Obstructive sleep apnea-associated hypertensive disorders in pregnancy: a literature review and clinical management strategies

Abstract

Obstructive sleep apnea (OSA) has long been recognized as a significant risk factor for hypertension, and in recent years, its association with hypertensive disorders of pregnancy (HDP) has gained increasing attention, especially in the unique population of pregnant women. However, this relationship remains underappreciated in clinical practice. While early studies have suggested a link between OSA and adverse pregnancy outcomes, the mechanisms connecting OSA to HDP are not fully understood. This literature review explores potential pathways, including intermittent hypoxia, oxidative stress, systemic inflammation, dysregulation of the sympathetic nervous system, endothelial dysfunction, and atherosclerosis. It also examines current treatments, especially CPAP therapy, and its variable effectiveness in managing HDP symptoms, as well as potential alternatives such as throat strengthening exercises and external hypoglossal stimulation. Future research should focus on improving OSA screening during pregnancy, developing better diagnostic tools, and integrating routine OSA evaluations in prenatal care for early intervention. Clarifying the mechanisms linking OSA and HDP will help refine treatment strategies. Large-scale, randomized controlled trials are needed to assess the efficacy of combination therapies and develop evidence-based clinical guidelines.

Introduction

Obstructive sleep apnea (OSA), the most severe manifestation of sleep-disordered breathing (SDB), has recently been recognized as an emerging risk factor for hypertension [1]. OSA is marked by frequent upper airway obstructions, resulting in interrupted breathing and fragmented sleep [2], and it is clinically defined as experiencing over 30 episodes of apnea or hypopnea during a 7-hour sleep period or having an Apnea-Hypopnea Index (AHI) of at least 5 events per hour [3].According to the AHI value, the severity of OSA is classified as mild OSA with 5–14.9 events/hour; moderate OSA with 15–29.9 events/hour; and severe OSA with ≥ 30 events/hour [4]. As a pregnancy-related complication, OSA is estimated to affect 3.6-27% of pregnant women, even in the absence of effective screening tools and standardized diagnostic criteria [2, 5]. Preliminary research has identified a close association between OSA and a range of adverse pregnancy outcomes, including hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), preterm birth, cesarean section, and the birth of small-for-gestational-age (SGA) newborns [6–8]. However, the mechanisms underlying the development of OSA during pregnancy and its impact on both the perinatal mother and fetus remain not well understood. HDP are among the primary contributors to the high rates of illness and death in pregnant women worldwide. These disorders are more prevalent in developing countries, and even in developed countries, the incidence rate remains as high as 4–10% [9]. HDP are diagnosed when a woman’s systolic blood pressure reaches or exceeds 140 mmHg, or her diastolic blood pressure reaches or exceeds 90 mmHg, following the 20th week of gestation. The American College of Obstetricians and Gynecologists (ACOG) identifies four distinct types of HDP: chronic hypertension, gestational hypertension, preeclampsia/eclampsia (PE), and chronic hypertension with superimposed PE. According to the time of onset, preeclampsia can be further classified as: early-onset preeclampsia, which occurs before 34 weeks of gestation; late-onset preeclampsia, which occurs at or after 34 weeks of gestation [10]. These hypertensive states are closely linked to numerous adverse perinatal outcomes, such as intrauterine growth restriction and neonatal intensive care admissions, as well as severe maternal complications including HELLP syndrome and eclampsia. Moreover, HDP poses an independent risk for maternal mortality due to its association with cerebrovascular incidents, cardiovascular deaths, and metabolic disorders [11].

Currently, OSA is gaining increasing attention as a novel risk factor for HDP. However, the clinical characteristics of OSA during pregnancy and its potential mechanisms affecting HDP remain unclear [12]. Therefore, we comprehensively reviewed the existing research to explore the potential pathological links between OSA and HDP, hoping to clarify the impact of OSA combined with HDP on pregnancy outcomes, and to provide clues for the diagnosis, prevention, and targeted treatment of OSA.

Characteristics of OSA during pregnancy

Women may present with two distinct phenotypes of OSA during pregnancy: one is chronic OSA that pre-exists before pregnancy, and the other is OSA that develops new during pregnancy. The latter symptoms tend to be more severe, given that research has indicated that pregnancy may act as a facilitator for the onset or exacerbation of OSA [13]. For instance, a study utilizing laboratory polysomnography (PSG) conducted in early and late pregnancy found a significant increase in the number of women meeting the diagnostic criteria for OSA (AHI ≥ 5 events/hour) in the third trimester compared to the first (26.7% versus 10.5%) [14]. Another prospective study involving 3,702 primigravidas conducted home sleep testing (HST) in early pregnancy and repeated it in the mid-to-late pregnancy, revealing an increased proportion of women diagnosed with OSA in the later stages of pregnancy (8.3% versus 3.6%) [15].

The increased risk of OSA during pregnancy can be attributed to a range of physiological changes that occur as the body of pregnant women bodies adapt to support the developing fetus. These changes include upper airway edema, mucosal hyperemia, narrowing of the oropharyngeal diameter and elevated Mallampati score, which indicates increased crowding of the airway, is also more common during pregnancy [16–18]. Beyond these physiological changes, there are additional risk factors that can increase the likelihood of developing OSA during pregnancy. These include maternal obesity, advanced maternal age, and a family history of OSA [19]. These risk factors, when combined with the aforementioned physiological changes, create a multifaceted risk profile for OSA in pregnant women.

The close association between OSA and HDP during pregnancy

Existing research indicates that confounding factors such as maternal obesity, age, and a history of pre-existing hypertension exert complex effects on the association between OSA and HDP. Obesity in pregnant women, as a common risk factor for both conditions, influences them through dual anatomical and metabolic mechanisms. Obesity increases pharyngeal collapsibility and loop gain, thereby raising the risk of airway obstruction and leading to the development of OSA [20, 21]. Meanwhile, obesity-related insulin resistance and inflammation indirectly increase the risk of HDP through endothelial dysfunction [22]. Age influences the physiological aspects in a multidimensional manner. With advancing age, decreased upper airway muscle tone and reduced arousal threshold are more likely to lead to OSA [23]. At the same time, the decline in cardiovascular reserve function (such as increased arterial stiffness) reduces the ability to compensate for the hemodynamic changes during pregnancy, thereby increasing susceptibility to HDP [24]. Furthermore, a history of pre-existing medical conditions is also a key factor influencing both OSA and HDP. Approximately 53% of women with pre-pregnancy hypertension have severe OSA [25], and about 60% of hospitalized patients with type 2 diabetes have OSA [26]. Pre-existing medical conditions such as hypertension and diabetes are also risk factors for HDP [27]. Despite the presence of these confounding factors, large-scale cohort studies have confirmed a significant association between OSA and hypertensive disorders of pregnancy after adjusting for obesity, age, and pre-pregnancy hypertension: preeclampsia (aOR 2.22; 95% CI 1.94–2.54), gestational hypertension (aOR 1.67; 95% CI 1.42–1.97), and eclampsia (aOR 2.95; 95% CI 1.08–8.02) [6]. Prospective studies further show that the risk of HDP in pregnant women with OSA remains significantly elevated after adjusting for BMI and underlying medical conditions [28, 29]. Although there are limitations in the existing research (such as reliance on BMI for assessing obesity without considering the heterogeneity of fat distribution), the results after multivariable adjustment strongly support OSA as an independent risk factor for HDP. This finding reveals a potential causal link between OSA and HDP, suggesting that even after controlling for multiple confounding factors, OSA may still influence the occurrence and development of HDP through its unique pathophysiological mechanisms.

The coexistence of OSA and HDP is increasingly recognized and is on the rise, posing a serious threat to maternal and fetal health. OSA, due to chronic hypoxemia, can have negative effects on multiple organ systems, potentially impacting the function of the heart, lungs, liver, and kidneys. In severe cases of OSA, it may even lead to pulmonary hypertension and right heart failure [30, 31]. Research by Malhamé et al. has indicated that pregnant women with OSA are at an increased risk of myocardial disease, congestive heart failure, and pulmonary edema during pregnancy or at the time of delivery, suggesting that OSA may be an independent risk factor for cardiovascular comorbidities during pregnancy [32]. Moreover, patients with HDP not only have a significantly increased risk of cardiac diseases, pulmonary embolism, and other cardiovascular conditions [33, 34], but also more commonly present with symptoms such as hypertension, proteinuria, and edema, which may lead to a decline in renal function [35]. Therefore, the comorbidity of HDP and OSA could impose a dual burden on multiple organ systems.

Existing studies have also indicated that the interaction between OSA and PE, may increase long-term cardiovascular risks [11, 36]. Two smaller cohort studies have investigated the relationship between OSA and maternal outcomes in women with HDP. The first study, with a sample size of 85, found no association between OSA and increased severity of hypertension or worsening antiangiogenic profiles in these women [37]. Conversely, the second study, which included 100 participants, found that the severity of OSA was correlated with blood pressure levels in those with HDP and PE [38]. Populations in both studies differed in several aspects, including pre-pregnancy body mass index (BMI) and geographic location. Moreover, the first study treated OSA as a binary variable, while the second study considered the severity of OSA as a continuous variable, which may partly explain the inconsistency in results. A large cohort study from Canada, which included 1,312,681 individuals, showed that women combining PE and OSA had twice the risk of intensive care unit (ICU) admission, acute renal failure, pulmonary edema, pulmonary embolism, congestive heart failure, cardiomyopathy, stroke, and death compared to women without OSA, and a fivefold higher risk of serious cardiovascular complications [32]. Therefore, OSA during pregnancy may be a predictor of adverse outcomes in women with HDP and an important risk factor to consider in the management of PE. Current research lacks a comprehensive analysis of the impact of various severities of OSA and types of HDP, including various subtypes of PE. Future studies with larger sample sizes are needed to explore the extent of damage OSA and HDP may cause to the various systems of pregnant women.

Pathogenesis of HDP and OSA during pregnancy

OSA shares some common and possibly converging pathophysiological pathways with HDP. The prevailing view is that OSA may induce PE by exacerbating the negative effects of a two-stage pathogenic process. The first stage involves erroneous remodeling of the uterine spiral arteries, leading to reduced placental perfusion and a hypoxic environment within the placenta, causing insufficient trophoblast invasion [39]. The hypoxemia exhibited by OSA patients may trigger or accelerate the creation of a hypoxic environment, potentially serving as a harbinger of PE in early pregnancy. In the second stage of PE development, placental ischemia-reperfusion induces oxidative stress, leading to the release of antiangiogenic factors, inflammatory cytokines, and oxidative stress markers from the placenta, triggering sympathetic nervous system (SNS) overactivation and maternal endothelial dysfunction, ultimately resulting in hypertension, proteinuria, and organ failure [40]. Similarly, the intermittent hypoxia experienced by OSA patients exacerbates the imbalance in the release of vascular endothelial factors, propagating endothelial dysfunction, triggering atherosclerosis, and causing systemic arterial hypertension, eventually leading to PE [41] (Fig. 1). The following are specific mechanisms by which OSA during pregnancy may be linked to HDP:

Fig. 1.

Current possible mechanisms of hypertensive disorders of pregnancy (HDP) caused by obstructive sleep apnea (OSA) during pregnancy

Intermittent hypoxemia

Intermittent nocturnal hypoxemia, a hallmark of OSA, is characterized by periodic drops in oxygen saturation lasting 15–60 s, followed by reoxygenation [42]. In human studies, placental tissues from women with OSA have been found to exhibit signs of hypoxia [43]; Meanwhile, in animal studies involving pregnant mice exposed to chronic intermittent hypoxia (CIH), the mice developed PE-like symptoms such as hypertension and proteinuria. Imbalances in angiogenic factors and vascular remodeling damage in their placentas are associated with significantly increased levels of soluble vascular endothelial growth factor receptor-1 (sFlt-1) in maternal serum, suggesting that CIH may trigger placental hypoxia, leading to endothelial dysfunction and an increased risk of HDP [44]. The study also found that the changes were milder in the two groups, indicating that the degree of hypoxia may affect the occurrence and severity of HDP [45].

In a study of 53 pregnant women, placental weight was found to be positively correlated with the AHI, potentially due to CIH-induced proliferation of fetal capillaries and trophoblast cells, which could be an adaptive response of the placenta to OSA-induced insufficiency [46–48]. In vitro and animal studies also indicate that changes in oxygen tension may induce the pathological placental development seen in PE. Pregnancy in rodents exposed to chronic hypoxia exhibits PE-like symptoms, possibly due to the hypoxic environment produced in the placenta, leading to insufficient trophoblast invasion [39, 49–51]. These suggest that OSA may influence placental development through CIH, thereby inducing HDP, making the placenta a potential target organ for the association between HDP and OSA. Hypoxia-inducible factors (HIFs), which are overexpressed in the placentas of women living at high altitudes [52], may play a key role in adapting to low-oxygen environments and the development of HDP [53]. Although research on the role of HIF in the relationship between OSA and HDP is limited, HIFs are known to be associated with OSA and hypertension in non-pregnant adults, participating in processes such as inflammation, SNS activation, oxidative stress, and endothelial dysfunction [54].

CIH may induce placental hypoxia, leading to insufficient invasion by trophoblast cells, promoting endothelial dysfunction, and ultimately triggering HDP in OSA patients. In Yang’s study, inhibition of Angiopoietin-like protein 8 (ANGPTL8) significantly attenuated the vascular remodeling induced by CIH and reduced hypertension and hyperlipidemia caused by CIH [55]. These findings provide new targets for future research into the pathophysiological mechanisms of intermittent hypoxia in HDP and OSA during pregnancy.

Oxidative stress

OSA may contribute to the development of PE by inducing oxidative stress. OSA is a condition known to be associated with enhanced oxidative stress and reduced antioxidant capacity [56, 57], and it is characterized by hypoxia/reoxygenation injury leading to increased production of reactive oxygen species (ROS) [58, 59]. Studies have shown that the severity of OSA, particularly the oxygen desaturation index, is independently correlated with oxidative stress levels [58, 60]. Oxidative stress is considered one of the key mechanisms in the development of HDP, with increased ROS stimulating the secretion of vascular regulatory agents such as vascular endothelial growth factor (VEGF) and HIF-1α [61–63], which are crucial for placental vascular formation and function. Recent research suggested that the clearance or reduction of ROS in the placenta may lead to poor placental vascular development and increase the risk of PE, indicating that maintaining ROS levels plays a balanced role in placental function and the pathogenesis of PE [64, 65]. Therefore, it can be speculated that the abnormal level of oxidative stress in patients with OSA may interfere with the balance of angiogenesis regulatory factors, affect the remodeling process of the uterine spiral arteries, and the placental vascular system, thereby leading to the occurrence of PE.

Inflammatory response

During normal pregnancy, inflammatory markers in pregnant women rise compared to non-pregnant ones, especially in patients with HDP, the inflammatory response rises more [66, 67]. Specifically, certain inflammatory cytokines, such as interleukin-1β (IL-1β), have been considered to regulate the motility and invasiveness of trophoblast cells, potentially leading to insufficient trophoblast invasion and the onset of PE [68]. Elevated levels of tumor necrosis factor-α (TNF-α) may lead to a decrease in VEGF, increase the cytotoxicity of natural killer (NK) cells, promote the generation of autoantibodies against angiotensin II type 1 (AT1) receptors [69, 70], causing an increase in blood pressure and ultimately leading to PE. C-reactive protein (CRP) interacts with placental-specific phosphocholine transferase (PCTY1b) and neurokinin B (NKB) to activate neurokinin 3 receptor (NK3R), leading to increased production of sFlt-1 and inducing PE [71]. Studies have indicated that patients with OSA exhibit elevated levels of inflammation markers, such as IL-6, IL-8, and TNF-α [72, 73], and it has been proposed that this increase in systemic inflammation is a primary mechanism connecting OSA to adverse pregnancy outcomes [74]. A Mendelian randomization study indicated a significant causal relationship between OSA and increased CRP levels [75], and elevated CRP is closely associated with the occurrence and severity of PE [76–78]. However, IL-10, an immunosuppressive cytokine that plays an important role in balancing pro-inflammatory and anti-inflammatory responses [79], was found to be higher in pregnant women with OSA compared to controls [73]. This is consistent with many studies that find serum levels of IL-10 are higher in complicated pregnancies than in healthy women, yet contradicts the decrease in IL-10 levels and an increase in CXCL-10 levels seen in PE [71]. Further studies must investigate the link between OSA-induced systemic inflammation and pregnancy hypertension, considering epigenetic changes from late pregnancy hypoxia. It’s crucial to exclude confounders such as obesity, age, and comorbidities, and to assess postpartum inflammation and the benefits of treating OSA better to evaluate pregnancy-related systemic inflammation risks [80].

SNS dysregulation

In non-pregnant individuals, hypertensive and obese adults, increased nocturnal blood pressure variability is associated with long-term adverse cardiovascular outcomes, including increased mortality [81, 82]. In women with PE, increased blood pressure variability and reduced baroreceptor sensitivity have also been observed, which are considered signs of SNS overactivity [83–85]. Patients with OSA experience repeated episodes of apnea at night, leading to hypercapnia, intermittent hypoxia, and reoxygenation cycles, which trigger chemoreceptor reflexes that stimulate SNS activation [86]. These disturbances, along with changes in intrathoracic pressure and frequent sleep interruptions, can lead to endothelial dysfunction [87, 88]. Studies have also found that OSA can activate the SNS and increase the production of catecholamines, and elevated levels of catecholamines have been found to be associated with PE [89, 90]. These pathophysiological processes may lead to hypertension in OSA patients and may play a role in the development of PE in OSA women [11]. Thus, OSA may exacerbate or induce HDP by affecting the activity of the SNS and increasing systemic vascular resistance. Future research could elucidate the link between OSA, HDP, and SNS activation by exploring catecholamines, their related protein factors, and pathways.

Endothelial dysfunction

Vascular balance is crucial for endothelial homeostasis, with angiogenic proteins like VEGF and PlGF, and antiangiogenic proteins like s-Eng and sFlt-1, being essential for placental function and overall physiological processes. However, the imbalance of these proteins is closely associated with the clinical features of PE, including vasoconstriction, hypertension, and the appearance of proteinuria [49, 91–94]. Currently, serum levels of s-Eng and sFlt-1 are used to predict and diagnose PE. In non-pregnant adult patients with OSA, elevated levels of sFlt-1 and s-Eng, which are associated with hypertension and endothelial dysfunction [95, 96]. For OSA during pregnancy, animal model studies suggested that prenatal intermittent hypoxia may inhibit vasodilation by releasing sFlt-1 and s-Eng, affecting the vasoreactivity of the uterine arteries, which in turn affects the vascular reactivity of uterine arteries through HIF1A, leading to PE [53, 97]. A case-control study showed that antiangiogenic biomarkers, particularly the sFlt-1/PlGF ratio, were significantly higher in pregnant women with OSA, further indicating the occurrence of PE [98]. However, studies have also noted that there are no significant differences in biomarkers, including markers of endothelial dysfunction, between pregnant women with and without OSA, which may be related to the severity of OSA [37, 95, 96]. These studies collectively suggest that antiangiogenic biomarkers may be important risk indicators and screening directions for the development of HDP in pregnant women with OSA.

Endothelin-1 is a potent vasoconstrictor known in PE, and its levels are associated with sFlt-1 and s-Eng [99]. The study has explored the antagonism of endothelin-1 and its downstream type A receptor (ETA) to mitigate the hypertensive effects of these proteins in animal models, which may serve as potential targets for future treatment of OSA-induced HDP [51, 100]. Additionally, studies have improved blood pressure control in women with severe preterm PE by continuous selective removal of sFlt-1 from plasma, reducing proteinuria, and prolonging pregnancy [101], which may also be a potential treatment approach. Recent research has found that OSA may induce endothelial dysfunction by affecting mitochondrial function. Specifically, OSA can lead to elevated levels of circulating microRNA-210 (miR-210) in endothelial cells. Sterol regulatory element-binding protein 2 can directly bind to the promoter of miR-210, thereby inhibiting the iron-sulfur assembly enzyme in vascular endothelial mitochondria, impairing mitochondrial respiration and function, representing a new mechanical link between OSA and endothelial dysfunction [102]. This provides a new direction for exploring the connection between OSA and the pathogenesis of HDP.

Atherosclerosis

Atherosclerosis is an important indicator of vascular health, closely linked to OSA [103]. Previous studies have shown that OSA is associated with exacerbation of atherosclerosis, and Continuous Positive Airway Pressure (CPAP) treatment can effectively improve arterial stiffness, especially in patients with OSA and resistant hypertension [104–106]. These suggest that atherosclerosis may be one of the indirect mechanisms linking OSA with HDP.

Research has shown that OSA promotes the formation of atherosclerosis through direct mechanisms such as neurologic dysfunction and inflammatory responses, as well as indirect mechanisms like hypertension. Some studies suggest that overactivation of cyclooxygenase (COX) may be a potential mechanism for adverse cardiovascular outcomes in OSA patients and HDP [107, 108]. The COX pathway involves two main enzymes: constitutive cyclooxygenase-1 (COX-1) and inducible cyclooxygenase-2 (COX-2). These enzymes regulate the synthesis of prostaglandins, playing important roles in various physiological processes such as pain, inflammation, and coagulation [109]. Research by Elodie Gautier-Veyret et al. observed the activation of the COX-1 pathway in ApoE-/- mice exposed to a CIH environment, which promoted the acceleration of atherosclerosis under hypoxic stimulation. Inhibition of the COX pathway [110, 111] or gene deletion [112, 113] delayed the progression of atherosclerosis. In OSA patients, CIH may also induce a shift in macrophage populations towards a pro-inflammatory, metabolically activated phenotype, promoting the recruitment of bone marrow-derived macrophages [114]. These macrophages, activated through the scavenger receptor CD36, play a role in disease models, mediating the progression of atherosclerosis [115–117].

OSA triggers atherosclerosis through the COX pathway and macrophage activation, potentially leading to HDP. However, there are no studies on the specific mechanisms of the COX pathway and the characteristics of macrophages in patients with OSA concurrent with HDP to date. Future research should focus on exploring the activation of macrophages and the COX pathway, along with their association with the development of HDP.

Melatonin

Melatonin, secreted by the pineal gland, influences fetal neural development, uterine contraction, and the onset of labor during pregnancy, as well as the body’s nocturnal blood pressure reduction mechanism [118, 119]. Studies in OSA patients have shown that approximately one-fourth of patients exhibit altered melatonin secretion rhythms, typically due to abnormal light exposure caused by frequent awakenings at night, and treatment with CPAP for three months may help restore normal melatonin secretion rhythms [120]. Melatonin is not only an efficient free radical scavenger and antioxidant; its cascade reactions can neutralize a variety of toxic oxygen derivatives, allowing a single melatonin molecule to scavenge more ROS, which is far more efficient than traditional antioxidants [121, 122].

Additionally, melatonin can engage in cascade reactions with nitric oxide synthase (NOS), thereby scavenging NOS, reducing the production of nitric oxide, and inhibiting inflammatory responses [123]. These cascade reactions allow melatonin to protect cells from oxidative stress more effectively than other antioxidants in the body [124, 125]. Therefore, melatonin has the potential to act as an endogenous antioxidant, protecting the body from severe oxidative stress, which may help prevent OSA as well as OSA-mediated HDP. Clinical trials have been registered to assess the potential benefits of melatonin in terms of antioxidation, stabilizing respiratory control, and reducing the severity of OSA. Nonetheless, further research is needed to clarify the specific mechanisms of melatonin in the relationship between OSA and HDP, particularly how melatonin may affect these conditions through changes in the sleep cycle. This line of research could provide new strategies and insights for preventing HDP induced by OSA.

OSA contributes to placental hypoxia and oxidative stress via intermittent hypoxia, leading to endothelial dysfunction and inflammation, which escalate HDP risk. Sympathetic nervous system dysfunction and atherosclerosis further strain the cardiovascular system, worsening HDP. Melatonin secretion disruption may also aggravate oxidative stress and affect sleep quality, influencing HDP development. These mechanisms offer potential therapeutic targets, but translating them into clinical practice is challenging. For example, aspirin, which inhibits COX activity and thromboxane A₂ synthesis, reduces platelet aggregation and improves placental ischemia [126], lowering the risk of preeclampsia by about one - quarter [127]. However, its effectiveness is limited in OSA patients. Although aspirin shows anti - atherosclerotic potential by inhibiting the COX pathway [128], its intervention effect in CIH animal models hasn’t been studied [108], possibly due to widespread aspirin resistance in OSA patients [129]. Determining an aspirin dose that prevents inflammation without causing side effects like increased bleeding risk is crucial. A recent cohort study found that continuous aspirin use might raise the risk of adverse cardiovascular events in hypertensive OSA patients [130], likely due to its platelet aggregation inhibition. While miR − 210 serves as a common biomarker for OSA and preeclampsia [131], its relationship with aspirin treatment remains unknown.

Future research could focus on developing drugs targeting key mechanisms linking OSA and HDP, such as COX inhibitors or miR − 210 modulators. Exploring the clinical significance of these molecular mechanisms and their potential in treating OSA and HDP may yield more effective therapeutic strategies for patients with both conditions.

The impact of OSA treatment on HDP

At present, a variety of therapies are employed in the treatment of OSA, which are mainly divided into physical and pharmacological modalities. These treatments include CPAP therapy, oral appliances, positional therapy, and other adjunctive therapies. CPAP is the standard treatment, which can improve blood pressure and reduce the incidence of pregnancy-induced hypertension and PE, although its effectiveness is influenced by individual variations [132, 133]. Oral appliances, particularly mandibular advancement devices, are suitable for patients with mild to moderate OSA and serve as an alternative to CPAP, but individualized treatment is still required. Positional therapy improves airway patency and reduces OSA symptoms by avoiding the supine position, though research on its use in pregnant women is still limited. Other treatments such as nasal expiratory positive airway pressure, myofunctional therapy, hypoglossal nerve stimulation, mineralocorticoid receptor antagonists, and acetylsalicylic acid have shown potential in certain cases, but most studies lack specialized evaluation in pregnant women, particularly those with concomitant HDP. Additionally, given the complex pathogenesis of OSA combined with HDP during pregnancy, future research needs to explore and attempt interventions on additional pathological processes, such as oxidative stress, inflammation, and endothelial dysfunction, and investigate potential therapeutic targets. The impact of OSA treatment on HDP is multifaceted, and further studies are needed to refine treatment strategies and ensure the maximization of therapeutic outcomes.

CPAP treatment

Currently, CPAP therapy is the standard treatment for OSA and other SDB conditions [134, 135]. Recent studies suggest that CPAP therapy may have a positive impact on cardiovascular metabolic outcomes and placental physiology [136, 137]. CPAP therapy may reduce the risk of HDP and its progression by improving hemodynamic responses in pregnant women, regulating blood pressure [138–140]. Additionally, CPAP may influence HDP and preeclampsia by adjusting the imbalance between pro-angiogenic and anti-angiogenic factors [141]. Moreover, CPAP therapy could potentially improve endothelial cell function, thereby ameliorating placental insufficiency and impacting HDP [142, 143].

A multicenter randomized controlled trial in Thailand found that CPAP treatment significantly reduced the incidence of preeclampsia and blood pressure, particularly Diastolic Blood Pressure (DBP) and Mean Arterial Pressure (MAP), in high-risk pregnant women with OSA [144]. Similarly, a randomized controlled trial by Poyares et al. also indicated that pregnant women with OSA had better blood pressure control and pregnancy outcomes after CPAP treatment [145]. A prospective cohort study by Guilleminault et al. [146] involving 12 women with chronic hypertension or risk factors for preeclampsia found that CPAP treatment in OSA pregnant women significantly reduced the incidence of preeclampsia (from 19 to 7%), consistent with the findings of a prospective cohort study by Stajić et al. [132]. Furthermore, a retrospective cohort study on 177 obese pregnant women with OSA found that CPAP treatment significantly reduced the incidence of HDP and preeclampsia [147]. In summary, CPAP treatment may have a positive effect on the incidence and progression of HDP and PE in pregnant women with OSA.

Despite the substantial evidence supporting the therapeutic effects of CPAP on HDP and PE during pregnancy, the effectiveness is still disputed in some studies due to differences in study design, sample size, duration of treatment, and study implementation. The randomized controlled trial by J Reid et al. found no significant improvement in blood pressure or inflammatory markers in the CPAP or mandibular advancement device groups [148]. Unlike the study designs of Edwards and Blyton et al. [138, 140] which included only severe PE patients, the study by J Reid et al. included all pregnant women with gestational hypertension, which may be one of the key reasons for the lack of significant CPAP effects. Additionally, in comparison to the RCT by Tantrakul et al. from Thailand (n = 310) [144], this study did not consider risk factors for HDP and PE (such as GDM) at the time of patient enrollment, and the sample size was too small (n = 24), which may be another important reason for the lack of significant changes in hemodynamic parameters after CPAP treatment. More importantly, this study was conducted in the late stages of pregnancy, with only one night of treatment, which was likely too short a duration to impact the inflammatory and hemodynamic disturbances associated with HDP. In the study by Tantrakul et al. in Thailand, CPAP intervention significantly reduced blood pressure in OSA patients in early pregnancy. Since women who develop GH in early pregnancy (< 30 weeks) are more likely to progress to PE [149], early intervention may improve the benefit rate of CPAP treatment. Similarly, in the study by Chirakalwasan et al. [150] CPAP was applied to OSA patients in mid to late pregnancy, and no significant differences were observed in the incidence of PE between the CPAP treatment group and the control group, or between those who received CPAP treatment for ≤ 2 weeks or ≥ 2 weeks. This suggests that the timing of CPAP intervention is crucial for improving blood pressure and preventing the development of HDP in OSA patients, but the results may also be related to the small sample size (n = 36) and low CPAP adherence (< 50%). Moreover, this study only included OSA patients with GDM and obesity, and the 2-week treatment period was likely insufficient to counteract the impact of hyperglycemia on blood pressure and overall hemodynamic disturbances [151]. However, a recent randomized controlled trial by Panyarath et al. also found no significant improvement in blood pressure and PE incidence between groups, despite achieving acceptable adherence to CPAP (> 50%) and a longer treatment duration (≥ 70 days) in 10 participants [152]. This may be due to the small sample size (n = 48) and the exclusion of participants with high-risk factors for HDP and PE. Interestingly, the control group in this study received additional nasal dilator strips(NDS) treatment, which may have partially improved oxidative stress and cardiovascular metabolic outcomes in OSA pregnant women, thereby offsetting the benefits of CPAP treatment.

It is noteworthy that the effectiveness of CPAP treatment may vary depending on the severity of OSA. A prospective cohort study by Stajić et al. found that CPAP treatment significantly reduced the incidence of PE in patients with mild to moderate OSA [132], consistent with the results of the RCT by Tantrakul et al. from Thailand [144]. Another real-world retrospective cohort study similarly showed similar results in reducing the incidence of HDP in high-risk pregnant women with moderate OSA who received CPAP treatment [147]. However, in a study involving 117 pregnant women with OSA and obesity, the use of CPAP treatment in the late stages of pregnancy for mild to moderate OSA did not show significant improvement in pregnancy outcomes. In contrast, for women with severe OSA, CPAP treatment significantly reduced the incidence of adverse pregnancy outcomes [153]. This may suggest that the severity of OSA influences patient adherence to CPAP treatment, and that the accumulation of subcutaneous fat in the neck has a smaller impact on the narrowing and relaxation of the upper airway in mild to moderate OSA patients [154].

Moreover, the effectiveness of CPAP treatment for OSA patients varies depending on the stage of pregnancy. A study by Guilleminault et al. showed that CPAP treatment had the most significant effect on reducing blood pressure in patients with OSA during mid-pregnancy [146]. An RCT conducted in Thailand also indicated that CPAP had a marked antihypertensive effect after six months of pregnancy, with fewer antihypertensive medications required in the CPAP group and better pregnancy outcomes [144]. This suggests that a treatment strategy combining CPAP with a small amount of antihypertensive medication might reduce the long-term effects of current antihypertensive treatments on both mother and fetus. However, a randomized controlled trial by Panyarath et al. [152] found that CPAP treatment did not significantly lower blood pressure in OSA patients during mid to late pregnancy, possibly due to the small sample size and the additional use of NDS in the control group. These studies suggest that the timing and duration of CPAP treatment may need to be linked with placental pathophysiological mechanisms associated with HDP or PE at different gestational stages to achieve better treatment outcomes [155, 156]. In Tantrakul’s study, CPAP treatment was effective only for late-onset preeclampsia, but not for early-onset preeclampsia [144]. This may be because CPAP treatment started too late, missing the critical period for placental formation (0–13 weeks) [155, 156], or due to insufficient automatic CPAP titration [157]. However, some case reports suggest that CPAP, as an adjunct to antihypertensive medications, can help control blood pressure in early-onset preeclampsia associated with OSA [158]. Most cohort studies examining the impact of CPAP treatment on HDP in OSA patients have not focused on the different subtypes of HDP or the classification of preeclampsia. However, the onset of different preeclampsia subtypes is closely related to placental implantation timing. It remains unclear whether maternal OSA and its treatment might alter the placental implantation process and thereby affect the pathogenesis of HDP, requiring further mechanistic studies to clarify this.

Research on the treatment of OSA in twin or multiple pregnancies is limited. A recent case report from Korea showed that CPAP, as an adjunctive treatment to antihypertensive medication, was able to control blood pressure in twin pregnancies with preeclampsia related to OSA [158], consistent with the conclusions of two case reports on CPAP treatment in multiple pregnancies [159, 160]. However, in a case report from Germany, satisfactory treatment results were only achieved using spontaneous/timed bilevel positive airway pressure (BiPAP-ST) combined with additional oxygen supplementation [161]. This suggests that CPAP treatment for OSA in multiple pregnancies may require additional oxygen supplementation and more complex non-invasive ventilation support [161]. With nearly 40 years of development in assisted reproductive technology, the number of infertile couples choosing this technology is increasing, and twin and multiple pregnancies, as common complications, have been proven to increase the risk of HDP. Therefore, twin and multiple pregnant women with OSA may be a high-risk group for HDP. Since most current studies are limited by small sample sizes, most have not fully assessed the efficacy of CPAP treatment on HDP in such pregnant women, which may become an important direction for future precision medicine research (Table 1).

Table 1.

Current research on the CPAP treatment of prevention of HDP in OSA

Author	Study characteristics			Exposure to CPAP		Reported outcomes
	Country, Population	Participants, n	Study design	Treatment indication	Timing: length of application	BP	PE	Adherence	Main study findings
Edwards et al., 2000(142)	Australia, Hospital	11	Observational study (two overnight sleep studies on and off CPAP)	Severe PE	Third trimester one night off & one night on	No BP increase in women with chronic hypertension on medication. Significant compared to untreated group. n = 7/n = 9	Overnight study in women diagnosed with PE, n = 11	NA	Reduction of SBP(-18mmHg) and DBP(-19mmHg)
Blyton et al., 2004(140)	Australia, Hospital	24 with severe PE 15 controls	Randomized controlled trial	Severe PE	Third trimester, one night off & one night on	CPAP treatment reduced BP during sleep, with an overall 3mmHg decrease in MAP compared to the non-treatment group (p = 0.005).	Overnight study only in women diagnosed with severe PE, n = 24	NA	Patients on CPAP experienced minimized reductions in cardiac output and in total peripheral resistance
Poyares et al., 2007(147)	Brazil, Cinics with pre-existing HTN	16 women: 7 CPAP, 9 no CPAP	Randomized controlled trial	Pre-existing hypertension on medication and chronic snoring	< 20 weeks	Significant change in systolic BP (p = 0.001) and higher Diastolic(p = 0.0003) BP at 32 weeks in control group Reduction in medication required for CPAP women.	PE occurred in one subject, the remaining eight patients had normal pregnancies and infant deliveries	7 women in the CPAP group used the machine for a mean of 6 h per night, 7 days a week	BP decrease significantly as compared to the control group at 6 months of gestation
Guilleminaultet al, 2007(148)	USA, Clinics	12	Prospective Longitudinal controlled study	High-risk for PE	First trimester until delivery	No significant BP increase over time in 7 women with history of chronic hypertension during pregnancy.	Two out of 12 women in ‘high risk’ group of PCS developed PE	All women using nasal CPAP nightly with a mean usage of 5.4 ± 0.6 h, 7 nights a week from early pregnancy until the end of pregnancy	All subjects with chronic hypertension maintained BP below 140/90 during pregnancy.
Blyton et al., 2013(140)	Australia, Hospital	10	Observational study of women with PE who underwent two sleep studies on and off treatment	Moderate to severe PE	Third trimester one night off & one night on	NA	NA	NA	Women with PE had inspiratory flow limitation and an increased number of oxygen desaturations during sleep (p = 0.008)
Reid et al., 2013(150)	Canada, Hospital	24 women 11 CPAP 13 MAD	Randomized controlled trial	GH (with or without proteinuria)	Two nights	45.5% (5/11) of CPAP subjects and 53.8% (7/13) MAD subjects had a DBP > 90 mm Hg In the morning after the diagnostic study	NA	a mean usage of 6.5 h in CPAP group	BP was not consistently improved with CPAP as compared to MAD
Chirakalwasanet al, 2018(152)	Thailand, Clinics	18 treatment 18 controls	Randomized controlled study	GDM on MNT BMI ≥ 25 OSA diagnosed by REI ≥ 5	Second and third trimester two weeks CPAP or waitlist control, then offered all	NA	No difference in PE between CPAP and wait-list control, no difference between CPAP treatment time ≤ 2 weeks and ≥ 2 weeks	Variable compliance, with an average rate of adherence of 46.7% (or 7 out 15 women who used the device)	Two weeks of CPAP in females with GDM and OSA did not improve glucose levels, but it enhanced insulin secretion in those adherent to CPAP.
Stajić et al., 2022(134)	Sebria, Clinics	110	Prospective longitudinal controlled study	High-risk for pregnancy ESS > 10 REI > 5 Significant night-time desaturation < 90% snoring Quantitative or qualitative pulse disorders	24 to 28 weeks’ gestation	NA	Patients with OSA treated conservatively had significantly milder and more moderate PE (24% vs. 8%, p = 0.02)	Median compliance to CPAP use was 6.1 ± 1.0 h per night for four weeks from 24 to 28 weeks	CPAP therapy significantly reduced the incidence of severe forms of hypertensive syndrome (mild and moderate PE) in pregnant women with OSA
Alexandra et al., 2023(149)	American, Clinics	177	Retrospective cohort study	Obesity BMI ≥ 35 kg/m2 average maternal age > 30 years old OSA diagnosed by REI ≥ 5	First trimester (30%), Second trimester (48%), Third trimester (22%), CPAP treatment for the remainder of pregnancy	NA	Hypertensive and PE outcomes were not statistically different, the composite hypertension outcomea occurred in 43% without OSA (n = 77), 64% with untreated OSA (N = 77), and 57% with treated OSA, compliant with CPAP (n = 23, p = 0.034).	average CPAP use of 5.9 ± 1.2 h, with an average of 84 ± 15% of days CPAP use of 4 h or longer	CPAP therapy may modulate the increased risk of hypertensive complications in pregnancies complicated by OSA
Tantrakul et al., 2023(146)	Thailand, Hospital	153 CPAP 157 usual-care	Randomized controlled trial	Women older than 18 with any high-risk condition and OSA	First trimester Until delivery every night	CPAP treatment significantly lowered DBP by -2.2 mmHg (p = 0.014), approximately − 0.5 mmHg per hour of use (p = 0.013)	PE rate was 13.1% (20/153) in the CPAP and 22.3% (35/157) in the usual-care group (p = 0.032) CPAP was effective only in late-onset, but not early-onset PE	CPAP adherence rate was 32.7% with average use of 2.5 h/night	CPAP treatment with even mild-to-moderate OSA and high-risk pregnancy demonstrated reductions in both DBP and the incidence of PE
Panyarath et al., 2024(154)	Canada, Clinics	27 CPAP 21 NDS	Randomized controlled trial	> 18 years of age with singleton pregnancies at > 12 weeks’ gestation with hypertension AHI ≥ 5 AHI < 30	Second and third trimester until delivery every night	Mean BP increased slightly from the baseline to the predelivery visit in both the CPAP and NDS groups. No notable differences in BP between groups at either time point.	PE rate was similar in the two groups, with no evident benefit conferred by CPAP treatment (35.7% vs. 7.7%, p > 0.05)	10 participants achieved acceptable adherence mean CPAP use was 3.1 ± 2.5 h/night over the 9.6 ± 4.0 weeks among the 14 CPAP participants 13 using NDSs 50% of nights	CPAP treatment showed no significant improvements in 24-hour blood pressure, arterial stiffness, or maternal and fetal outcomes compared to the control group

Note: BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, Mean arterial pressure; PE, preeclampsia; CPAP, continuous positive airway pressure; ESS, epworth sleepiness scale; GDM, gestational diabetes mellitus; HTN, hypertension; MNT, medical nutrition therapy; BMI, body mass index; OSA, obstructive sleep apnea; REM, rapid eye movement; REI, respiratory event index; MAD, mandibular advancement device; GH, gestational hypertension; AHI, Apnea/hypoxia index; NDS, nasal dilator strip

^a The composite hypertension outcome included Gestational hypertension, Severe gestational hypertension, Preeclampsia, HELLP and eclampsia

In summary, CPAP treatment has had a positive impact on the incidence and progression of HDP and PE in pregnant women with OSA, but its effectiveness and safety have not been fully assessed, and more large-sample, multicenter, high-quality clinical randomized controlled trial evidence is needed to support it. Additionally, future research should further investigate the regulation of blood pressure trajectories by CPAP treatment and its impact on placental physiology, determine the appropriate timing and duration of intervention, and improve the treatment effect of CPAP. Finally, although compliance among OSA patients presents challenges, CPAP is still recognized as the most effective treatment method, and more research is needed to optimize the HDP treatment strategy for pregnant women with OSA and develop individualized and precise treatment plans to ensure compliance and treatment effectiveness.

Oral appliance therapy

Although CPAP is a common and effective treatment for sleep - related breathing disorders, oral appliances (OAs) offer an alternative for many patients with OSA that does not require electricity and is easy to use. Oral appliances improve mandibular advancement and activate the stretch receptors of the aerodigestive supportive musculature. This increases the space in the oropharyngeal and hypopharyngeal airways, thereby improving respiratory patency. This mechanism not only helps to relieve symptoms of OSA but may also reduce cardiovascular burden in OSA patients through alleviation of nocturnal hypoxia, which in turn may decrease inflammation and oxidative stress levels as well as improve endothelial function and vascular stiffness [162]. Given that these factors, including endothelial dysfunction, play a key role in the pathogenesis of HDP, especially PE, OA therapy may help indirectly reduce the risk of HDP by improving these underlying pathological processes [163].

Mandibular advancement device (MAD)

As the most commonly used and effective oral appliance for treating OSA, the MAD has been extensively studied [164]. It works by advancing the mandible, thereby increasing the space in the oropharyngeal area, reducing airway obstruction, and improving airflow [165]. Numerous studies on OSA patients have shown that MAD is suitable for patients with mild to moderate OSA (Grade A recommendation) and those who are intolerant to CPAP. Compared to placebo devices, MAD can reduce sleep apnea events and daytime sleepiness, while improving quality of life [166].

In two studies focused on pregnant women with OSA, the first was a clinical trial conducted in Canada, analyzing data from 37 CPAP users and 15 MAD users. The study found that although most MAD users had good compliance, some still experienced residual sleep apnea, indicating that MAD may require personalized adjustments for optimal effectiveness. It also highlighted that within the first 30 days of CPAP and MAD treatment, nearly half of the patients struggled to adapt to the treatment, suggesting that early treatment during pregnancy may help identify patients with poor adherence [167]. The second study, conducted by Huynh et al., evaluated the effect of MAD on mild to moderate SDB pregnant women from pregnancy to six months postpartum. The results showed that MAD significantly reduced nighttime snoring duration [25.9 ± 24.5% vs. 6.4 ± 7.8% (p = 0.003)] and AHI values [17.6 ± 5.1 vs. 12.9 ± 6.3 (p = 0.02)].

Adherence to treatment is a critical factor influencing its effectiveness. Both studies observed that patients faced difficulties in adapting to the treatment, suggesting that personalized treatment plans may be necessary to improve adherence. Additionally, although most participants showed good compliance with MAD, some still experienced residual sleep apnea (AHI > 10), emphasizing the importance of tailoring the treatment plan according to the individual patient’s needs. These findings not only highlight the potential benefits of MAD treatment during pregnancy but also point out challenges that future research must address, such as conducting larger randomized controlled trials to verify the preliminary findings and exploring strategies to enhance patient adherence.

Tongue retaining device (TRD)

TRD is another intraoral device suggested for treating OSA patients. This device is designed to enlarge the upper airway dimension during sleep by sucking the tongue forward into a bulbous front part. Currently, there is insufficient evidence regarding TRD, and more research may be needed in the future to assess the effectiveness of this device in patients with OSA combined with HDP [168].

Overview

However, there is currently a lack of large-scale RCTs on the effects of OAs for the treatment of OSA in pregnant women, especially in those with OSA and concomitant HDP. Future research may need to focus on this group to analyze the more comprehensive impact of OA treatment on pregnant women. Although there is currently a lack of studies on blood pressure in pregnant women, existing research indicates that oral appliance therapy has a positive effect on blood pressure control in patients with mild to moderate OSA. For example, a meta-analysis showed that OA treatment for mild to moderate sleep apnea improved blood pressure control. OA therapy was associated with reductions in SBP, DBP, and nocturnal SBP. Although the reduction in blood pressure in OA patients is modest, these effects are comparable to those reported for CPAP therapy.

Additionally, some studies have assessed the impact of oral appliance therapy on oxidative stress, inflammatory responses, endothelial function, and arterial stiffness. A RCT by Dal-Fabbro et al. found that after one month of OA treatment, there was no significant change in oxidative stress parameters, but vitamin B6 levels significantly increased, which may be related to the treatment’s effect on specific oxidative stress pathways. Another study by Galic et al. found that OA therapy significantly reduced inflammatory markers, such as high-sensitivity C-reactive protein. A few studies have also indicated that OA therapy can improve endothelial function and reduce arterial stiffness. However, the results of these studies are inconsistent, possibly due to differences in study design, sample size, treatment duration, and patient selection criteria. Furthermore, the limitations of these studies include small sample sizes, short follow-up periods, and a lack of long-term follow-up data to assess the persistence of treatment effects. These factors may lead to bias in the evaluation of the cardiovascular effects of OA treatment, and larger, well-designed randomized controlled trials are needed to further validate these preliminary findings.

OA therapy is suitable for individuals with simple snoring and mild to moderate OSA, especially those with retrognathia. For pregnant women with mild to moderate OSA who cannot tolerate CPAP therapy, oral appliance therapy is also a feasible option. Oral appliances are divided into four types: custom-made versus non-custom-made, and adjustable versus non-adjustable. Differences in the design characteristics of these devices may affect treatment outcomes. Some studies have found that adjustable devices may be more effective than non-adjustable devices in reducing the AHI. However, considering that the devices usually need to be customized and adjusted during pregnancy, oral appliances are not recommended as a first-line treatment. Moreover, it is still unclear which specific type of OA is most effective in reducing AHI, and more research is needed to determine the impact of different OA types on pregnant women with OSA. For moderate to severe OSA patients, especially those with hypertension, more complex treatment plans may be required, including echocardiography and multidisciplinary collaboration.

Positional therapy

According to existing studies, approximately 53-56% of OSA patients have positional OSA (POSA), defined as an AHI greater than 5 per hour, with the AHI in the supine position being at least twice that of other positions [169]. This means that apnea and hypopnea events are more frequent in specific sleeping positions, particularly in the supine position [170, 171]. Sleep tests, such as polysomnography (PSG) or home sleep apnea testing (HSAT), are the gold standards for diagnosing POSA [172]. According to existing research, approximately 53-56% of patients with OSA are POSA, meaning that apnea and hypopnea events are more frequent in certain sleep positions, particularly supine [170, 171]. According to Cartwright’s criteria, the patient’s AHI in the supine position is at least twice that of other positions [173]. In pregnant women, the supine position can lead to decreased oxygen saturation, changes in cardiac output, and early closure of the airway due to uterine compression of the inferior vena cava [174, 175]. Furthermore, elevated levels of the hormone progesterone during pregnancy may exacerbate the narrowing of the already edematous airway due to pregnancy, leading to further airway obstruction [176, 177]. The supine position can not only cause aortic compression, increasing systemic arterial pressure, but may also reduce venous return due to compression of the inferior vena cava, leading to increased blood pressure. Therefore, it is recommended that pregnant women avoid lying supine for extended periods during pregnancy to reduce the risk of aortocaval compression. A study in the United States suggests that the lateral sleeping position may help prevent apnea and hypopnea events [178]. Research by Ozcan Ozeke et al. further indicated that when comparing the AHI of OSA patients on their left and right sides, the AHI decreased during right-side sleep, especially in patients with moderate and severe OSA [179].

Positional therapy, which involves changing the sleep position to reduce AHI, has been proven effective for OSA patients [180–183] and has been included in clinical guidelines [184]. Methods for implementing positional therapy include the tennis ball technique (sewing a ball onto the back of the sleep shirt to prevent lying on the back) and sleep position trainers, among others [185]. However, organizations such as the American Academy of Sleep Medicine recommend that positional therapy should only be initiated after OSA is diagnosed through sleep testing (PSG or HSAT with positional monitoring) [172, 186]. If POSA is highly suspected clinically, treatment may be attempted based on sleep-related symptoms and polysomnography results, but it still requires subsequent validation [187]. If POSA is highly suspected clinically, treatment may be attempted based on sleep-related symptoms and polysomnography results, but further verification is required (PMID: 31041813IF: 8.8 Q1 B2). Studies have shown that elevating the upper body of postpartum OSA patients by 45° can increase the cross-sectional area of the upper airway, alleviating OSA symptoms [], but these studies did not measure blood pressure values and HDP-related indicators. Currently, recommendations for positional therapy for this special group of pregnant and postpartum women are insufficient, especially as the abdomen of pregnant women grows larger with the progression of pregnancy, making them more inclined to lie supine. Therefore, the potential benefits of lateral sleeping for pregnant women with OSA combined with HDP need to be balanced with considerations of the potential long-term impact of prolonged lateral sleeping on the baby.

In conclusion, positional therapy as a simple, non-invasive alternative to CPAP treatment may help reduce patient discomfort, especially for those who are intolerant or noncompliant with CPAP treatment. However, further research is needed on the effects and recommendations of positional therapy for pregnant women, particularly the exploration of its efficacy in the link between OSA and HDP, which is less studied, possibly because such positional sleep interventions are difficult to quantify with objective data.

Others

Nasal expiratory positive airway pressure (EPAP)

Nasal EPAP is a novel device that generates high resistance during exhalation through a unidirectional valve, creating positive pressure throughout the entire exhalation cycle, which helps to keep the upper airway open and provides resistance against collapse for subsequent inhalation. EPAP therapy has shown efficacy in treating patients with mild to moderate OSA and hospitalized patients who are unable to tolerate CPAP, reducing symptoms of sleep apnea and improving quality of life [188, 189]. However, current evaluations of EPAP devices involve only a limited number of trials, with follow-up periods not exceeding one year, and lack studies specifically targeting pregnant women. Furthermore, some clinical trials were funded by Ventus Medical, the manufacturer of Provent, which means the conclusions from these data and the device’s effectiveness in pregnant women with OSA, particularly those with coexisting HDP, should be interpreted with caution.

Myofunctional therapy

Myofunctional therapy reduces airway obstruction by enhancing the strength and coordination of the pharyngeal muscles, offering potential benefits for patients with mild OSA or as an adjunct to other treatment methods. Interventions include oropharyngeal exercises, controlled breathing, and muscle training through electrical stimulation [190]. However, the current evidence quality is low, primarily based on small randomized controlled trials, and this treatment provides only minimal, possibly transient, benefits [186]. Additionally, the implementation of myofunctional therapy is limited by a shortage of trained professionals, costs, and a lack of long-term data. Existing studies mainly focus on OSA patients, with no specialized research on OSA combined with HDP, so caution is needed when directly applying these findings to OSA patients with HDP.

Hypoglossal nerve stimulation (HNS)

HNS involves the implantation of a neurostimulator that stimulates the hypoglossal nerve during breathing, activating the geniohyoid muscle, increasing the airway diameter, and maintaining airway patency. This FDA-approved device has been validated as an alternative treatment for moderate to severe OSA patients (with BMI under 32), though it is currently available only in a limited number of selected medical centers [191, 192]. The quality of the existing evidence is low, primarily based on a small number of randomized controlled trials, and these trials show inconsistencies in both design and result reporting, limiting its widespread clinical application. Furthermore, the invasive nature of hypoglossal nerve stimulation means that it is irreversible, which further restricts its suitability. Nevertheless, for symptomatic OSA patients who cannot be adequately treated with CPAP or MAD, hypoglossal nerve stimulation may be a beneficial remedial treatment option.

Mineralocorticoid receptor antagonist (MRA) therapy

Recent studies have shown that OSA may induce hypertension and other cardiovascular diseases through the excessive activation of MR, particularly closely related to resistant hypertension [193, 194]. Although CPAP is the standard therapy for OSA, its antihypertensive effect may be relatively limited [195]. A recent study has indicated that MRAs can significantly reduce blood pressure in patients with resistant hypertension and moderate to severe OSA [196, 197]. Therefore, MRAs may have specific benefits in treating resistant hypertension in pregnant women with OSA(Table 2).

Table 2.

Current research on the MRA treatment of prevention of HDP in OSA

Author	Study design	Participants	Baseline AHI (events/h)	Baseline 24 h DBP (mmHg)	Baseline 24 h SBP (mmHg)	Number of patients treated with MRA	MRA (dosage)	Follow-up	Decrease in AHI (events/h); significance	Decrease in 24 h DBP (mmHg); significance	Decrease in 24 h SBP (mmHg); significance
Gaddam et al. 2010(201)	Observational	Patients with RHT and moderate-to-severe OSA	39.8	82.0	147	12	Spironolactone (25–50 mg)	8 weeks	–17.8a; p > 0.05b	–10.0a; p = 0.051b	–17a; p = 0.025b
Kasai et al. 2014(203)(	Observational	Patients with uncontrolled hypertension and moderate-to-severe OSA	57.7	71.0	143	16	Spironolactone (25–50 mg)c	2 weeks	–9.2a; p = 0.005b	–11.3a; p = 0.020b	–11a; p = 0.085b
Yang et al. 2016(200)	Randomized blank-controlled	Patients with RHT and moderate-to-severe OSA	36.6	88.6	127	15	Spironolactone (20–40 mg)	12 weeks	–21.8; p > 0.05d	–14.9; p > 0.05d	–16; p > 0.05d
Krasinka et al.2016(199)	Observational	Patients with RHT and OSA	49.5	87.9	147	31	Eplerenone (50 mg)	3 months	–20.8a; p > 0.05b	–3.8a; p > 0.05b	–11a; p > 0.05b
Wolley et al. 2017(202)	Observational	Patients with PA and OSA	19.2	89.0	148	13e	Spironolactone (12.5–50 mg)	3 months	–7.2a; p = 0.11b	–6.0a; p = 0.04b	–7a; p = 0.03b

^a Calculated based on the mean values at baseline and after treatment provided in the publication; ^b Compared with baseline values; ^c Patients were receiving also metolazone 2.5 mg; ^d Compared to the change in the control group; ^e Study included 20 patients with PA, 13 of those patients were treated medically: 10 with spironolactone, 2 with amiloride, and one with spironolactone and amiloride. In Table 1 data regarding patients treated medically are presented excluding patients who underwent adrenalectomy

AHI: Apnea/hypoxia index; MRA: Mineralocorticoid receptor antagonists; OSA: Obstructive sleep apnea; RHT: Resistant hypertension

Spironolactone, as a type of MRA, has been used to treat gestational hypertension [195]. In a study by Gaddam et al. [198] spironolactone was administered to 12 patients with resistant hypertension and OSA for 8 weeks, and it was found that both systolic and diastolic blood pressure significantly decreased. However, the study was limited by its small sample size and the lack of a control group. A single-center randomized controlled trial by Yang et al. [197] showed that spironolactone could effectively reduce the severity of OSA and blood pressure in patients with moderate to severe OSA and resistant hypertension, consistent with the results of a prospective observational study by Wolley et al. [199] though this benefit was not observed in the study by Kasai et al. [200] (Table 2).

Eplerenone is another selective MRA antagonist, which may have benefits in treating resistant hypertension [195]. A recent case report suggested that eplerenone can stabilize the blood pressure of patients with OSA and HDP [201]. A prospective study by Krasinka et al. [196] also indicated that eplerenone can reduce both the severity of OSA and blood pressure in patients with resistant hypertension(Table 2).

Given that the current evidence primarily comes from limited case reports and small sample studies, further high-quality randomized controlled trials or prospective studies are needed to validate the effectiveness of MRA treatment in patients with OSA and HDP, explore the effective dosing for treatment, and assess any potential long-term adverse effects on both the mother and newborn.

Acetylsalicylic acid (ASA) prevention

ASA, as a non-specific COX inhibitor, has clear benefits in the prevention of cardiovascular diseases [202], but its role in pregnancy-related hypertension associated with OSA remains to be explored. More than 30% of OSA patients are unable to tolerate CPAP therapy, which may increase the risk of cardiovascular and pregnancy-related hypertension. Studies have shown that ASA can improve vascular remodeling induced by chronic intermittent hypoxia [203], but its effects on the prostaglandin pathway in OSA patients have not been fully evaluated. Although some studies have found that low-dose aspirin (LDA) can reduce the risk of preeclampsia by about 25% [126, 127], suggesting potential dual benefits for OSA patients with HDP, the results regarding the duration of LDA treatment and the length of time for aspirin to prevent preeclampsia in pregnant women are contradictory. Moreover, there is currently a lack of guidelines on the dosage, administration, initiation time, and duration of aspirin treatment for preeclampsia in patients with OSA, a high-risk factor. The efficacy of aspirin in OSA patients with HDP remains unclear. Therefore, further high-quality research is needed to explore and evaluate these aspects in the future.

Surgical treatment

There are many surgical methods for treating OSA, aimed at bypassing the obstructed area (such as tracheostomy), modifying the obstructed site (e.g., uvulopalatopharyngoplasty, UPPP), or indirectly treating OSA (e.g., weight loss surgery). Tracheostomy is considered the “gold standard” for treating OSA, but its application is limited due to its social implications, and most patients are unwilling to undergo the procedure. UPPP is the most commonly performed surgical method, but its success rate is only around 40–50%. Mandibular advancement surgery is the most successful surgical approach for treating OSA, with reports indicating a cure rate of 80–90% in patients. However, OSA during pregnancy typically improves or resolves completely after delivery, and the risks associated with anesthesia and surgery during pregnancy are high, so upper airway surgical treatments are not recommended for OSA in pregnant women.

Although the aforementioned treatments show some potential in the management of OSA, current research primarily focuses on OSA patients themselves, with a lack of specialized studies on the preventive effects of these treatments for HDP in pregnant women and on OSA combined with HDP. Therefore, caution is required when directly applying these research findings to OSA patients with coexisting HDP.

Conclusion

OSA is increasingly recognized as a significant risk factor for HDP, yet it remains underappreciated in current clinical practice. Although preliminary studies have revealed associations between OSA and adverse pregnancy outcomes, the specific mechanisms linking OSA with HDP are not fully elucidated. This literature review summarizes the pathophysiological mechanisms through which OSA may contribute to HDP, which offer potential directions for future translational research and therapeutic strategies. Current therapeutic strategies for OSA during pregnancy are primarily focused on CPAP treatment, which has shown positive effects in alleviating symptoms of HDP. However, findings are inconsistent, with some studies reporting significant benefits, while others indicate minimal impact. These discrepancies may be attributable to factors such as study design, sample size, duration of treatment, patient compliance, and timing of interventions. The potential of combination therapies also warrants attention, including pharmacological interventions such as MRAs and ASA, as well as non-pharmacological approaches like positional therapy. However, the efficacy and safety of these treatment modalities require further investigation.

Prospects

The management of OSA during pregnancy represents a critical opportunity to improve maternal and neonatal outcomes. Future research should place a heightened emphasis on the screening of OSA in pregnancy, developing more effective screening tools and standardized diagnostic criteria, and incorporating OSA assessments into routine prenatal care to facilitate early identification and timely initiation of proactive and effective interventions for high-risk pregnant women. Furthermore, the specific mechanisms underlying the relationship between OSA and HDP remain unclear; future studies should aim to elucidate the complex pathophysiological pathways through which OSA affects HDP, with particular consideration of placental hypoxia, oxidative stress, inflammatory responses, endothelial cell function, and the potential impact of OSA on placental development and vascular health. A deeper understanding of these mechanisms is crucial for the development of precise therapeutic strategies and the improvement of pregnancy outcomes.

In terms of therapeutic strategies, the treatment of OSA during pregnancy should not only continue to optimize CPAP treatment protocols but also explore the potential of combination therapies. Research should focus on the synergistic effects of CPAP with pharmacological treatments (such as MRAs, ASA) and non-pharmacological approaches (such as positional therapy), assessing their comprehensive impact on maternal and neonatal health. High-quality, large-scale, multicenter randomized controlled trials are warranted to evaluate the efficacy and safety of these combination therapies and to develop evidence-based guidelines for clinical practice.

Abbreviations

OSA

Obstructive sleep apnea

SDB

Sleep-disordered breathing

AHI

Apnea-Hypopnea Index

HDP

Hypertensive disorders of pregnancy

GDM

Gestational diabetes mellitus

SGA

Small-for-gestational-age

ACOG

The American College of Obstetricians and Gynecologists

PE

Preeclampsia

PSG

Polysomnography

HST

Home sleep testing

HSAT

Home sleep apnea testing

BMI

Body mass index

ICU

Intensive care unit

SNS

Sympathetic nervous system

CIH

Chronic intermittent hypoxia

sFlt-1

Soluble vascular endothelial growth factor receptor-1

HIF

Hypoxia-inducible factors

ANGPTL8

Angiopoietin-like protein 8

ROS

Reactive oxygen species

VEGF

Vascular endothelial growth factor

TNF-α

Tumor necrosis factor-α

NK

Natural killer

AT1

Angiotensin II type 1

CRP

C-reactive protein

PCTY1b

Placental-specific phosphocholine transferase

NKB

neurokinin B

NK3R

Neurokinin 3 receptor

ETA

Endothelin-1 and its downstream type A receptor

miR-210

MicroRNA-210

CPAP

Continuous Positive Airway Pressure

COX

Cyclooxygenase

NOS

Nitric oxide synthase

MRA

Mineralocorticoid Receptor Antagonists

POSA

Positional obstructive sleep apnea

DBP

Diastolic Blood Pressure

MAP

Mean Arterial Pressure

NDS

Nasal dilator strips

BiPAP-ST

Spontaneous/timed bilevel positive airway pressure

OA

Oral appliances

MAD

Mandibular advancement device

EPAP

Nasal expiratory positive airway pressure

HNS

Hypoglossal nerve stimulation

CVD

Cardiovascular disease

LDA

Low-dose aspirin

UPPP

Uvulopalatopharyngoplasty

ASA

Acetylsalicylic acid

Author contributions

Wei-Zhen Tang: Conceptualization, Methodology, Software, Data Curation, Original Draft Preparation, Visualization. Kang-Jin Huang: Conceptualization, Methodology, Validation, Investigation, Data Curation, Original Draft Preparation, Visualization, Supervision, Project Administration. Hong-Yu Xu: Conceptualization, Methodology, Validation. Qin-Yu Cai: Validation, Investigation, Data Curation, Visualization. Tian-Qi Fan: Software, Validation, Investigation, Data Curation, Visualization. Yao Zhang: Validation, Investigation, Writing-Review and Editing, Supervision, Project Administration. Ying-Ping Song: Validation, Investigation, Writing-Review and Editing, Supervision. Tai-Hang Liu: Software, Validation, Investigation, Visualization, Project Administration, Funding Acquisition. Ying-Bo Li: Conceptualization, Methodology, Data Curation, Original Draft Preparation, Writing-Review and Editing, Supervision, Project Administration.

Funding

This work was funded by the Natural Science Foundation of Chongqing (No. CSTB2024NSCQ-MSX0706) and College Students’ Innovation and Entrepreneurship Training Program (No. S202410631066).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.