Shike Zhang
Hui He
Xinyu Li4*
Yi Guo- 1Research Center of Experimental Acupuncture, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- 2National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- 3Department of Reproductive Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- 4College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
Hyperemesis gravidarum (HG), an extreme form of nausea and vomiting during pregnancy (NVP), significantly impairs the quality of life of affected individuals. This review examines the multifactorial etiology of the HG and evaluates the efficacy of non-traditional therapeutic approaches, namely, vagus nerve stimulation (VNS) and electroacupuncture. By synthesizing a comprehensive body of literature, we highlight the neurophysiological mechanisms underlying these therapies and propose a novel model for the HG management. The model focuses on vagus nerve modulation through targeted stimulation at the auricular and cervical points, suggesting a promising avenue for effective and safe treatment strategies against the NVP/HG.
1 Introduction
Hyperemesis gravidarum (HG) encompasses a range of severe symptoms associated with nausea and vomiting during pregnancy (NVP) (1). Nausea, which is characterized by a sensation of upper abdominal discomfort and imminent vomiting, can be accompanied by symptoms associated with vagal nerve excitation. Vomiting can be defined as a phenomenon in which the contents of the stomach or duodenum are forced out of the body through the esophagus or mouth by strong contraction of the stomach, diaphragm, and other abdominal muscles (2). According to a recent international consensus, signs of dehydration or metabolic disorders (weight loss, electrolyte deficiency, or undernourishment) are considered helpful in defining the HG (3). In pregnant women, NVP symptoms commonly appear before 9 weeks of conception and disappear after 20 weeks of conception (4). However, the NVP affects up to 70% of pregnant women (5). Albeit the HG is a pathological form of the NVP that reportedly occurs in 0.3% to 3% of gravidas (6). Approximately 10% of gravidas with the HG are affected during gestation (7). In addition, the HG is the most common reason for hospital admission in the first trimester of pregnancy and is associated with a substantial estimated economic burden (8). In addition to considerable maternal morbidity during pregnancy, the HG poses a significant risk to the long-term health of both mothers and children (9–11).
Growth and Differentiation Factor 15 (GDF15), a placenta-derived protein, is associated with NVP symptoms (12). As a nonspecific blood biomarker of the HG, GDF15 crosses the blood-brain barrier and binds to the glial cell-derived neurotrophic factor family receptor α-like (GFRAL) receptor in the area postrema (AP) and nucleus of the solitary tract (NTS) of the brainstem, which influences food intake, nausea, body weight, and insulin sensitivity (13, 14). Because metformin increases circulating GDF15 levels, its use before pregnancy lowers the risk of severe NVP and HG (15, 16). Activated AP/NTS neurons project to the hypothalamic arcuate nucleus (ARC), where vagal efferent signaling suppresses gastric motility (17). Furthermore, 5-HT plays a critical role in the body's regulation of vomiting, and its receptor, 5-hydroxytryptamine receptor (5-HT3R), is present in both vagal afferent fibers and AP/NTS neurons in the hindbrain terminal (18). 5-HT3 receptor antagonists have been approved for the NVP/HG management, including ondansetron by the Food and Drug Administration (FDA) (19, 20). First-trimester exposure correlates with a slightly increased risk of oral clefts (21). Although newer antiemetics show improved safety profiles, teratogenicity concerns persist, compromising treatment adherence (6, 22). Current evidence for HG therapies remains limited (23, 24), underscoring the need for novel non-pharmacological interventions (5).
Despite these challenges, emerging evidence has supported the use of alternative approaches. A systematic review and meta-analysis found that acupuncture alleviated the symptoms in pregnant women with NVP (25). Another meta-analysis suggested that acupuncture is effective in treating the HG (26). From a neurophysiological perspective, contemporary research suggests that acupuncture may alleviate the NVP/HG by regulating the activity of the vagus nerve, highlighting the pivotal role of vagal regulation in the treatment of the NVP/HG. This assertion is supported by the results of recent neurophysiological studies. For example, acupuncture can increase parasympathetic nerve activation (27). Low-frequency electroacupuncture at acupoints in the lower limbs can decrease sympathetic nerve activity (28). Additionally, the anti-inflammatory responses to acupuncture stimulation require activation of the vagus nerve pathway (29). Owing to the unique significance of the vagus nerve in the human body, an increasing number of studies have been conducted on vagus nerve stimulation (VNS) (30). Anatomically, VNS mainly regulates the vagus nerve in the cervical or auricular region. In this review, we systematically examined the existing literature on the use of acupuncture and related techniques in the management of the NVP/HG. Based on a systematic literature review, we propose that electroacupuncture at auricular/cervical points, by leveraging VNS, can potentially offer a novel treatment avenue for the NVP/HG.
2 Pathogenesis
Although NVP and HG are common conception disorders, studies of their pathogenesis are lacking. Related literature has outlined the historical presuppositions on the nosogenesis of the NVP and HG, including hormonal factors, Helicobacter pylori (H. pylori), gastrointestinal dysmotility, placenta-related factors, psychosocial factors, and newly discovered genetic factors (5, 31, 32).
2.1 Hormonal factors
Elevated human chorionic gonadotropin (HCG) levels during the first trimester of pregnancy have been implicated in the pathogenesis of the NVP (22). Clinical evidence from 8,195 women demonstrated a significant correlation between the HCG concentration and the NVP severity (33). A meta-analysis indicated that the HG in pregnant women is associated with elevated HCG serum levels (34). High levels of HCG may result in disturbed gastrointestinal motility, delayed gastric emptying, and increased nausea and vomiting. Regarding estrogen, a positive correlation between estradiol levels and NVP intensity has been documented (35). Consistently, two independent seroepidemiological studies revealed significantly higher estradiol concentrations in HG patients compared to controls (36, 37). Notably, the peak levels of sex hormones did not temporally align with the onset of HG symptoms. Progesterone involvement was supported by a recent meta-analysis that identified associations between elevated serum progesterone concentrations and HG in two studies (38–40). However, contradictory evidence suggests that high progesterone levels—whether endogenous or exogenous—may not independently drive the HG pathogenesis (41). Elevated serum GDF15 levels were documented in HG patients at 12 gestational weeks, whereas no significant difference in HCG levels was observed between cases and controls (42). Furthermore, while circulating the GDF15 demonstrated a strong positive correlation with the HCG and was associated with second-trimester vomiting severity and antiemetic use, HCG levels showed no significant elevation in women experiencing second-trimester vomiting (43). Consequently, research must prioritize elucidating the molecular pathogenesis of the NVP and HG over traditional hormone HCG-centric paradigms.
2.2 Gastrointestinal dysfunction (abnormal gastrointestinal motility)
Abnormal upper gastrointestinal motility is assumed to be a cause of the NVP and HG (44). Numerous studies have found that women with NVP may have a slow gastric wave rhythm, which may be attributed to elevated levels of endogenous estrogen and progesterone (45–47). Furthermore, Owyang et al. found that progesterone and estrogen may make individuals susceptible to disturbances in gastric slow-wave rhythm and inevitably affect peristalsis and stomach emptying, resulting in NVP (48, 49). In addition, GDF15-mediated gastric emptying delay represents a pathophysiological mechanism contributing to nausea (5). In ex vivo rodent gastric smooth muscle, where GDF15 receptors were detected, exposure to GDF15 caused depolarization and increased mechanical activation (50).
2.3 Placenta-related factors and emerging factors identified by genetics
Several studies have revealed a close association between the HG or NVP and factors such as placental weight, hormones produced by the placenta, and genes (GDF15, IGFBP7, and PGR) expressed within the placenta (51–53). The placenta is the primary tissue that exhibits elevated levels of GDF15 under normal physiological conditions during prenatal development (54). GDF15 is primarily secreted by the placenta in response to various stressors (55, 56) and interacts with its receptor to mediate nausea-associated behaviors (57). Furthermore, the data show that elevated circulating levels of GDF15 are significantly associated with both second-trimester NVP and HG (42, 43).
Genetic susceptibility is pivotal, with an NVP heritability of 73% (58). Familial aggregation reveals extreme recurrence; sisters of HG patients have a 17-fold elevated risk, and mother-daughter recurrence exceeds 27-fold with maternal history plus two affected daughters (59, 60). Genome-wide association studies (GWAS) identified the placental gene loci GDF15 and IGFBP7 as principal genetic determinants of HG (61). GDF15 has emerged as a paramount genetic risk factor, with placental-derived GDF15 protein activating brainstem nausea pathways via its receptor GFRAL (62). Notably, GWAS signals implicate both GDF15 and its receptor GFRAL, suggesting ligand-receptor co-regulation in HG pathophysiology (61). Insulin-like growth factor binding protein 7 (IGFBP7) is involved in the implantation and decidualization of the pregnant uterus (63). Both GDF15 and IGFBP7 demonstrate synchronous post-implantation upregulation and sustained placental expression, establishing a shared molecular framework for appetite dysregulation and vomiting reflexes during pregnancy (64).
2.4 Helicobacter pylori infection
A meta-analysis revealed that H. pylori infection is associated with an increased likelihood of the HG during pregnancy (65). Helicobacter pylori infection is an independent risk factor for vomiting during pregnancy (66). Many case-control studies have shown a significant positive association between the HG and H. pylori infection in pregnancy studies (67–69). In addition, a systematic review found that the prevalence of the HG in H. pylori-infected pregnant women was higher than in uninfected ones (70). A case-control study of 444 gravidas (148 cases and 296 controls) identified Helicobacter pylori as a determinant of the HG (71). Interestingly, in a study on walnut polyphenol extract (WPE) against H. pylori infection, GDF15 was identified as one of the key genes significantly upregulated by WPE (72).
2.5 Psychosocial factors
Psychological factors are increasingly being recognized as contributors to the NVP and HG. Studies indicate that pregnant women with pre-existing psychological disorders are more susceptible to these conditions (73). Furthermore, adverse psychological states—including depression, anxiety, and stress—have been specifically associated with the HG and/or NVP (74–76). Supporting this, a prospective study by Tan et al. (77) found that 57.4% of HG women met the criteria for depression or experienced significant anxiety. Annagür et al. (78) also reported that anxiety in pregnant women was associated with the pathogenesis of HG, while Koken et al. (79) found a positive correlation between the severity of nausea and vomiting and that of anxiety and depression early in pregnancy. Notably, elevated plasma GDF15 concentrations, implicated in both nausea/vomiting pathways and depressive states (80, 81), may represent a potential biological link between these psychological factors and the development or severity of the HG/NVP.
3 Selection of acupuncture points and vagus nerve stimulation for NVP/HG treatment
With a growing focus on treating the NVP, especially the HG, and concerns about the side effects of antiemetic drugs, acupuncture, as a significant constituent of complementary and alternative medicine, has emerged because of its positive curative outcomes, cost-effectiveness, straightforward operation, and minimal adverse reactions, and it provides a wide range of choices for doctors and patients. Modern physiologists have put forward a “neural hypothesis,” proposing that acupuncture can primarily irritate sensory nerves close to the interposing needle underneath the skin, deliver signals to the cerebrum, and produce clinical influence (82). Neiguan (PC6) is located three finger widths (5 cm) above the transverse crease of the wrist and between the palmaris longus tendon and the flexor radialis carpi tendon, whereas Zusanli (ST36) is located at four finger widths (7.2–8 cm) from the lower edge of the patella and one finger width (1.8–2 cm) lateral to the anterior tibial crest (83, 84). In recent years, acupuncture has been increasingly employed to treat the NVP, especially in Asia. Acupressure at the PC6 acupoint has also been proven to be an efficacious non-medicinal intervention to alleviate NVP (85). Acupuncture at PC6 was found to be more effective in alleviating the NVP and HG than placebo acupuncture (86, 87). In both British and Canadian guidelines, PC6 acupressure and acupuncture are considered safe and effective (88, 89). In addition, two meta-analysis studies (90, 91) found that massage at PC6 had some effect on alleviating NVP. A randomized controlled trial arrived at the conclusion that electroacupuncture at PC6 and ST36 is more effective in relieving emesis than the medicinal treatment of antiemetic pharmacotherapy alone (92). However, the American College of Obstetricians and Gynecologists (ACOG) concluded that acupuncture at PC6 currently lacks sufficient medical evidence (93). Therefore, in 2023, Wu et al. (94) published the results of a multicenter, randomized, double-blind, placebo-controlled, and 2 × 2 factorial trial with 352 women in the first trimester with moderate-to-severe NVP from 13 tertiary hospitals in mainland China. This study demonstrated the efficacy of acupuncture and doxylamine-pyridoxine alone in treating moderate and severe NVP. However, doxylamine-pyridoxine was associated with a significantly higher risk of small-for-gestational-age (SGA) births than placebo [odds ratio (OR) 3.8, 95% CI 1.0–14.1]. PC6 and ST36 were chosen as core acupuncture points. This latest clinical study, corroborating the strongest evidence-based medical support for acupuncture in treating NVP, concurs with Mazzone et al.'s (95) viewpoint that acupuncture may alleviate NVP through vagal modulation via local acupoint stimulation. The therapeutic effect of electroacupuncture (EA) at PC6 is achieved through the vagus nerve (VN) (96). EA at ST36 can increase the VN's efferent activity (97). In addition, non-invasive TEA at ST36 is effective in enhancing vagal and suppressing sympathetic activities (98).
Anatomically, the median nerve is located below the PC6 acupoint, which originates from the lateral and medial sides of the brachial plexus and has ventral roots of C5–C7 (lateral) and C7–T1 (medial). Jamigorn et al. (99) found that relieving nausea and vomiting by applying pressure at PC6 irritates the median nerve. Neuroanatomically, the ST36 is primarily located close to the sciatic nerve and its branches. The sciatic nerve is composed of lumbar 4/5 and sacral 1/2/3 nerves. Intriguingly, Zhang et al. (100) found that EA at ST36 can exert protective effects via the sciatic nerve and cervical NV. Specifically, acupuncture points on the abdomen can stimulate the sympathetic nervous system of the corresponding segment to inhibit stomach movement, whereas those on the limbs can stimulate the vagus nerve to promote gastric movement (101, 102). When the former is stimulated, sympathetic nerves are activated to restrain gastric motility (103). EA at PC6 in the upper limb can remarkably affect C-Fos immunoreactivity in the dorsal motor nucleus of the vagus (DMV) and nucleus tractus solitarius (NTS) (104). Furthermore, EA at PC6, primarily by inhibiting the transmission of gamma-aminobutyric acid (GABA) to the DMV, can alleviate the inhibition of efferent vagal motor fibers and thus promote efferent VN activity and gastric motility (105). The DMV and NTS exhibit commonality in their involvement with ST36 (106). EA at ST36 has been shown to increase c-Fos expression in DMV neurons and promote gastric myoelectric activity, which is regulated by VN (107). ST36′s effects are contingent on the VN, and EA at ST36 has been shown to enhance gastric myoelectric activity in rats (108). EA at ST36 can activate different adrenergic receptors through the spinal afferent-brainstem-vagus efferent-neuropeptide Y (NPY) + adrenal chromaffin cell-norepinephrine (NE) pathway to inhibit inflammation (109). The studies reported in the literature we cited above corroborate that the international academic community in this area has recognized the efficacy of acupuncture in NVP/HG treatment, which is supported by strong evidence-based medical data. Taken together, these studies suggest that the vagus nerve is significantly involved in EA at PC6 and ST36, and that its regulation may explain the mechanism by which acupuncture treats NVP or HG.
4 Vagus nerve stimulation
The VNS has garnered increased attention from researchers and practitioners in the medical community as a potential therapeutic intervention for various diseases. The early VNS device required surgical implantation of an electrode around the left vagus nerve, making it an invasive procedure (110). In recent years, non-invasive vagus nerve stimulation devices (nVNS), such as GammaCore and NEMOS, have emerged as significant areas of interest and are increasingly used for treating patients because of their relative safety and tolerance (111). GammaCore is a handheld and independent nVNS device authorized by the FDA. By directly touching the cervical skin surfaces, it delivers electrical signals to the vagus (112). NEMOS is an external device that provides transcutaneous VNS (ta-VNS) using a dedicated intra-auricular electrode (like an earphone) that stimulates the auricular branch of the VN (113). The pathogenesis of HG involves multiple systemic interactions, with the vagus nerve serving as the core pathway connecting the central nervous system, gastrointestinal tract, and placenta. In addition, vagus nerve stimulation mediates GDF15 signaling, gastrointestinal motility disorders, and anti-inflammatory and psychological stress responses in NVP/HG treatment.
4.1 Vagus nerve regulation of gastrointestinal motility in NVP/HG
The VN can mediate information transmission between the central nervous system (CNS) and the stomach. Tong et al. (114) found that the VN was most densely distributed in the stomach. After receiving VN signals, the NTS serves as the primary lower center for visceral primary sensory processing, except for the pelvic organs. Sensations such as the gastric stretch reaction and fullness can be transmitted to the NTS through the VN (115). Additionally, the dominant gastric vagal efferent fibers, which carry parasympathetic motor signals to the gastrointestinal (GI) tract, originate in the dorsal motor nucleus of the vagus (DMV), reinforcing VN's critical role in GI regulation (116). DMV and NTS together constitute the dorsal vagal complex (DVC), integrating visceral sensory afferent signals and gut parasympathetic preganglionic efferent signals (117). Taken together, these factors play a pivotal role in the regulation of gastrointestinal functional activities. The dense innervation of the VN in the gastrointestinal system is widely acknowledged for its regulatory role in gastric emptying, peristalsis, and gastric acid secretion, as well as in the excitation and inhibition of intestinal function (118, 119). A preliminary rodent study confirmed that 25 Hz VNS using optimal parameters was effective in improving gastric dyskinesia and promoting gastric emptying via the vagal-cholinergic pathway, suggesting that VNS may have therapeutic potential for functional gastrointestinal disorders (119). High-intensity EA in the deep tissue of ST36 in mice significantly promotes gastric motility, and the effect is entirely dependent on the vagal pathway (120). In depressive-like mice, electroconvulsive therapy enhances distal colonic motility via the subdiaphragmatic vagus nerve, which is abolished by vagotomy (121). Additionally, motilin-stimulated feeding is linked to gastric motility through the vagus nerve and increased c-Fos expression in tyrosine hydroxylase (TH) neurons in the AP and NST of the brain stem, as well as in activated neuropeptide Y and TH neurons in the arcuate nucleus of the hypothalamus (122). Electrical cervical vagus nerve stimulation (cVNS) affects gastric motility via slow gastric waves (123). EA provides a novel molecular mechanism for improving gastrointestinal motility in diabetic gastroparesis (DGP) via peripheral stimulation (ST36), spinal afferent (L4–L6), brainstem integration (NTS), and vagal efferent (gastric) circuits (124). Collectively, these findings demonstrated that VNS alleviates HG/NVP by normalizing gastrointestinal motility.
4.2 Vagus nerve alleviates NVP/HG by regulating the markers (GDF15) of genes and placenta
Evidence suggesting that GDF15 is a primary cause of hyperemesis gravidarum indicates that therapies targeting this pathway could be effective in treating this condition. Area postrema (AP) is anatomically linked to and interacts with the NTS (125). There has been an increasing amount of evidence suggesting that AP is a target site for the signaling marker GDF15 (126–129). The DMV, which, in turn, cooperates with the AP and NTS, forms the DVC (130, 131). According to Tsai et al. (13), the effect of GDF15 depends on the action of AP/NTS, and the absence of AP/NTS reduces the effectiveness of GDF15 treatment. GDF15 is also a nonspecific blood biomarker of HG, which crosses the blood-brain barrier to bind to the glial cell-derived neurotrophic factor family receptor α-like (GFRAL) receptor in the area postrema (AP) and nucleus of the solitary tract (NTS) of the brainstem to influence food intake, nausea, body weight, and insulin sensitivity (13, 14). Critically, activated AP/NTS neurons project to the hypothalamic arcuate nucleus (ARC), where vagal efferent signaling reduces gastric motility (17). TaVNS promotes the release of acetylcholine (ACh) to improve placental function (132). Maternal VNS treatment is safe during pregnancy and ameliorates L-NAME-induced preeclampsia-like symptoms in rats through inhibition of the inflammatory response (133, 134). The above literature suggests that the vagus nerve targets the AP/NTS of the DVC to modulate the GDF15 signaling, which may alleviate NVP/HG.
4.3 Vagus nerve regulation of H. pylori-related inflammation in NVP/HG
Treating and eradicating H. pylori can alleviate nausea and vomiting during pregnancy (135). H. pylori infection may contribute to an imbalance in the human gastrointestinal flora. “The gut-brain axis” is composed of multiple components, including the VN, immune system, and bacterial metabolites and products (136). Substantial evidence has demonstrated that VNS can ameliorate pro-inflammatory effects induced by gut dysbiosis and modulate immune functions (137). VN inhibits the production of pro-inflammatory cytokines that constitute the cholinergic anti-inflammatory pathway (138). A systematic review and meta-analysis of various VNS methods, including transcutaneous auricular VNS (taVNS), transcutaneous cervical VNS (tcVNS), invasive cervical VNS (iVNS), and electroacupuncture VNS (eaVNS), indicated the ability of VNS to modulate inflammatory markers such as C-reactive protein (CRP), interleukin (IL)-10, and interferon (IFN)-γ (139). The VN, therefore, exerts potent anti-inflammatory effects (118). Inhibition of enhanced efferent vagus nerve activity can counteract oxidative stress/inflammation/apoptosis/autophagy signaling involving H. pylori (140). In fact, vagus nerve stimulation has been shown to alleviate symptoms of inflammatory bowel disease (IBD) via the inflammatory reflex to reduce cytokines and colonic inflammation (141). Additionally, vagus nerve stimulation (VNS) has been demonstrated to reduce the inflammation induced by endotoxemia and decrease gut permeability (142, 143). Beyond local gut functions, microbiota influence stress responses and neurological health via inflammasome-derived cytokines, linking gut-derived signals to systemic diseases through the vagus nerve and the HPA axis (144). We, therefore, propose that the vagus nerve may represent a potential therapeutic agent for HG/NVP by regulating the intestinal flora and immune function, thereby exerting anti-inflammatory effects against H. pylori.
4.4 Vagus nerve regulation of psychosocial factors in NVP/HG
Studies on both rodents and humans have demonstrated that VNS can mitigate mental disorders such as anxiety and depression (145–149). Electrical stimulation of the cervical VN is an FDA-approved therapy for depression (150). Recent studies have confirmed that symptoms of depression can increase the risk of dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis (151). Notably, VNS can attenuate dysfunction in the HPA axis (152, 153). Subdiaphragmatic vagotomy reversed behavioral changes suggestive of depression and anxiety in rats with functional dyspepsia (FD) (154). VN signaling can modulate depressive-like behaviors by communicating both the pro- and antidepressant effects of gut molecules to the brain, while loss of gut-originating vagal signaling also has anxiolytic effects (155). Clinical trials conducted in individuals suffering from major depressive disorder (MDD) have revealed that transcutaneous VNS (tVNS) is effective in reducing depressive symptoms (156, 157). The tVNS reduces reactivity to emotionally charged stimuli in MDD (158). The gain of vagal function with stimulation of the left vagus nerve at the cervical level in male rats reduces anxiety-like behaviors in the exploration of open areas in the elevated plus maze (EPM) (148). Given the contraindications for psychotropic drugs during pregnancy, we propose VNS as a safe neuromodulatory intervention for HG/NVP that normalizes stress responses.
5 VNS-targeted electroacupure at auricular/cervical points: a novel therapeutic model for NVP/HG
In fact, both acupuncture and VNS are auxiliary alternative physical therapies that act on the human body, with mechanisms that can serve as references for treatment approaches. EA, which combines acupuncture with electrophysiological techniques, is commonly used in clinical practice and in basic research. It is not only widely used in TCM to treat diseases but has also been recommended by the World Health Organization (WHO) and the National Institutes of Health (NIH) as surface stimulation therapy (159, 160). The biological mechanism often involves regulation of the autonomic nervous system (ANS). ANS can interconnect external somatosensory inputs with internal organ responses via the central nervous system (CNS) (161). According to the principle of anatomical acupoint selection, the VN in the auricular and cervical regions is also the preferred site for VNS. Whether stimulating the VN or inhibiting the sympathetic nerve, EA at acupuncture points in the auricular and cervical regions can regulate the VN more notably than traditional acupuncture (162, 163), especially when the latter stimulates PC6 in the upper limb and ST36 in the lower limb. Despite this mechanistic synergy, few studies have addressed vagus nerve-targeted acupoint selection in NVP/HG. This lack of literature underscores the gap and pioneering nature of employing the vagus nerve as a preferred acupuncture point for addressing these conditions. For pregnant patients, therapeutic safety is paramount. Our clinical experience demonstrates that electroacupuncture at cervical/auricular acupoints safely and effectively treats sudden sensorineural hearing loss in the first trimester of pregnancy (164). VNS serves as a viable therapeutic alternative or adjunct for managing gestational headaches (165). In emergency department management of supraventricular tachycardia (SVT) with stable hemodynamics during pregnancy, VNS should be considered (166). VNS is a promising, feasible, and effective intervention for antenatal depression (167). Although the vagus nerve interfaces with reproductive pathways, current evidence suggests that VNS remains relatively safe and effective for both the mother and fetus during pregnancy (168). To conclude, we propose that EA at auricular/cervical acupoints may effectively regulate vagal signaling, thus providing enhanced therapeutic efficacy against NVP/HG.
6 Conclusion and future directions
HG represents a severe pathological form of NVP for which no definitive or permanent cure currently exists. Bottom of FormGiven this, physicians focus on providing treatments that alleviate symptoms and offer supportive care. As the disease burden of severe NVP and HG is largely beyond the estimation, developing novel therapeutics for gravidas with NVP or HG is of vital importance. The current review provides the strongest evidence-based data and literature that confirms the effectiveness of EA in treating NVP/HG by selecting PC6 and ST36 as core acupuncture points that are closely linked to the vagus nerve. Neurophysiologically, this review, based on an extensive literature search and review of current studies, proposes that acupuncture can significantly alleviate NVP/HG through modulation of the vagus nerve by stimulating local acupuncture points. Despite extensive research on the VNS, few investigations have been conducted on its use for the treatment of NVP/HG. Studies have confirmed that the VNS can regulate the pathogenesis of NVP/HG, as revealed in our review. Therefore, we propose a VNS-based model, which acts on multiple possible pathways for alleviating NVP/HG by (1) attenuating disruptions in gastrointestinal tract movement and function, (2) managing markers (e.g., GDF15/MIC-1) of genes and placental function, (3) regulating Helicobacter pylori, and (4) managing psychosocial factors such as anxiety and depression. However, there exists scant literature that considers the location of the vagus nerve as a site for acupuncture points for treating the NVP/HG. Compared to PC6 and ST36, anatomically speaking, since the VNS regulates primarily the vagus nerve in the cervical and/or auricular regions, we propose that electroacupuncture in the cervical and auricular regions can more effectively regulate the vagus nerve and alleviate the NVP/HG (Figures 1, 2). Therefore, electroacupuncture at the cervical and auricular points to regulate the vagus nerve may be a novel therapeutic approach with great potential for treating NVP/HG.
Figure 1. EA at classic acupoints for NVP/HG management.
Figure 2. VNS/EA at novel anatomical sites for NVP/HG management.
Author contributions
SZ: Writing – original draft, Conceptualization. HH: Writing – original draft, Conceptualization. XL: Conceptualization, Software, Data curation, Writing – original draft. YG: Writing – review & editing, Conceptualization, Funding acquisition.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This study was supported by National key R&D Program of China (2024YFC3507302), the Key Project of National Natural Science Foundation of China (Grant no. 82030125), Manned Space Engineering Space Medical Experiment Project of China (Grant no. HYZHXMX02002), and 2024 Tianjin University of Traditional Chinese Medicine Graduate Research Innovation Project (202430133034).
Acknowledgments
We thank Professor Yue Jiang of Xi'an Jiaotong University, Xi'an, China, for his meticulous revision and editing of the manuscript. We thank BioRender (https://www.Biorender.com/) for providing schematic elements used in Figure 1. We thank Yiming Liu for providing the schematic elements shown in Figure 2.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1. Ryva BA, Wylie BJ, Aung MT, Schantz SL, Strakovsky RS. Endocrine-disrupting chemicals and persistent nausea among pregnant women enrolled in the Illinois Kids Development Study (I-KIDS). Environ Health Perspect. (2025) 133:57008. doi: 10.1289/EHP15547
2. Golembiewski J, Chernin E, Chopra T. Prevention and treatment of postoperative nausea and vomiting. Am J Health Syst Pharm. (2005) 62:1247–60. doi: 10.1093/ajhp/62.12.1247
3. Jansen LAW, Koot MH, Van't Hooft J, Dean CR, Bossuyt PMM, Ganzevoort W, et al. The windsor definition for hyperemesis gravidarum: a multistakeholder international consensus definition. Eur J Obstet Gynecol Reprod Biol. (2021) 266:15–22. doi: 10.1016/j.ejogrb.2021.09.004
4. Jarvis S, Nelson-Piercy C. Management of nausea and vomiting in pregnancy. BMJ. (2011) 342:d3606. doi: 10.1136/bmj.d3606
5. Fejzo MS, Trovik J, Grooten IJ, Sridharan K, Roseboom TJ, Vikanes Å, et al. Nausea and vomiting of pregnancy and hyperemesis gravidarum. Nat Rev Dis Primers. (2019) 5:62. doi: 10.1038/s41572-019-0110-3
6. Vinnars MT, Forslund M, Claesson IM, Hedman A, Peira N, Olofsson H, et al. Treatments for hyperemesis gravidarum: a systematic review. Acta Obstet Gynecol Scand. (2024) 103:13–29. doi: 10.1111/aogs.14706
7. Geeganage G, Iturrino J, Shainker SA, Ballou S, Rangan V, Nee J. Emergency department burden of hyperemesis gravidarum in the United States from 2006 to 2014. AJOG Glob Rep. (2023) 3:100166. doi: 10.1016/j.xagr.2023.100166
8. Aye ILMH, Tong S, Charnock-Jones DS, Smith GCS. The human placenta and its role in reproductive outcomes revisited. Physiol Rev. (2025) 105:2305–76. doi: 10.1152/physrev.00039.2024
9. Nijsten K, Jansen LAW, Limpens J, Finken MJJ, Koot MH, Grooten IJ, et al. Long-term health outcomes of children born to mothers with hyperemesis gravidarum: a systematic review and meta-analysis. Am J Obstet Gynecol. (2022) 227:414–29.e17. doi: 10.1016/j.ajog.2022.03.052
10. Jansen LAW, Nijsten K, Limpens J, van Eekelen R, Koot MH, Grooten IJ, et al. Perinatal outcomes of infants born to mothers with hyperemesis gravidarum: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. (2023) 284:30–51. doi: 10.1016/j.ejogrb.2023.03.004
11. Thygerson J, Oyler D, Thomas J, Muse B, Brooks BD, Pullan JE. GDF15 targeting for treatment of hyperemesis gravidarum. Medicines. (2024) 11:17. doi: 10.3390/medicines11070017
12. Hüllwegen M, Kleinert M, von Haehling S, Fischer A, et al. GDF15: from biomarker to target in cancer cachexia. Trends Cancer. (2025) 9:S2405-8033(25)00150-5. doi: 10.1016/j.trecan.2025.06.007
13. Tsai VW, Manandhar R, Jørgensen SB, Lee-Ng KK, Zhang HP, Marquis CP, et al. The anorectic actions of the TGFβ cytokine MIC-1/GDF15 require an intact brainstem area postrema and nucleus of the solitary tract. PloS ONE. (2014) 9:e100370. doi: 10.1371/journal.pone.0100370
14. Sharma N, MacGibbon KW, Brecht-Doscher A, Cortessis, Fejzo M. Pre-pregnancy metformin use associated with lower risk of severe nausea and vomiting of pregnancy and hyperemesis gravidarum. Am J Obstet Gynecol. (2025) S0002-9378(25)00441-7. doi: 10.1016/j.ajog.2025.06.055
15. Sillis L, Heinonen EW, Ceulemans M, Johnson D, Luo Y, Chambers CD. Metformin for the prevention of hyperemesis gravidarum: an observational cohort study. BJOG. (2025). doi: 10.1111/1471-0528.18238
16. Tsai VWW, Husaini Y, Sainsbury A, Brown DA, Breit SN, et al. The MIC-1/GDF15-GFRAL pathway in energy homeostasis: implications for obesity, cachexia, and other associated diseases. Cell Metab. (2018) 28:353–68. doi: 10.1016/j.cmet.2018.07.018
17. Li J, Hu X, Xie Z, Li J, Huang C, Huang Y. Overview of growth differentiation factor 15 (GDF15) in metabolic diseases. Biomed Pharmacother. (2024) 176:116809. doi: 10.1016/j.biopha.2024.116809
18. Goodwin TM. Hyperemesis gravidarum. Obstet Gynecol Clin North Am. (2008) 35:401–17, viii. doi: 10.1016/j.ogc.2008.04.002
19. Huybrechts KF, Hernández-Díaz S, Bateman BT. Contextualizing potential risks of medications in pregnancy for the newborn-the case of ondansetron. JAMA Pediatr. (2020) 174:747–8. doi: 10.1001/jamapediatrics.2020.1325
20. Tamay AG, Kuşçu NK. Hyperemesis gravidarum: current aspect. J Obstet Gynaecol. (2011) 31:708–12. doi: 10.3109/01443615.2011.611918
21. Huybrechts KF, Hernández-Díaz S, Straub L, Gray KJ, Zhu Y, Patorno E, et al. Association of maternal first-trimester ondansetron use with cardiac malformations and oral clefts in offspring. JAMA. (2018) 320:2429–37. doi: 10.1001/jama.2018.18307
22. Liu C, Zhao G, Qiao D, Wang L, He Y, Zhao M, et al. Emerging progress in nausea and vomiting of pregnancy and hyperemesis gravidarum: challenges and opportunities. Front Med. (2022) 8:809270. doi: 10.3389/fmed.2021.809270
23. Dormuth CR, Winquist B, Fisher A, Wu F, Reynier P, Suissa S, et al. Comparison of pregnancy outcomes of patients treated with ondansetron vs alternative antiemetic medications in a multinational, population-based cohort. JAMA Netw Open. (2021) 4:e215329. doi: 10.1001/jamanetworkopen.2021.5329
24. Boelig RC, Barton SJ, Saccone G, Kelly AJ, Edwards SJ, Berghella V. Interventions for treating hyperemesis gravidarum. Cochrane Database Syst Rev. (2016) 2016:CD010607. doi: 10.1002/14651858.CD010607.pub2
25. Hu Y, Yang Q, Hu X. The efficacy and safety of acupuncture and moxibustion for the management of nausea and vomiting in pregnant women: a systematic review and meta-analysis. Heliyon. (2024) 10:e24439. doi: 10.1016/j.heliyon.2024.e24439
26. Sridharan K, Sivaramakrishnan G. Interventions for treating hyperemesis gravidarum: a network meta-analysis of randomized clinical trials. J Matern Fetal Neonatal Med. (2020) 33:1405–11. doi: 10.1080/14767058.2018.1519540
27. Park M, Kim S. A modern clinical approach of the traditional Korean Saam acupuncture. Evid Based Complement Alternat Med. (2015) 2015:703439. doi: 10.1155/2015/703439
28. Raja-Khan N, Stener-Victorin E, Wu X, Legro RS. The physiological basis of complementary and alternative medicines for polycystic ovary syndrome. Am J Physiol Endocrinol Metab. (2011) 301:E1–E10. doi: 10.1152/ajpendo.00667.2010
29. Lim HD, Kim KJ, Jo BG, Park JY, Namgung U. Acupuncture stimulation attenuates TNF-α production via vagal modulation in the concanavalin A model of hepatitis. Acupunct Med. (2020) 38:417–25. doi: 10.1177/0964528420907338
30. Mertens A, Raedt R, Gadeyne S, Carrette E, Boon P, Vonck K. Recent advances in devices for vagus nerve stimulation. Expert Rev Med Devices. (2018) 15:527–39. doi: 10.1080/17434440.2018.1507732
31. Lu H, Zheng C, Zhong Y, Cheng L, Zhou Y. Effectiveness of acupuncture in the treatment of hyperemesis gravidarum: a systematic review and meta-analysis. Evid Based Complement Alternat Med. (2021) 2021:2731446. doi: 10.1155/2021/2731446
32. Clark SM, Costantine MM, Hankins GD. Review of NVP and HG and early pharmacotherapeutic intervention. Obstet Gynecol Int. (2012) 2012:252676. doi: 10.1155/2012/252676
33. Korevaar TI, Steegers EA, de Rijke YB, Schalekamp-Timmermans S, Visser WE, Hofman A, et al. Reference ranges and determinants of total hCG levels during pregnancy: the generation R study. Eur J Epidemiol. (2015) 30:1057–66. doi: 10.1007/s10654-015-0039-0
34. Farshbaf-Khalili A, Salehi-Pourmehr H, Najafipour F, Alamdari NM, Pourzeinali S, Ainehchi N. Is hyperemesis gravidarum associated with transient hyperthyroidism? A systematic review and meta-analysis. Taiwan J Obstet Gynecol. (2023) 62:205–25. doi: 10.1016/j.tjog.2022.11.008
35. Lagiou P, Tamimi R, Mucci LA, Trichopoulos D, Adami HO, Hsieh CC. Nausea and vomiting in pregnancy in relation to prolactin, estrogens, and progesterone: a prospective study. Obstet Gynecol. (2003) 101:639–44. doi: 10.1097/00006250-200304000-00006
36. Depue RH, Bernstein L, Ross RK, Judd HL, Henderson BE. Hyperemesis gravidarum in relation to estradiol levels, pregnancy outcome, and other maternal factors: a seroepidemiologic study. Am J Obstet Gynecol. (1987) 156:1137–41. doi: 10.1016/0002-9378(87)90126-8
37. Oruç AS, Mert I, Akturk M, Aslan E, Polat B, Buyukkagnici U, et al. Ghrelin and motilin levels in hyperemesis gravidarum. Arch Gynecol Obstet. (2013) 287:1087–92. doi: 10.1007/s00404-012-2705-8
38. Niemeijer MN, Grooten IJ, Vos N, Bais JM, van der Post JA, Mol BW, et al. Diagnostic markers for hyperemesis gravidarum: a systematic review and metaanalysis. Am J Obstet Gynecol. (2014) 211:150.e1–15. doi: 10.1016/j.ajog.2014.02.012
39. Taşkin S, Taşkin EA, Seval MM, Atabekoglu CS, Berker B, Söylemez F. Serum levels of adenosine deaminase and pregnancy-related hormones in hyperemesis gravidarum. J Perinat Med. (2009) 37:32–5. doi: 10.1515/JPM.2009.013
40. Yoneyama Y, Kobayashi H, Kato M, Chihara H, Yamada T, Otsubo Y, et al. Plasma 5'-nucleotidase activities increase in women with hyperemesis gravidarum. Clin Biochem. (2002) 35:561–4. doi: 10.1016/S0009-9120(02)00384-3
41. Verberg MF, Gillott DJ, Al-Fardan N, Grudzinskas JG. Hyperemesis gravidarum, a literature review. Hum Reprod Update. (2005) 11:527–39. Erratum in: Hum Reprod Update. (2007) 13:207. doi: 10.1093/humupd/dmi021
42. Fejzo MS, Fasching PA, Schneider MO, Schwitulla J, Beckmann MW, Schwenke E, et al. Analysis of GDF15 and IGFBP7 in hyperemesis gravidarum support causality. Geburtshilfe Frauenheilkd. (2019) 79:382–8. doi: 10.1055/a-0830-1346
43. Petry CJ, Ong KK, Burling KA, Barker P, Goodburn SF, Perry JRB, et al. Associations of vomiting and antiemetic use in pregnancy with levels of circulating GDF15 early in the second trimester: a nested case-control study.” Wellcome Open Res. (2018) 3:123. doi: 10.12688/wellcomeopenres.14818.1
44. Vaisman N, Kaidar R, Levin I, Lessing JB. Nasojejunal feeding in hyperemesis gravidarum–a preliminary study. Clin Nutr. (2004) 23:53–7. doi: 10.1016/S0261-5614(03)00088-8
45. Walsh JW, Hasler WL, Nugent CE, Owyang C. Progesterone and estrogen are potential mediators of gastric slow-wave dysrhythmias in nausea of pregnancy. Am J Physiol. (1996) 270:G506–14. doi: 10.1152/ajpgi.1996.270.3.G506
46. Koch KL, Stern RM, Vasey M, Botti JJ, Creasy GW, Dwyer A. Gastric dysrhythmias and nausea of pregnancy. Dig Dis Sci. (1990) 35:961–8. doi: 10.1007/BF01537244
47. Riezzo G, Pezzolla F, Darconza G, Giorgio I. Gastric myoelectrical activity in the first trimester of pregnancy: a cutaneous electrogastrographic study. Am J Gastroenterol. (1992) 87:702–7.
48. Owyang C, Hasler WL. Physiology and pathophysiology of the interstitial cells of Cajal: from bench to bedside. VI Pathogenesis and therapeutic approaches to human gastric dysrhythmias. Am J Physiol Gastrointest Liver Physiol. (2002) 283:G8–15. doi: 10.1152/ajpgi.00095.2002
49. Li FY, Jiang LS, Cheng JQ, Mao H, Li N, Cheng NS. Clinical application prospects of gastric pacing for treating postoperative gastric motility disorders. J Gastroenterol Hepatol. (2007) 22:2055–9. doi: 10.1111/j.1440-1746.2007.05018.x
50. Garella R, Palmieri F, Tarchi L, Tani A, Chellini F, Guarnieri G, et al. Growth differentiation factor 15 induces gastric fundus contraction involving cholinergic excitation: morphofunctional evidence in rodent models. J Cell Mol Med. (2025) 29:e70629. doi: 10.1111/jcmm.70629
51. Gadsby R, Barnie-Adshead AM, Jagger C. Pregnancy nausea related to women's obstetric and personal histories. Gynecol Obstet Invest. (1997) 43:108–11. doi: 10.1159/000291833
52. Vandraas KF, Vikanes ÅV, Støer NC, Vangen S, Magnus P, Grjibovski AM. Is hyperemesis gravidarum associated with placental weight and the placental weight-to-birth weight ratio? A population-based Norwegian cohort study. Placenta. (2013) 34:990–4. doi: 10.1016/j.placenta.2013.08.001
53. Lowry P, Woods R. The placenta controls the physiology of pregnancy by increasing the half-life in blood and receptor activity of its secreted peptide hormones. J Mol Endocrinol. (2018) 60:R23–30. doi: 10.1530/JME-17-0275
54. Siddiqui JA, Pothuraju R, Khan P, Sharma G, Muniyan S, Seshacharyulu P, et al. Pathophysiological role of growth differentiation factor 15 (GDF15) in obesity, cancer, and cachexia. Cytokine Growth Factor Rev. (2022) 64:71–83. doi: 10.1016/j.cytogfr.2021.11.002
55. Lockhart SM, Saudek V, O'Rahilly S. GDF15: a hormone conveying somatic distress to the brain. Endocr Rev. (20200 41:bnaa007. doi: 10.1210/endrev/bnaa007
56. Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science. (2015) 347:1260419. doi: 10.1126/science.1260419
57. Zhang C, Kaye JA, Cai Z, Wang Y, Prescott SL, Liberles SD. Area postrema cell types that mediate nausea-associated behaviors. Neuron. (2021) 109:461–72.e5. doi: 10.1016/j.neuron.2020.11.010
58. Colodro-Conde L, Jern P, Johansson A, Sánchez-Romera JF, Lind PA, Painter JN, et al. Nausea and vomiting during pregnancy is highly heritable. Behav Genet. (2016) 46:481–91. doi: 10.1007/s10519-016-9781-7
59. Zhang Y, Cantor RM, MacGibbon K, Romero R, Goodwin TM, Mullin PM, et al. Familial aggregation of hyperemesis gravidarum. Am J Obstet Gynecol. (2011) 204:230.e1–7. doi: 10.1016/j.ajog.2010.09.018
60. Vikanes A, Skjaerven R, Grjibovski AM, Gunnes N, Vangen S, Magnus P. Recurrence of hyperemesis gravidarum across generations: population based cohort study. BMJ. (2010) 340:c2050. doi: 10.1136/bmj.c2050
61. Fejzo MS, Sazonova OV, Sathirapongsasuti JF, Hallgrímsdóttir IB, Vacic V, MacGibbon KW, et al. Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum. Nat Commun. (2018) 9:1178. doi: 10.1038/s41467-018-03258-0
62. Fejzo MS, MacGibbon KW, First O, Quan C, Mullin PM. Whole-exome sequencing uncovers new variants in GDF15 associated with hyperemesis gravidarum. BJOG. (2022) 129:1845–52. doi: 10.1111/1471-0528.17129
63. Loncar G, Omersa D, Cvetinovic N, Arandjelovic A, Lainscak M. Emerging biomarkers in heart failure and cardiac cachexia. Int J Mol Sci. (2014) 15:23878–96. doi: 10.3390/ijms151223878
64. Liu Z-K, Wang R-C, Han B-C, Yang Y, Peng J-P. A novel role of IGFBP7 in mouse uterus: regulating uterine receptivity through Th1/Th2 lymphocyte balance and decidualization. PLoS ONE. (2012) 7:e45224. doi: 10.1371/journal.pone.0045224
65. Ng QX, Venkatanarayanan N, De Deyn MLZQ, Ho CYX, Mo Y, Yeo WS. A meta-analysis of the association between Helicobacter pylori (H. pylori) infection and hyperemesis gravidarum. Helicobacter. (2018) 23:1. doi: 10.1111/hel.12455
66. Grooten IJ, Den Hollander WJ, Roseboom TJ, Kuipers EJ, Jaddoe VW, Gaillard R, et al. Helicobacter pylori infection: a predictor of vomiting severity in pregnancy and adverse birth outcome. Am J Obstet Gynecol. (2017) 216:512.e1–e9. doi: 10.1016/j.ajog.2017.01.042
67. Guven MA, Ertas IE, Coskun A, Ciragil P. Serologic and stool antigen assay of Helicobacter pylori infection in hyperemesis gravidarum: which test is useful during early pregnancy? Taiwan J Obstet Gynecol. (2011) 50:37–41. doi: 10.1016/j.tjog.2009.11.003
68. Feng Y, Huang Q, Luo M, Wei J, Gao T, Chu D, et al. The association between Helicobacter pylori and gastrointestinal disorders during pregnancy: a multicenter retrospective study. Helicobacter. (2024) 29:e13032. doi: 10.1111/hel.13032
69. Wang SJ, Hsieh CJ, Su YH, Lin LL, Chen WC, Chen HH, et al. Assessment of adverse pregnancy outcomes associated with Helicobacter pylori infection. Sci Rep. (2024) 14:32023. doi: 10.1038/s41598-024-83694-9
70. Golberg D, Szilagyi A, Graves L. Hyperemesis gravidarum and Helicobacter pylori infection: a systematic review. Obstet Gynecol. (2007) 110:695–703. doi: 10.1097/01.AOG.0000278571.93861.26
71. Asrade L, Misikir D, Alemu H, Belachew A, Almaw H. Determinants of hyperemesis gravidarum among pregnant women attending antenatal care at public and private hospitals in Bahir Dar City, North-West Ethiopia, 2022: a multicenter unmatched case control study. BMC Womens Health. (2023) 23:225. doi: 10.1186/s12905-023-02386-0
72. Park JM, Han YM, Lee HJ, Hwang SJ, Kim SJ, Hahm KB. Transcriptome profiling analysis of the response to walnut polyphenol extract in Helicobacter pylori-infected cells. J Clin Biochem Nutr. (2021) 68:201–14. doi: 10.3164/jcbn.20-128
73. Mitchell-Jones N, Lawson K, Bobdiwala S, Farren JA, Tobias A, Bourne T, et al. Association between hyperemesis gravidarum and psychological symptoms, psychosocial outcomes and infant bonding: a two-point prospective case-control multicentre survey study in an inner city setting. BMJ Open. (2020) 10:e039715. doi: 10.1136/bmjopen-2020-039715
74. Uguz F, Gezginc K, Kayhan F, Cicek E, Kantarci AH. Is hyperemesis gravidarum associated with mood, anxiety and personality disorders: a case-control study. Gen Hosp Psychiatry. (2012) 34:398–402. doi: 10.1016/j.genhosppsych.2012.03.021
75. Hizli D, Kamalak Z, Kosus A, Kosus N, Akkurt G. Hyperemesis gravidarum and depression in pregnancy: is there an association? J Psychosom Obstet Gynaecol. (2012) 33:171–5. Erratum in: J Psychosom Obstet Gynaecol. (2022) 43:384. doi: 10.3109/0167482X.2012.717129
76. Kuo SH, Wang RH, Tseng HC, Jian SY, Chou FH. A comparison of different severities of nausea and vomiting during pregnancy relative to stress, social support, and maternal adaptation. J Midwifery Womens Health. (2007) 52:e1–7. doi: 10.1016/j.jmwh.2006.10.002
77. Tan PC, Vani S, Lim BK, Omar SZ. Anxiety and depression in hyperemesis gravidarum: prevalence, risk factors and correlation with clinical severity. Eur J Obstet Gynecol Reprod Biol. (2010) 149:153–8. doi: 10.1016/j.ejogrb.2009.12.031
78. Annagür BB, Kerimoglu ÖS, Gündüz S, Tazegül A. Are there any differences in psychiatric symptoms and eating attitudes between pregnant women with hyperemesis gravidarum and healthy pregnant women? J Obstet Gynaecol Res. (2014) 40:1009–14. doi: 10.1111/jog.12274
79. Köken G, Yilmazer M, Cosar E, Sahin FK, Cevrioglu S, Gecici O. Nausea and vomiting in early pregnancy: relationship with anxiety and depression. J Psychosom Obstet Gynaecol. (2008) 29:91–5. doi: 10.1080/01674820701733697
80. Kochlik B, Herpich C, Moreno-Villanueva M, Klaus S, Müller-Werdan U, Weinberger B, et al. Associations of circulating GDF15 with combined cognitive frailty and depression in older adults of the MARK-AGE study. GeroScience. (2024) 46:1657–69. doi: 10.1007/s11357-023-00902-6
81. Frye MA, Nassan M, Jenkins GD, Kung S, Veldic M, Palmer BA, et al. Feasibility of investigating differential proteomic expression in depression: implications for biomarker development in mood disorders. Transl Psychiatry. (2015) 5:e689. doi: 10.1038/tp.2015.185
82. Qin Z, Xiang K, Su DF, Sun Y, Liu X. Activation of the cholinergic anti-inflammatory pathway as a novel therapeutic strategy for COVID-19. Front Immunol. (2021) 11:595342. doi: 10.3389/fimmu.2020.595342
83. Habek D, Barbir A, Habek JC, Janculiak D, Bobić-Vuković M. Success of acupuncture and acupressure of the Pc 6 acupoint in the treatment of hyperemesis gravidarum. Forsch Komplementarmed Klass Naturheilkd. (2004) 11:20–3. doi: 10.1159/000077192
84. Can Gürkan O, Arslan H. Effect of acupressure on nausea and vomiting during pregnancy. Complement Ther Clin Pract. (2008) 14:46–52. doi: 10.1016/j.ctcp.2007.07.002
85. Shin HS, Song YA, Seo S. Effect of Nei-Guan point (P6) acupressure on ketonuria levels, nausea and vomiting in women with hyperemesis gravidarum. J Adv Nurs. (2007) 59:510–9. doi: 10.1111/j.1365-2648.2007.04342.x
86. Smith C, Crowther C, Beilby J. Acupuncture to treat nausea and vomiting in early pregnancy: a randomized controlled trial. Birth. (2002) 29:1–9. doi: 10.1046/j.1523-536X.2002.00149.x
87. Carlsson CP, Axemo P, Bodin A, Carstensen H, Ehrenroth B, Madegård-Lind I, et al. Manual acupuncture reduces hyperemesis gravidarum: a placebo-controlled, randomized, single-blind, crossover study. J Pain Symptom Manage. (2000) 20:273–9. doi: 10.1016/S0885-3924(00)00185-8
88. Wise J. Women with nausea and vomiting in pregnancy should be offered more support, say RCOG guidelines. BMJ. (2016) 353:i3509. doi: 10.1136/bmj.i3509
89. Campbell K, Rowe H, Azzam H, Lane CA. The management of nausea and vomiting of pregnancy. J Obstet Gynaecol Can. (2016) 38:1127–37. doi: 10.1016/j.jogc.2016.08.009
90. McParlin C, O'Donnell A, Robson SC, Beyer F, Moloney E, Bryant A, et al. Treatments for hyperemesis gravidarum and nausea and vomiting in pregnancy: a systematic review. JAMA. (2016) 316:1392–401. doi: 10.1001/jama.2016.14337
91. Matthews A, Haas DM, O'Mathúna DP, Dowswell T. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev. (2015) 2015:CD007575. doi: 10.1002/14651858.CD007575.pub4
92. Committee on Practice Bulletins-Obstetrics. ACOG practice bulletin no. 189: nausea and vomiting of pregnancy. Obstet Gynecol. (2018) 131:e15–30. doi: 10.1097/AOG.0000000000002456
93. Shen J, Wenger N, Glaspy J, Hays RD, Albert PS, Choi C, et al. Electroacupuncture for control of myeloablative chemotherapy-induced emesis: a randomized controlled trial. JAMA. (2000) 284:2755–61. doi: 10.1001/jama.284.21.2755
94. Wu XK, Gao JS, Ma HL, Wang Y, Zhang B, Liu ZL, et al. Acupuncture and doxylamine-pyridoxine for nausea and vomiting in pregnancy: a randomized, controlled, 2 × 2 factorial trial. Ann Intern Med. (2023) 176:922–33. doi: 10.7326/M22-2974
95. Mazzone SB, Undem BJ. Vagal afferent innervation of the airways in health and disease. Physiol Rev. (2016) 96:975–1024. doi: 10.1152/physrev.00039.2015
96. Wu Z, Xia Y, Wang C, Lu W, Zuo H, Wu D, et al. Electroacupuncture at Neiguan (PC6) attenuates cardiac dysfunction caused by cecal ligation and puncture via the vagus nerve. Biomed Pharmacother. (2023) 162:114600. doi: 10.1016/j.biopha.2023.114600
97. Wang H, Liu WJ, Shen GM, Zhang MT, Huang S, He Y. Neural mechanism of gastric motility regulation by electroacupuncture at RN12 and BL21: a paraventricular hypothalamic nucleus-dorsal vagal complex-vagus nerve-gastric channel pathway. World J Gastroenterol. (2015) 21:13480–9. doi: 10.3748/wjg.v21.i48.13480
98. Kang Y, Xu F, Wang Y, Gao X, Dong W, Lu L, et al. Accelerative effects of transcutaneous electrical acustimulation on postoperative recovery after thoracolumbar vertebral fracture associated with suppressed sympathetic activity and interleukin-6. Neuromodulation. (2025) 28):690–9. doi: 10.1016/j.neurom.2024.11.011
99. Jamigorn M, Phupong V. Acupressure and vitamin B6 to relieve nausea and vomiting in pregnancy: a randomized study. Arch Gynecol Obstet. (2007) 276:245–9. doi: 10.1007/s00404-007-0336-2
100. Zhang Y, Zheng L, Deng H, Feng D, Hu S, Zhu L, et al. Electroacupuncture alleviates LPS-induced ARDS through α7 nicotinic acetylcholine receptor-mediated inhibition of ferroptosis. Front Immunol. (2022) 13:832432. doi: 10.3389/fimmu.2022.832432
101. Li YQ, Zhu B, Rong PJ, Ben H, Li YH. Effective regularity in modulation on gastric motility induced by different acupoint stimulation. World J Gastroenterol. (2006) 12:7642–8. doi: 10.3748/wjg.v12.i47.7642
102. Li YQ, Zhu B, Rong PJ, Ben H, Li YH. Neural mechanism of acupuncture-modulated gastric motility. World J Gastroenterol. (2007) 13:709–16. doi: 10.3748/wjg.v13.i5.709
103. Noguchi E. Acupuncture regulates gut motility and secretion via nerve reflexes. Auton Neurosci. (2010) 156:15–8. doi: 10.1016/j.autneu.2010.06.010
104. Wang C, Zhou DF, Shuai XW, Liu JX, Xie PY. Effects and mechanisms of electroacupuncture at PC6 on frequency of transient lower esophageal sphincter relaxation in cats. World J Gastroenterol. (2007) 13:4873–80. doi: 10.3748/wjg.v13.i36.4873
105. Lu M, Chen C, Li W, Yu Z, Xu B, EA. At PC6 promotes gastric motility: role of brainstem vagovagal neurocircuits. Evid Based Complement Alternat Med. (2019) 2019:7457485. doi: 10.1155/2019/7457485
106. Lee CH, Jung HS, Lee TY, Lee SR, Yuk SW, Lee KG, et al. Studies of the central neural pathways to the stomach and Zusanli (ST36). Am J Chin Med. (2001) 29:211–20. doi: 10.1142/S0192415X01000241
107. Kim MH, Park YC, Namgung U. Acupuncture-stimulated activation of sensory neurons. J Acupunct Meridian Stud. (2012) 5:148–55. doi: 10.1016/j.jams.2012.05.002
108. Jiang H, Shang Z, You L, Zhang J, Jiao J, Qian Y, et al. Electroacupuncture pretreatment at Zusanli (ST36) ameliorates hepatic ischemia/reperfusion injury in mice by reducing oxidative stress via activating vagus nerve-dependent Nrf2 pathway. J Inflamm Res. (2023) 16:1595–610. doi: 10.2147/JIR.S404087
109. Fan M, Chen T, Tian J, Zhang C, Zhao Z, Liu X, et al. Electroacupuncture at ST36 relieves visceral hypersensitivity based on the vagus-adrenal axis in the remission stage of ulcerative colitis. Neuromodulation. (2025) 28:812–4. doi: 10.1016/j.neurom.2024.12.006
110. Levy ML, Levy KM, Hoff D, Amar AP, Park MS, Conklin JM, et al. Vagus nerve stimulation therapy in patients with autism spectrum disorder and intractable epilepsy: results from the vagus nerve stimulation therapy patient outcome registry. J Neurosurg Pediatr. (2010) 5:595–602. doi: 10.3171/2010.3.PEDS09153
111. Diener HC, Goadsby PJ, Ashina M, Al-Karagholi MA, Sinclair A, Mitsikostas D, et al. Non-invasive vagus nerve stimulation (nVNS) for the preventive treatment of episodic migraine: the multicentre, double-blind, randomised, sham-controlled PREMIUM trial. Cephalalgia. (2019) 39:1475–87. doi: 10.1177/0333102419876920
112. Ben-Menachem E, Revesz D, Simon BJ, Silberstein S. Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability. Eur J Neurol. (2015) 22:1260–8. doi: 10.1111/ene.12629
113. Van Leusden JW, Sellaro R, Colzato LS. Transcutaneous Vagal Nerve Stimulation (tVNS): a new neuromodulation tool in healthy humans? Front Psychol. (2015) 6:102. doi: 10.3389/fpsyg.2015.00102
114. Tong WD, Ridolfi TJ, Kosinski L, Ludwig K, Takahashi T. Effects of autonomic nerve stimulation on colorectal motility in rats. Neurogastroenterol Motil. (2010) 22:688–93. doi: 10.1111/j.1365-2982.2009.01461.x
115. Carlson SH, Osborn JW. Splanchnic and vagal denervation attenuate central Fos but not AVP responses to intragastric salt in rats. Am J Physiol. (1998) 274:R1243–52. doi: 10.1152/ajpregu.1998.274.5.R1243
116. Ruffoli R, Giorgi FS, Pizzanelli C, Murri L, Paparelli A, Fornai F. The chemical neuroanatomy of vagus nerve stimulation. J Chem Neuroanat. (2011) 42:288–96. doi: 10.1016/j.jchemneu.2010.12.002
117. Ladic LA, Buchan AM. Association of substance P and its receptor with efferent neurons projecting to the greater curvature of the rat stomach. J Auton Nerv Syst. (1996) 58:25–34. doi: 10.1016/0165-1838(96)00114-2
118. Sun H, Zhao P, Liu W, Li L, Ai H, Ma X. Ventromedial hypothalamic nucleus in regulation of stress-induced gastric mucosal injury in rats. Sci Rep. (2018) 8:10170. doi: 10.1038/s41598-018-28456-0
119. Li S, Ye F, Zhang S, Liu Y, Chen JDZ. Effect and mechanism of vagal nerve stimulation on gastric motility: a preliminary rodent study. Neuromodulation. (2025) 28:767–74. doi: 10.1016/j.neurom.2024.12.005
120. Shun D, Zhao L, Liu J, Sha X, Wu Y, Liu W, et al. Neuroanatomical organization of electroacupuncture in modulating gastric function in mice and humans. Neuron. (2025) 17:S0896-6273(25)00504-5. doi: 10.1016/j.neuron.2025.06.023
121. Dai M, Li Y, Tian Y. Electroconvulsive therapy improves distal colonic motility via the subdiaphragmatic vagus nerve in depressive-like mice. Sci Rep. (2025) 15:19597. doi: 10.1038/s41598-025-04114-0
122. Huang J, Watanabe A, Kanaya M, Gomi A, Yokoyama H, Ishii H, et al. Motilin stimulates food intake linked to gastric motility in Suncus murinus: simultaneous recordings of food intake and gastric motility in the conscious state. Proc Natl Acad Sci USA. (2025) 122:e2424363122. doi: 10.1073/pnas.2424363122
123. Athavale ON, Avci R, Clark AR, Cheng LK, Du P. Acute cervical vagus nerve stimulation modulates gastric slow waves in the distal rat stomach. Neurogastroenterol Motil. (2025) 37:e70030. doi: 10.1111/nmo.70030
124. Zhang Y, Tang YW, Zhou J, Wei YR, Peng YT, Yan Z, et al. Electroacupuncture at ST36 ameliorates gastric dysmotility in rats with diabetic gastroparesis via the nucleus tractus solitarius-vagal axis. World J Gastroenterol. (2025) 31:107395. doi: 10.3748/wjg.v31.i21.107395
125. Vigier D, Rouvière A. Afferent and efferent connections of the area postrema demonstrated by the horseradish peroxidase method. Arch Ital Biol. (1979) 117:325–39.
126. Bauskin AR, Brown DA, Kuffner T, Johnen H, Luo XW, Hunter M, et al. Role of macrophage inhibitory cytokine-1 in tumorigenesis and diagnosis of cancer. Cancer Res. (2006) 66:4983–6. doi: 10.1158/0008-5472.CAN-05-4067
127. Staff AC, Bock AJ, Becker C, Kempf T, Wollert KC, Davidson B. Growth differentiation factor-15 as a prognostic biomarker in ovarian cancer. Gynecol Oncol. (2010) 118:237–43. doi: 10.1016/j.ygyno.2010.05.032
128. Welsh JB, Sapinoso LM, Kern SG, Brown DA, Liu T, Bauskin AR, et al. Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum. Proc Natl Acad Sci USA. (2003) 100:3410–5. doi: 10.1073/pnas.0530278100
129. Zimmers TA, Jin X, Gutierrez JC, Acosta C, McKillop IH, Pierce RH, et al. Effect of in vivo loss of GDF-15 on hepatocellular carcinogenesis. J Cancer Res Clin Oncol. (2008) 134:753–9. doi: 10.1007/s00432-007-0336-4
130. Borner T, Arnold M, Ruud J, Breit SN, Langhans W, Lutz TA, et al. Anorexia-cachexia syndrome in hepatoma tumour-bearing rats requires the area postrema but not vagal afferents and is paralleled by increased MIC-1/GDF15. J Cachexia Sarcopenia Muscle. (2017) 8:417–27. doi: 10.1002/jcsm.12169
131. Perelló M, Cornejo MP, De Francesco PN, Fernandez G, Gautron L, Valdivia LS. The controversial role of the vagus nerve in mediating ghrelin's actions: gut feelings and beyond. IBRO Neurosci Rep. (2022) 12:228–39. doi: 10.1016/j.ibneur.2022.03.003
132. Zhao J, Yang Y, Qin J, Tao S, Jiang C, Huang H, et al. Transcutaneous auricular vagus nerve stimulation ameliorates preeclampsia-induced apoptosis of placental trophoblastic cells via inhibiting the mitochondrial unfolded protein response. Neurosci Bull. (2024) 40:1502–18. doi: 10.1007/s12264-024-01244-9
133. Wang Z, Zhao G, Zibrila AI, Li Y, Liu J, Feng W. Acetylcholine ameliorated hypoxia-induced oxidative stress and apoptosis in trophoblast cells via p38 MAPK/NF-κB pathway. Mol Human Reprod. (2021) 27:gaab045. doi: 10.1093/molehr/gaab045
134. Zheng L, Tang R, Shi L, Zhong M, Zhou Z. Vagus nerve stimulation ameliorates L-NAME-induced preeclampsia-like symptoms in rats through inhibition of the inflammatory response. BMC Pregnancy Childbirth. (2021) 21:177. doi: 10.1186/s12884-021-03650-7
135. Mansour GM, Nashaat EH. Helicobacter pylori and hyperemesis gravidarum. Int J Gynaecol Obstet. (2009) 106:63–4. Erratum in: Int J Gynaecol Obstet. (2009) 107:177. doi: 10.1016/j.ijgo.2009.03.059
136. Rutsch A, Kantsjö JB, Ronchi F. The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology. Front Immunol. (2020) 11:604179. doi: 10.3389/fimmu.2020.604179
137. Jakob MO, Murugan S, Klose CSN. Neuro-immune circuits regulate immune responses in tissues and organ homeostasis. Front Immunol. (2020) 11:308. doi: 10.3389/fimmu.2020.00308
138. Kressel AM, Tsaava T, Levine YA, Chang EH, Addorisio ME, Chang Q, et al. Identification of a brainstem locus that inhibits tumor necrosis factor. Proc Natl Acad Sci USA. (2020) 117:29803–10. doi: 10.1073/pnas.2008213117
139. de Melo PS, Gianlorenco AC, Marduy A, Kim CK, Choi H, Song JJ, et al. A mechanistic analysis of the neural modulation of the inflammatory system through vagus nerve stimulation: a systematic review and meta-analysis. Neuromodulation. (2025) 28:43–53. doi: 10.1016/j.neurom.2024.03.002
140. Cheng Y-H, Li H-K, Chang K-H, Lin Y-K, Lin Y-H, Chiang C-F, et al. Bacillus coagulans TCI803 confers gastroesophageal protection against Helicobacter pylori-evoked gastric oxidative stress and acid-induced lower esophageal sphincter inflammation. JCMA. (2025) 88:545–60. doi: 10.1097/JCMA.0000000000001246
141. Huerta TS, Chen AC, Chaudhry S, Tynan A, Morgan T, Park K, et al. Neural representation of cytokines by vagal sensory neurons. Nat Commun. (2025) 16:3840. doi: 10.1038/s41467-025-59248-6
142. Wu Y, Zhang Y, Xie B, Zhang X, Wang G, Yuan S. Esketamine mitigates cognitive impairment following exposure to LPS by modulating the intestinal flora/subdiaphragmatic vagus nerve/spleen axis. Int Immunopharmacol. (2024) 126:111284. doi: 10.1016/j.intimp.2023.111284
143. Pan L, Xie L, Yang W, Feng S, Mao W, Ye L, et al. The role of brain-liver-gut axis in neurological disorders. Burns Trauma. (2025) 13:tkaf011. doi: 10.1093/burnst/tkaf011
144. De Luca R, Arrè V, Nardone S, Incerpi S, Giannelli G, Trivedi P, et al. Gastrointestinal microbiota and inflammasomes interplay in health and disease: a gut feeling. Gut. (2025) gutjnl-2025-334938. doi: 10.1136/gutjnl-2025-334938
145. Noble LJ, Chuah A, Callahan KK, Souza RR, McIntyre CK. Peripheral effects of vagus nerve stimulation on anxiety and extinction of conditioned fear in rats. Learn Mem. (2019) 26:245–51. doi: 10.1101/lm.048447.118
146. Austelle CW, Cox SS, Connolly DJ, Baker Vogel B, Peng X, Wills K, et al. Accelerated transcutaneous auricular vagus nerve stimulation for inpatient depression and anxiety: the iWAVE open label pilot trial. Neuromodulation. (2025) 28:672–81. doi: 10.1016/j.neurom.2025.02.003
147. Keatch C, Lambert E, Woods W, Kameneva T. Phase-amplitude coupling in response to transcutaneous vagus nerve stimulation: focus on regions implicated in mood and memory. Neuromodulation. (2025) 28:663–71. doi: 10.1016/j.neurom.2025.01.011
148. Mathew E, Tabet MN, Robertson NM, Hays SA, Rennaker RL, Kilgard MP, et al. Vagus nerve stimulation produces immediate dose-dependent anxiolytic effect in rats. J Affect Disord. (2020) 265:552–7. doi: 10.1016/j.jad.2019.11.090
149. Zhang S, Cao C, Han Y, Hu H, Zheng X. A nonlinear relationship between the triglycerides to high-density lipoprotein cholesterol ratio and stroke risk: an analysis based on data from the China health and retirement longitudinal study. Diabetol Metab Syndr. (2024) 16:96. doi: 10.1186/s13098-024-01339-3
150. Groves DA, Brown VJ. Vagal nerve stimulation: a review of its applications and potential mechanisms that mediate its clinical effects. Neurosci Biobehav Rev. (2005) 29:493–500. doi: 10.1016/j.neubiorev.2005.01.004
151. Fiksdal A, Hanlin L, Kuras Y, Gianferante D, Chen X, Thoma MV, et al. Associations between symptoms of depression and anxiety and cortisol responses to and recovery from acute stress. Psychoneuroendocrinology. (2019) 102:44–52. doi: 10.1016/j.psyneuen.2018.11.035
152. O'Keane V, Dinan TG, Scott L, Corcoran C. Changes in hypothalamic-pituitary-adrenal axis measures after vagus nerve stimulation therapy in chronic depression. Biol Psychiatry. (2005) 58:963–8. doi: 10.1016/j.biopsych.2005.04.049
153. Chen X, Liang H, Hu K, Sun Q, Sun B, Bian L, et al. Vagus nerve stimulation suppresses corticotropin-releasing factor-induced adrenocorticotropic hormone release in rats. Neuroreport. (2021) 32:792–6. doi: 10.1097/WNR.0000000000001656
154. Cordner ZA, Li Q, Liu L, Tamashiro KL, Bhargava A, Moran TH, et al. Vagal gut-brain signaling mediates amygdaloid plasticity, affect, and pain in a functional dyspepsia model. JCI Insight. (2021) 6:e144046. doi: 10.1172/jci.insight.144046
155. Décarie-Spain L, Hayes AMR, Lauer LT, Kanoski SE. The gut-brain axis and cognitive control: a role for the vagus nerve. Semin Cell Dev Boil. (2024) 156:201–9. doi: 10.1016/j.semcdb.2023.02.004
156. Tu Y, Fang J, Cao J, Wang Z, Park J, Jorgenson K, et al. A distinct biomarker of continuous transcutaneous vagus nerve stimulation treatment in major depressive disorder. Brain Stimul. (2018) 11:501–8. doi: 10.1016/j.brs.2018.01.006
157. Aaronson ST, Sears P, Ruvuna F, Bunker M, Conway CR, Dougherty DD, et al. A 5-year observational study of patients with treatment-resistant depression treated with vagus nerve stimulation or treatment as usual: comparison of response, remission, and suicidality. Am J Psychiatry. (2017) 174:640–8. doi: 10.1176/appi.ajp.2017.16010034
158. De Smet S, Baeken C, Seminck N, Tilleman J, Carrette E, Vonck K, et al. Non-invasive vagal nerve stimulation enhances cognitive emotion regulation. Behav Res Ther. (2021) 145:103933. doi: 10.1016/j.brat.2021.103933
159. Chavez LM, Huang SS, MacDonald I, Lin JG, Lee YC, Chen YH. Mechanisms of acupuncture therapy in ischemic stroke rehabilitation: a literature review of basic studies. Int J Mol Sci. (2017) 18:2270. doi: 10.3390/ijms18112270
160. Qin Z, Liu Y, Zhou K, Wu J, Pang R, Li N, et al. Acupuncture for chronic prostatitis/chronic pelvic pain syndrome: study protocol for a randomized controlled trial. Trials. (2017) 18:616. doi: 10.1186/s13063-017-2383-8
161. Kavoussi B, Ross BE. The neuroimmune basis of anti-inflammatory acupuncture. Integr Cancer Ther. (2007) 6:251–7. doi: 10.1177/1534735407305892
162. Zhang S, He H, Wang Y, Wang X, Liu X. Transcutaneous auricular vagus nerve stimulation as a potential novel treatment for polycystic ovary syndrome. Sci Rep. (2023) 13:7721. doi: 10.1038/s41598-023-34746-z
163. Zhang SK, Gao WB, Liu Y, He H. [Therapeutic effect of cervical Jiaji electroacupuncture on postoperative intractable hiccup of liver neoplasms] Zhonghua Zhong Liu Za Zhi. [Chinese Journal of Oncology] (2018) 40:138–40. doi: 10.3760/cma.j.issn.0253-3766.2018.02.011
164. He H, Zhang SK, Liu Y, Gao WB. [22 cases of sudden deafness during pregnancy treated with electroacupuncture at the cervical and auricular points] Zhong hua er ke xue za zhi [Chinese Journal of Otology] (2018) 16:107–9. doi: 10.3969/j.issn.1672-2922.2018.024
165. Smirnoff L, Bravo M, Hyppolite T. Neuromodulation for headache management in pregnancy. Curr Pain Headache Rep. (2025) 29:14. doi: 10.1007/s11916-024-01344-1
166. Pan D, Chen Z, Chen H. Managing supraventricular tachyarrhythmia in pregnant patients within the emergency department. Front Cardiovasc Med. (2024) 11:1517990. doi: 10.3389/fcvm.2024.1517990
167. Konstantinou GN, Vigod SN, Mehta S, Daskalakis ZJ, Blumberger DM. A systematic review of non-invasive neurostimulation for the treatment of depression during pregnancy. J Affect Disord. (2020) 272:259–68. doi: 10.1016/j.jad.2020.03.151
Keywords: hyperemesis gravidarum, nausea and vomiting of pregnancy, electroacupuncture, vagus nerve stimulation, acupuncture, growth and differentiation factor 15
Citation: Zhang S, He H, Li X and Guo Y (2025) Electroacupuncture and vagus nerve stimulation are emerging therapies for hyperemesis gravidarum management. Front. Neurol. 16:1615635. doi: 10.3389/fneur.2025.1615635
Received: 21 April 2025; Accepted: 12 August 2025;
Published: 15 October 2025.
Edited by:
Enshe Jiang, Henan University, ChinaReviewed by:
Nazeer Hussain Khan, University of Illinois Chicago, United StatesLintao Wang, Wuhan University, China
Wei Keong Chieng, Ng Teng Fong General Hospital, Singapore
Copyright © 2025 Zhang, He, Li and Guo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yi Guo, Z3VveWlfMTY4QDE2My5jb20=; Xinyu Li, eHl1bGkwMzEzQDE2My5jb20=
†These authors share first authorship