bethesda) . 2006 ; 21 : 29 – 37 . OpenUrl CrossRef PubMed [3]. ↵ Glover V , O’Donnell KJ , O’Connor TG , Fisher J . Prenatal maternal stress, fetal programming, and mechanisms underlying later psychopathology—A global perspective . Development and psychopathology . 2018 ; 30 : 843 – 54 . OpenUrl CrossRef PubMed [4]. ↵ O’Donnell KJ , Jensen AB , Freeman L , Khalife N , O’Connor TG , Glover V . Maternal prenatal anxiety and downregulation of placental 11β-HSD2 . Psychoneuroendocrinology . 2012 ; 37 : 818 – 26 . OpenUrl CrossRef PubMed Web of Science [5]. ↵ Coussons-Read ME , Okun ML , Schmitt MP , Giese S . Prenatal stress alters cytokine levels in a manner that may endanger human pregnancy . Biopsychosocial Science and Medicine . 2005 ; 67 : 625 – 31 . OpenUrl [6]. ↵ Class QA , Lichtenstein P , Långström N , D’onofrio BM . Timing of prenatal maternal exposure to severe life events and adverse pregnancy outcomes: a population study of 2.6 million pregnancies . Psychosomatic medicine . 2011 ; 73 : 234 – 41 . OpenUrl Abstract / FREE Full Text [7]. ↵ Davis EP , Sandman CA . The timing of prenatal exposure to maternal cortisol and psychosocial stress is associated with human infant cognitive development . Child Dev . 2010 ; 81 : 131 – 48 . OpenUrl CrossRef PubMed Web of Science [8]. ↵ Cuffe J , O’sullivan L , Simmons D , Anderson S , Moritz K . Maternal corticosterone exposure in the mouse has sex-specific effects on placental growth and mRNA expression . Endocrinology . 2012 ; 153 : 5500 – 11 . OpenUrl CrossRef PubMed [9]. Mairesse J , Lesage J , Breton C , Bréant B , Hahn T , Darnaudéry M , et al. Maternal stress alters endocrine function of the feto-placental unit in rats . American Journal of Physiology-Endocrinology and Metabolism . 2007 ; 292 : E1526 – E33 . OpenUrl CrossRef PubMed Web of Science [10]. ↵ Gotlieb N , Wilsterman K , Finn SL , Browne MF , Bever SR , Iwakoshi-Ukena E , et al. Impact of chronic prenatal stress on maternal neuroendocrine function and embryo and placenta development during early-to-mid-pregnancy in mice . Frontiers in Physiology . 2022 ; 13 : 886298 . OpenUrl PubMed [11]. ↵ Mahrer NE , Guardino C , Hobel C , Dunkel Schetter C . Maternal stress before conception is associated with shorter gestation . Annals of behavioral medicine . 2021 ; 55 : 242 – 52 . OpenUrl PubMed [12]. ↵ Brunton PJ . Effects of maternal exposure to social stress during pregnancy: consequences for mother and offspring . Reproduction . 2013 ; 146 : R175 – 89 . OpenUrl Abstract / FREE Full Text [13]. ↵ Govindaraj S , Shanmuganathan A , Rajan R . Maternal psychological stress-induced developmental disability, neonatal mortality and stillbirth in the offspring of Wistar albino rats . PLoS One . 2017 ; 12 : e0171089 . OpenUrl PubMed [14]. ↵ Garcia-Flores V , Romero R , Furcron A-E , Levenson D , Galaz J , Zou C , et al. Prenatal maternal stress causes preterm birth and affects neonatal adaptive immunity in mice . Frontiers in immunology . 2020 ; 11 : 254 . OpenUrl PubMed [15]. ↵ Boersma GJ , Tamashiro KL . Individual differences in the effects of prenatal stress exposure in rodents . Neurobiology of stress . 2015 ; 1 : 100 – 8 . OpenUrl PubMed [16]. ↵ Kunkele J , Trillmich F . Are precocial young cheaper? Lactation energetics in the guinea pig . Physiol Zool . 1997 ; 70 : 589 – 96 . OpenUrl CrossRef PubMed [17]. Mess A . The Guinea pig placenta: model of placental growth dynamics . Placenta . 2007 ; 28 : 812 – 5 . OpenUrl CrossRef PubMed Web of Science [18]. ↵ Morrison JL , Botting KJ , Darby JRT , David AL , Dyson RM , Gatford KL , et al. Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic . J Physiol . 2018 ; 596 : 5535 – 69 . OpenUrl CrossRef PubMed [19]. ↵ Mitchell BF , Taggart MJ . Are animal models relevant to key aspects of human parturition? Am J Physiol Regul Integr Comp Physiol . 2009 ; 297 : R525 – 45 . OpenUrl CrossRef PubMed Web of Science [20]. ↵ Palliser HK , Zakar T , Symonds IM , Hirst JJ . Progesterone receptor isoform expression in the guinea pig myometrium from normal and growth restricted pregnancies . Reprod Sci . 2010 ; 17 : 776 – 82 . OpenUrl CrossRef PubMed Web of Science [21]. ↵ Dalle M , Delost P . Plasma and adrenal cortisol concentrations in foetal, newborn and mother guinea-pigs during the perinatal period . J Endocrinol . 1976 ; 70 : 207 – 14 . OpenUrl Abstract / FREE Full Text [22]. ↵ Keightley MC , Fuller PJ . Cortisol resistance and the guinea pig glucocorticoid receptor . Steroids . 1995 ; 60 : 87 – 92 . OpenUrl CrossRef PubMed [23]. ↵ Challis JR , Sloboda D , Matthews SG , Holloway A , Alfaidy N , Patel FA , et al. The fetal placental hypothalamic-pituitary-adrenal (HPA) axis, parturition and post natal health . Mol Cell Endocrinol . 2001 ; 185 : 135 – 44 . OpenUrl CrossRef PubMed Web of Science [24]. ↵ Ishimoto H , Jaffe RB . Development and function of the human fetal adrenal cortex: a key component in the feto-placental unit . Endocr Rev . 2011 ; 32 : 317 – 55 . OpenUrl CrossRef PubMed Web of Science [25]. ↵ Page MJ , McKenzie JE , Bossuyt PM , Boutron I , Hoffmann TC , Mulrow CD , et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews . BMJ . 2021 ; 372 : n71 . OpenUrl FREE Full Text [26]. ↵ !!! INVALID CITATION !!! [26-38] . [27]. ↵ Iqbal U , Brien J , Banjanin S , Andrews M , Matthews S , Reynolds J . Chronic prenatal ethanol exposure alters glucocorticoid signalling in the hippocampus of the postnatal guinea pig . Journal of Neuroendocrinology . 2005 ; 17 : 600 – 8 . OpenUrl CrossRef PubMed [28]. ↵ Schöpper H , Palme R , Ruf T , Huber S . Chronic stress in pregnant guinea pigs (Cavia aperea f. porcellus) attenuates long-term stress hormone levels and body weight gain, but not reproductive output . Journal of Comparative Physiology B: Biochemical, Systemic, and Environmental Physiology . 2011 ; 181 : 1089 – 100 . OpenUrl CrossRef PubMed [29]. ↵ Shero N , Fiset S , Plamondon H , Thabet M , Rioux FM . Increase serum cortisol in young guinea pig offspring in response to maternal iron deficiency . Nutr Res . 2018 ; 54 : 69 – 79 . OpenUrl PubMed [30]. ↵ Wilson RL , Davenport BN , Jones HN . Mid-Pregnancy Placental Transcriptome in a Model of Placental Insufficiency with and without Novel Intervention . Reproductive Sciences . 2025 ; 32 : 435 – 43 . OpenUrl PubMed [31]. ↵ Maki Y , Nygard K , Hammond RR , Regnault TRH , Richardson BS . Maternal Undernourishment in Guinea Pigs Leads to Fetal Growth Restriction with Increased Hypoxic Cells and Oxidative Stress in the Brain . Dev Neurosci . 2019 ; 41 : 290 – 9 . OpenUrl CrossRef PubMed [32]. ↵ Hewitt AJ , Dobson CC , Brien JF , Wynne-Edwards KE , Reynolds JN . Chronic ethanol exposure increases the non-dominant glucocorticoid, corticosterone, in the near-term pregnant guinea pig . Alcohol . 2014 ; 48 : 477 – 81 . OpenUrl PubMed [33]. ↵ Hewitt AJ , Walker KR , Kobus SM , Poklewska-Koziell M , Reynolds JN , Brien JF . Differential effects of chronic ethanol exposure on cytochrome P450 2E1 and the hypothalamic–pituitary–adrenal axis in the maternal–fetal unit of the guinea pig . Neurotoxicology & Teratology . 2010 ; 32 : 164 – 70 . OpenUrl PubMed [34]. ↵ Emack J , Kostaki A , Walker C-D , Matthews SG . Chronic maternal stress affects growth, behaviour and hypothalamo–pituitary–adrenal function in juvenile offspring . Hormones & Behavior . 2008 ; 54 : 514 – 20 . OpenUrl PubMed [35]. ↵ Emack J , Matthews SG . Effects of chronic maternal stress on hypothalamo–pituitary–adrenal (HPA) function and behavior: No reversal by environmental enrichment . Hormones & Behavior . 2011 ; 60 : 589 – 98 . OpenUrl PubMed [36]. ↵ Bennett GA , Palliser HK , Saxby B , Walker DW , Hirst JJ . Effects of prenatal stress on fetal neurodevelopment and responses to maternal neurosteroid treatment in guinea pigs . Developmental Neuroscience . 2013 ; 35 : 416 – 26 . OpenUrl PubMed [37]. ↵ Bennett GA , Palliser HK , Shaw JC , Walker D , Hirst JJ . Prenatal stress alters hippocampal neuroglia and increases anxiety in childhood . Developmental Neuroscience . 2015 ; 37 : 533 – 45 . OpenUrl PubMed [38]. ↵ Crombie GK , Palliser HK , Shaw JC , Hodgson DM , Walker DW , Hirst JJ . Neurosteroid-based intervention using Ganaxolone and Emapunil for improving stress-induced myelination deficits and neurobehavioural disorders . Psychoneuroendocrinology . 2021 ; 133 . [39]. ↵ Crombie GK , Palliser HK , Shaw JC , Hodgson DM , Walker DW , Hirst JJ . Effects of prenatal stress on behavioural and neurodevelopmental outcomes are altered by maternal separation in the neonatal period . Psychoneuroendocrinology . 2021 ; 124 . [40]. ↵ Hodyl NA , Walker FR , Krivanek KM , Clifton V , Hodgson DM . Modelling prenatal bacterial infection: Functional consequences of altered hypothalamic pituitary adrenal axis development . Behavioural Brain Research . 2007 ; 178 : 108 – 14 . OpenUrl CrossRef PubMed [41]. ↵ Kapoor A , Matthews SG . Short periods of prenatal stress affect growth, behaviour and hypothalamo–pituitary–adrenal axis activity in male guinea pig offspring . Journal of Physiology . 2005 ; 566 : 967 – 77 . OpenUrl CrossRef PubMed Web of Science [42]. ↵ Kapoor A , Matthews SG . Testosterone is involved in mediating the effects of prenatal stress in male guinea pig offspring . Journal of Physiology . 2011 ; 589 : 755 – 66 . OpenUrl CrossRef PubMed [43]. ↵ Owen D , Matthews SG . Repeated maternal glucocorticoid treatment affects activity and hippocampal NMDA receptor expression in juvenile guinea pigs . Journal of Physiology . 2006 ; 578 : 249 – 57 . OpenUrl PubMed [44]. ↵ Sasaki A , Eng ME , Lee AH , Kostaki A , Matthews SG . DNA methylome signatures of prenatal exposure to synthetic glucocorticoids in hippocampus and peripheral whole blood of female guinea pigs in early life . Translational Psychiatry . 2021 ; 11 . [45]. ↵ Cumberland AL , Palliser HK , Rani P , Walker DW , Hirst JJ . Effects of combined IUGR and prenatal stress on the development of the hippocampus in a fetal guinea pig model . JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE . 2017 ; 8 : 584 – 96 . OpenUrl [46]. ↵ Dean F , Yu C , Lingas RI , Matthews SG . Prenatal glucocorticoid modifies hypothalamo-pituitary-adrenal regulation in prepubertal guinea pigs . Neuroendocrinology . 2001 ; 73 : 194 – 202 . OpenUrl CrossRef PubMed Web of Science [47]. ↵ Safa A , Lau AR , Aten S , Schilling K , Bales KL , Miller VA , et al. Pharmacological Prevention of Neonatal Opioid Withdrawal in a Pregnant Guinea Pig Model . Frontiers in Pharmacology . 2021 ; 11 . [48]. ↵ Tolcos M , Mallard C , McGregor H , Walker D , Rees S . Exposure to prenatal carbon monoxide and postnatal hyperthermia: Short and long-term effects on neurochemicals and neuroglia in the developing brain . Experimental Neurology . 2000 ; 162 : 235 – 46 . OpenUrl PubMed [49]. ↵ Von Engelhardt N , Kowalski GJ , Guenther A . The maternal social environment shapes offspring growth, physiology, and behavioural phenotype in guinea pigs . Frontiers in Zoology . 2015 ; 12 . [50]. ↵ Figueroa EG , Castillo RL , Paz AA , Monsalves-Alvarez M , Salas-Pérez F , Calle X , et al. Redox Imbalance Is Associated with Neuronal Apoptosis in the Cortex of Neonates Gestated Under Chronic Hypoxia . Antioxidants . 2025 ; 14 : 736 . OpenUrl PubMed [51]. ↵ Bennett GA , Palliser HK , Walker D , Hirst J . Severity and timing: How prenatal stress exposure affects glial developmental, emotional behavioural and plasma neurosteroid responses in guinea pig offspring . Psychoneuroendocrinology . 2016 ; 70 : 47 – 57 . OpenUrl PubMed [52]. ↵ Iqbal M , Moisiadis VG , Kostaki A , Matthews SG . Transgenerational effects of prenatal synthetic glucocorticoids on hypothalamic-pituitary-adrenal function . Endocrinology . 2012 ; 153 : 3295 – 307 . OpenUrl CrossRef PubMed [53]. ↵ Moisiadis VG , Mouratidis A , Kostaki A , Matthews SG . Asinglecourseofsyntheticglucocorticoidsinpregnant Guinea pigs programs behavior and stress response in two generations of offspring . Endocrinology . 2018 ; 159 : 4065 – 76 . OpenUrl PubMed [54]. ↵ Krause BJ , Peñaloza E , Candia A , Cañas D , Hernández C , Arenas GA , et al. Adult vascular dysfunction in foetal growth-restricted guinea-pigs is associated with a neonate-adult switching in Nos3 DNA methylation . Acta Physiologica . 2019 ; 227 :N.PAG-N.PAG. [55]. ↵ Paz AA , Jiménez TA , Ibarra-Gonzalez J , Astudillo-Maya C , Beñaldo FA , Figueroa EG , et al. Gestational hypoxia elicits long-term cardiovascular dysfunction in female guinea pigs . Life Sciences . 2025 ; 361 . [56]. ↵ Thompson LP , Dong Y . Chronic Hypoxia Decreases Endothelial Nitric Oxide Synthease Protein Expression in Fetal Guinea Pig Hearts . Journal of the Society for Gynecologic Investigation . 2005 ; 12 : 388 – 95 . OpenUrl CrossRef PubMed Web of Science [57]. ↵ Gauthier TW , Ping XD , Harris FL , Wong M , Elbahesh H , Brown LAS . Fetal alcohol exposure impairs alveolar macrophage function via decreased glutathione availability . Pediatric Research . 2005 ; 57 : 76 – 81 . OpenUrl CrossRef PubMed Web of Science [58]. ↵ Xiao-Du P , Harris FL , Brown LAS , Gauthier TW . In Vivo Dysfunction of the Term Alveolar Macrophage After in Utero Ethanol Exposure . Alcoholism: Clinical & Experimental Research . 2007 ; 31 : 308 – 16 . OpenUrl CrossRef PubMed Web of Science [59]. ↵ Hashimoto K , Pinkas G , Evans L , Liu HS , Al-Hasan Y , Thompson LP . Protective Effect of N-acetylcysteine on Liver Damage During Chronic Intrauterine Hypoxia in Fetal Guinea Pig . REPRODUCTIVE SCIENCES . 2012 ; 19 : 1001 – 9 . OpenUrl CrossRef PubMed [60]. ↵ Morimoto C , Nario K , Nishimura T , Shimokura R , Hosoi H , Kitahara T . Effects of noise exposure on neonatal auditory brainstem response thresholds in pregnant guinea pigs at different gestational periods . J Obstet Gynaecol Res . 2017 ; 43 : 78 – 86 . OpenUrl PubMed [61]. ↵ Schjoldager JG , Paidi MD , Lindblad MM , Birck MM , Kjærgaard AB , Dantzer V , et al. Maternal vitamin C deficiency during pregnancy results in transient fetal and placental growth retardation in guinea pigs . European journal of nutrition . 2015 ; 54 : 667 – 76 . OpenUrl PubMed [62]. ↵ Michel CL , Chastel O , Bonnet X . Ambient temperature and pregnancy influence cortisol levels in female guinea pigs and entail long-term effects on the stress response of their offspring . General and Comparative Endocrinology . 2011 ; 171 : 275 – 82 . OpenUrl PubMed [63]. ↵ Wang B , Navath RS , Menjoge AR , Balakrishnan B , Bellair R , Dai H , et al. Inhibition of bacterial growth and intramniotic infection in a guinea pig model of chorioamnionitis using PAMAM dendrimers . Int J Pharm . 2010 ; 395 : 298 – 308 . OpenUrl CrossRef PubMed [64]. ↵ Hensel ME , Chaki SP , Stranahan L , Gregory AE , Van Schaik EJ , Garcia-Gonzalez DG , et al. Intratracheal inoculation with brucella melitensis in the pregnant guinea pig is an improved model for reproductive pathogenesis and vaccine studies . Infect Immun . 2020 ; 88 . [65]. ↵ Vartazarmian R , Malik S , Baker GB , Boksa P . Long-term effects of fluoxetine or vehicle administration during pregnancy on behavioral outcomes in guinea pig offspring . Psychopharmacology . 2005 ; 178 : 328 – 38 . OpenUrl CrossRef PubMed [66]. ↵ Rollman TB , Berkebile ZW , Hicks DM , Hatfield JS , Chauhan P , Pravetoni M , et al. CD4+ but not CD8+ T cells are required for protection against severe guinea pig cytomegalovirus infections . PLoS Pathog . 2024 ; 20 . [67]. ↵ Kaiser S , Sachser N . Social stress during pregnancy and lactation affects in guinea pigs the male offsprings’ endocrine status and infantilizes their behaviour . Psychoneuroendocrinology . 2001 ; 26 : 503 – 19 . OpenUrl CrossRef PubMed [68]. ↵ Hansen SN , Schjoldager JG , Paidi MD , Lykkesfeldt J , Tveden-Nyborg P . Maternal vitamin C deficiency does not reduce hippocampal volume and β-tubulin III intensity in prenatal Guinea pigs . Nutr Res . 2016 ; 36 : 696 – 702 . OpenUrl PubMed [69]. ↵ Faralla C , Bastounis EE , Ortega FE , Light SH , Rizzuto G , Nocadello S , et al. Listeria monocytogenes InlP interacts with afadin and facilitates basement membrane crossing . PLoS Pathog . 2018 ; 14 . [70]. ↵ Roberts D , Brown J , Medley N , Dalziel SR . Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth . Cochrane Database Syst Rev . 2017 ; 3 : CD004454 . OpenUrl CrossRef PubMed [71]. ↵ Liggins GC , Howie RN . A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants . Pediatrics . 1972 ; 50 : 515 – 25 . OpenUrl CrossRef PubMed Web of Science [72]. ↵ Kaiser S , Brendel H , Sachser N . Effects of ACTH applications during pregnancy on the female offsprings’ endocrine status and behavior in guinea pigs . Physiol Behav . 2000 ; 70 : 157 – 62 . OpenUrl PubMed [73]. ↵ Abu-Saad K , Fraser D . Maternal nutrition and birth outcomes . Epidemiol Rev . 2010 ; 32 : 5 – 25 . OpenUrl CrossRef PubMed Web of Science [74]. ↵ Catalano PM , Shankar K . Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child . BMJ . 2017 ; 356 : j1 . OpenUrl Abstract / FREE Full Text [75]. ↵ Christian LM . Physiological reactivity to psychological stress in human pregnancy: current knowledge and future directions . Prog Neurobiol . 2012 ; 99 : 106 – 16 . OpenUrl CrossRef PubMed [76]. ↵ de Weerth C , Buitelaar JK . Physiological stress reactivity in human pregnancy—a review . Neuroscience & Biobehavioral Reviews . 2005 ; 29 : 295 – 312 . OpenUrl PubMed [77]. ↵ Kourtis AP , Read JS , Jamieson DJ . Pregnancy and infection . N Engl J Med . 2014 ; 370 : 2211 – 8 . OpenUrl CrossRef PubMed Web of Science [78]. ↵ Silasi M , Cardenas I , Kwon JY , Racicot K , Aldo P , Mor G . Viral infections during pregnancy . Am J Reprod Immunol . 2015 ; 73 : 199 – 213 . OpenUrl CrossRef PubMed [79]. ↵ Dyson RM , Palliser HK , Kelleher MA , Hirst JJ , Wright IMR . The guinea pig as an animal model for studying perinatal changes in microvascular function . Pediatric Research . 2012 ; 71 : 20 – 4 . OpenUrl CrossRef PubMed Web of Science [80]. Pavy CL , Shaw JC , Dyson RM , Palliser HK , Moloney RA , Sixtus RP , et al. Ganaxolone Therapy After Preterm Birth Restores Cerebellar Oligodendrocyte Maturation and Myelination in Guinea Pigs . Dev Psychobiol . 2024 ; 66 . [81]. ↵ Shaw JC , Palliser HK , Dyson RM , Hirst JJ , Berry MJ . Long-term effects of preterm birth on behavior and neurosteroid sensitivity in the Guinea pig . Pediatric Research . 2016 ; 80 : 275 – 83 . OpenUrl CrossRef PubMed [82]. ↵ Di Renzo GC , Tosto V , Giardina I . The biological basis and prevention of preterm birth . Best Pract Res Clin Obstet Gynaecol . 2018 ; 52 : 13 – 22 . OpenUrl CrossRef [83]. ↵ Ahmed B , Abushama M , Konje JC . Prevention of spontaneous preterm delivery - an update on where we are today . J Matern Fetal Neonatal Med . 2023 ; 36 : 2183756 . OpenUrl PubMed [84]. ↵ Challis JR , Heap RB , Illingworth DV . Concentrations of oestrogen and progesterone in the plasma of non-pregnant, pregnant and lactating guinea-pigs . J Endocrinol . 1971 ; 51 : 333 – 45 . OpenUrl Abstract / FREE Full Text [85]. ↵ Illingworth DV , Perry JS . The effect of hypophysial stalk-section on the corpus luteum of the guinea-pig . J Endocrinol . 1971 ; 50 : 625 – 35 . OpenUrl Abstract / FREE Full Text [86]. ↵ Heap RB , Deanesly R . Progesterone in systemic blood and placentae of intact and ovariectomized pregnant guinea-pigs . J Endocrinol . 1966 ; 34 : 417 – 23 . OpenUrl Abstract / FREE Full Text [87]. ↵ Csapo AI , Puri CP , Tarro S . Relationship between timing of ovariectomy and maintenance of pregnancy in the guinea-pig . Prostaglandins . 1981 ; 22 : 131 – 40 . OpenUrl CrossRef PubMed Web of Science [88]. ↵ Sharma R , Bulmer D . The effects of ovariectomy and subsequent progesterone replacement on the uterus of the pregnant mouse . J Anat . 1983 ; 137 (Pt 4 ): 695 – 703 . OpenUrl PubMed [89]. ↵ Goldenberg RL , Culhane JF , Iams JD , Romero R . Epidemiology and causes of preterm birth . Lancet . 2008 ; 371 : 75 – 84 . OpenUrl CrossRef PubMed Web of Science [90]. Bryant AS , Worjoloh A , Caughey AB , Washington AE . Racial/ethnic disparities in obstetric outcomes and care: prevalence and determinants . Am J Obstet Gynecol . 2010 ; 202 : 335 – 43 . OpenUrl CrossRef PubMed Web of Science [91]. Bramham K , Parnell B , Nelson-Piercy C , Seed PT , Poston L , Chappell LC . Chronic hypertension and pregnancy outcomes: systematic review and meta-analysis . BMJ . 2014 ; 348 : g2301 . OpenUrl Abstract / FREE Full Text [92]. ↵ Kaul P , Savu A , Nerenberg KA , Donovan LE , Chik CL , Ryan EA , Johnson JA . Impact of gestational diabetes mellitus and high maternal weight on the development of diabetes, hypertension and cardiovascular disease: a population-level analysis . Diabet Med . 2015 ; 32 : 164 – 73 . OpenUrl CrossRef PubMed [93]. ↵ Staneva A , Bogossian F , Pritchard M , Wittkowski A . The effects of maternal depression, anxiety, and perceived stress during pregnancy on preterm birth: A systematic review . Women Birth . 2015 ; 28 : 179 – 93 . OpenUrl PubMed [94]. ↵ Fleming TP , Watkins AJ , Velazquez MA , Mathers JC , Prentice AM , Stephenson J , et al. Origins of lifetime health around the time of conception: causes and consequences . Lancet . 2018 ; 391 : 1842 – 52 . OpenUrl CrossRef PubMed [95]. ↵ Stephenson J , Heslehurst N , Hall J , Schoenaker D , Hutchinson J , Cade JE , et al. Before the beginning: nutrition and lifestyle in the preconception period and its importance for future health . Lancet . 2018 ; 391 : 1830 – 41 . OpenUrl CrossRef PubMed View the discussion thread. Back to top Previous Next Posted November 24, 2025. Download PDF Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Understanding the Causal Impact of Elevated Maternal Stress During Pregnancy: A Systematic Literature Review of Guinea Pig Models Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Understanding the Causal Impact of Elevated Maternal Stress During Pregnancy: A Systematic Literature Review of Guinea Pig Models Rebecca L. Wilson , Caitlin Messiah , Adetola F. Louis-Jacques bioRxiv 2025.07.30.667555; doi: https://doi.org/10.1101/2025.07.30.667555 Share This Article: Copy Citation Tools Understanding the Causal Impact of Elevated Maternal Stress During Pregnancy: A Systematic Literature Review of Guinea Pig Models Rebecca L. Wilson , Caitlin Messiah , Adetola F. Louis-Jacques bioRxiv 2025.07.30.667555; doi: https://doi.org/10.1101/2025.07.30.667555 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Physiology Subject Areas All Articles Animal Behavior and Cognition (7618) Biochemistry (17633) Bioengineering (13856) Bioinformatics (41841) Biophysics (21399) Cancer Biology (18529) Cell Biology (25422) Clinical Trials (138) Developmental Biology (13352) Ecology (19860) Epidemiology (2067) Evolutionary Biology (24282) Genetics (15582) Genomics (22462) Immunology (17700) Microbiology (40295) Molecular Biology (17140) Neuroscience (88419) Paleontology (666) Pathology (2823) Pharmacology and Toxicology (4813) Physiology (7632) Plant Biology (15107) Scientific Communication and Education (2042) Synthetic Biology (4284) Systems Biology (9808) Zoology (2267)