The impact of menstrual cycle phases on postoperative nausea and vomiting in premenopausal women undergoing laparoscopic gastrointestinal surgery: a secondary analysis of a randomized controlled trial

1 Introduction

Postoperative nausea and vomiting (PONV) is a common discomfort after surgery and anesthesia, which can lead to serious complications in high-risk patients. These complications include dehydration, electrolyte and acid-base imbalances, esophageal tears, abdominal wound dehiscence and bleeding, subcutaneous emphysema, aspiration, aspiration pneumonia, and asphyxiation. Such complications can delay recovery, postpone hospital discharge, and increase medical expenses (1–3). The estimated incidence of postoperative nausea and vomiting is approximately 50% and 30%, respectively, and may reach 80% in high-risk patients (4–6). A comprehensive assessment of various risk factors is crucial for preventing and managing PONV. Factors associated with PONV include anesthetic techniques, surgical procedures, and individual predisposing (7, 8), such as sex, age, smoking status, and history of motion sickness. Among these, female sex is considered a strong predictor, with women experiencing PONV two to four times more frequently than men (9). While the precise mechanism is not fully understood, sex-specific hormonal variations likely contribute (9, 10).

Menstruation is characterized by cyclical sloughing and bleeding of the endometrium, coinciding with regular fluctuations in sex hormones. The interval between the first day of two periods defines the menstrual cycle (11), segmented into three phases based on cyclical changes in follicular development: the follicular, ovulatory, and luteal phases. During the follicular phase, the pituitary gland typically releases follicle-stimulating hormone (FSH) and luteinizing hormone (LH), stimulating the ovaries to produce estrogen. As estrogen levels rise and progesterone remains low, a surge in LH triggers ovulation. The luteal phase follows, characterized by elevated levels of both estrogen and progesterone (12). Research has suggested hormonal fluctuations can modulate the function of various body organs and systems, including the cardiovascular system, autonomic reactivity, gastrointestinal motility, coagulation processes, and water-electrolyte metabolism (13–17). Previous studies investigating the effect of menstrual cycle phases on PONV in premenopausal women have focused on gynecological surgeries, and they have shown inconsistent and contradictory results. Some studies suggested increased PONV risk during the follicular phase (18–20), while another study reported higher risk during the luteal phase (21), suggesting that the impact of menstrual cycle phases on PONV may vary in different situations.

The laparoscopic approach has been reported to be associated with a higher risk of PONV than other surgical procedures (7, 8). Gastrointestinal surgery may, to a certain extent, also elevate the risk of PONV due to direct manipulation or irritation of the stomach and intestines (22, 23). Given the numerous laparoscopic gastrointestinal surgeries performed annually, we conducted this retrospective study to evaluate the impact of menstrual cycle phases on PONV in premenopausal women undergoing laparoscopic gastrointestinal surgery.

2 Materials and methods

2.1 Study design and participants

This retrospective cohort study utilized data from a prior prospective, randomized, double-blind, placebo-controlled trial conducted from April 2021 to April 2022, which received approval from the Institutional Ethical Committee of the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (approval number: 2021ZSLYEC-78). All participants provided written informed consent before enrolling in the previous trial. The previously published article outlines the original inclusion and exclusion criteria in detail (24). The prior randomized controlled trial included individuals aged 18–75 years, presenting with three or four Apfel risk factors, and scheduled for laparoscopic gastrointestinal surgery under general anesthesia. Exclusion criteria included patients with American Society of Anesthesiologists (ASA) physical status classifications of 4, 5, or 6, severe hepatic impairment, or contraindications to fosaprepitant, 5-HT3 receptor antagonists, or dexamethasone. Additionally, patients who had taken preoperative medications with known antiemetic effects or hormonal medications, had mental health issues or communication difficulties, or were pregnant or nursing were excluded. All participants were recruited from the surgical wards of the participating hospital through direct conversations with qualified investigators, and provided written informed consent. Participants retain the right to withdraw from the study at any point during the research process.

This retrospective study was also approved by the same ethics committee (approval number: 2024ZSLYEC-495). The requirement for informed consent was waived, as this study relied solely on pre-existing anonymous information and posed minimal risk to participants. This retrospective cohort study included participants from the previous trial, adding further exclusion criteria for male patients, postmenopausal females, women with irregular menstrual cycles, those unable to recall the exact onset of their last menstruation, and those who did not undergo laparoscopic gastrointestinal surgery. A regular menstrual cycle is defined as one occurring consistently every 21 days to 35 days, with a maximum variation of four days between consecutive cycles (25).

2.2 Definition of each menstrual cycle phase

The menstrual cycle consists of three phases: follicular, ovulatory, and luteal. The follicular phase begins on the first day of menstruation and ends three days before ovulation. The ovulatory phase covers the two days leading up to ovulation and lasts until the day of ovulation itself. The luteal phase starts after ovulation and lasts until the end of the menstrual cycle (26). Ovulation is estimated to occur approximately 14 days before the onset of next menstruation. Drawing upon the starting date of the last menstrual cycle and its duration, we predicted the onset of the next menstrual cycle along with the estimated ovulation period. Subsequently, the menstrual cycle phase of each patient was calculated on the day of surgery.

Given that the ovulatory phase is short and patients rarely schedule surgeries during this time, we categorized the patients into two groups: luteal and non-luteal, a classification highly relevant for clinical purposes. Additionally, in our sensitivity analyses, we categorized the patients into three groups—follicular, ovulatory, and luteal—to explore whether the incidence of PONV varied among these groups, ensuring the robustness of our findings.

2.3 Prophylaxis for PONV, and anesthetic techniques

As detailed in our previous publication (24), the anesthetic technique was standardized, and total intravenous anesthesia (TIVA) was administered. Prior to anesthesia induction, patients received an intravenous infusion of either 150 mg fosaprepitant or a placebo, depending on their randomized group assignment in the previous trial. Upon induction of anesthesia, 5 mg of dexamethasone and 0.075 mg of palonosetron were administered intravenously. Throughout the general anesthesia procedure, all participants were continuously monitored using electrocardiography, pulse oximetry, capnography, blood pressure measurements, and the bispectral index. The use of fentanyl and midazolam was strictly prohibited. Total intravenous anesthesia was achieved through effect-site target-controlled infusion of propofol (2–6 μg/mL, using the Schnider model) and remifentanil (2–6 ng/mL, employing the Minto model). The target concentrations of these agents were dynamically adjusted based on the bispectral index and blood pressure readings. Sufficient muscle relaxation was ensured by the administration of cisatracurium. At the conclusion of surgery, participants were given surgical site infiltration with 0.5% ropivacaine. Additional analgesics or antiemetics were available at any time post-surgery, based on patient requests, physician's discretion, or a combination of both, with all medications fully documented.

2.4 Outcomes

The primary outcome was PONV during 0–24 h post-surgery, including symptoms such as nausea, retching, and vomiting. Nausea is defined as the continuous sensation of needing to vomit. Retching refers to the involuntary attempt to vomit without expelling stomach contents. Vomiting involves the forceful expulsion of gastric content from the stomach. Emetic episodes encompassed both retching and vomiting or any combination of the two (3).

Secondary outcomes included PONV during 25–120 h post-surgery, the incidence of nausea and emetic episodes, as well as the use of postoperative antiemetic medications during 0–24 h and 25–120 h post-surgery.

In the previous randomized controlled trial, trained and blinded investigators gathered outcome data, which were documented by participants, their family members, or the medical staff every 24 h during the first 120 h after the surgical procedure.

2.5 Sample size

Based on data from our previous randomized controlled trial, the incidence of PONV during 0–24 h post-surgery among premenopausal women was estimated to be 45%. According to the standard procedure for developing a risk model, the event per variable (EPV) ratio is typically used to determine the appropriate sample size, with an EPV of at least 10 recommended to prevent overfitting (27). In this particular study, four predetermined factors—female sex, general anesthesia, avoidance of volatile anesthetics, and the type of surgery—were included, as per the Fourth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting (7). A sample size of 240 patients was sufficient to accommodate an additional ten factors, such as the menstrual cycle phase, within the risk model.

2.6 Statistical analysis

The Kolmogorov–Smirnov test was used to assess whether numerical variables followed a normal distribution within distinct groups. Continuous variables with a normal distribution were expressed as mean [standard deviation (SD)], while non-normally distributed continuous variables were presented as medians [interquartile range (IQR)]. Categorical variables were displayed as frequencies (percentages). Differences between groups were analyzed as follows: Student's t-test for normally distributed continuous variables, Mann–Whitney U-test for non-normally distributed continuous variables, Pearson's chi-squared test, or Fisher's exact test for categorical variables. A logistic regression model was applied to evaluate the association between menstrual cycle phases, categorized as luteal and non-luteal, and the incidence of PONV, nausea, emetic episodes, or use of postoperative antiemetic medications. Odds ratio (OR) and 95% confidence intervals (CI) were calculated to quantify effect sizes.

In the sensitivity analysis, patients were divided into three groups: follicular, ovulatory, and luteal. A logistic regression model was employed to assess the association between these menstrual cycle phases and the incidence of PONV, nausea, emetic episodes, or use of postoperative antiemetic medication, with the follicular phase serving as the reference group.

Besides, the exposure-response relationship between the surgery-to-ovulation interval (calculated by subtracting the ovulation date from the surgery date) and the occurrence of PONV, nausea, emetic episodes, or use of postoperative antiemetic medications was analyzed using a restricted cubic spline with three knots. A logistic regression model was also used to evaluate the association between the time interval, both as continuous data and categorized into tri-sectional quantiles, and the incidence of PONV, nausea, emetic episodes, or use of postoperative antiemetic medications.

The logistic regression models were progressively adjusted for potential confounders. Model 1 was unadjusted. Model 2 included demographic variables, such as age, body mass index (BMI), menstrual cycle length, smoking status, and history of PONV and/or motion sickness. Model 3 encompassed all the factors from Model 2, along with additional variables such as the Apfel score, administration of fosaprepitant, surgical site, utilization of neostigmine, and postoperative opioid consumption.

All statistical analyses were performed using the R software (Version 4.3.3, Vienna, Austria). All statistical tests were two-sided, with a P-value of less than 0.05 considered statistically significant.

3 Results

3.1 Participants

A total of 1,154 patients from the previous randomized controlled trial were screened for eligibility. After excluding 40 male patients, 831 postmenopausal female patients, 12 patients unable to recall the precise onset of their last menstruation, 29 patients with irregular menstrual cycles, and two patients who did not undergo laparoscopic gastrointestinal surgery, 240 patients with regular menstrual cycles were included in this secondary analysis (Figure 1). Among these, 119 patients were in the non-luteal phase, and 121 patients were in the luteal phase. The baseline characteristics of patients and perioperative data are presented in Table 1, showing a general balance between the patients in these two phases, except for a slight difference in menstrual cycle duration.

Table 1. Patients' baseline and intraoperative characteristics by non-luteal and luteal cycle phase.

Continuous variables were presented as medians [interquartile range (IQR)]. Categorical variables were displayed as frequencies (percentages). BMI, body mass index; PONV, postoperative nausea and vomiting; ASA, american society of anesthesiologists; SAS, self-rating anxiety scale.

3.2 Primary outcome

The incidence of PONV during 0–24 h post-surgery did not significantly differ between the non-luteal and luteal patients [53 (44.5%) vs. 57 (47.1%); adjusted OR 1.10 (95% CI: 0.62 to 1.95); adjusted P = 0.735; Table 2, Supplementary Table S1 and Figure 2].

Table 2. Primary outcome and secondary outcomes by non-luteal and luteal cycle phase.

PONV, postoperative nausea and vomiting.

In the sensitivity analysis, the surgery-to-ovulation interval was also found to be unrelated to the occurrence of PONV during 0–24 h post-surgery. Furthermore, no non-linear relationship was observed between this interval and the primary outcome (Figure 3, Supplementary Table S2, Figure S1A). Moreover, when the menstrual cycle phase was categorized into three phases—follicular, ovulatory, and luteal, the menstrual cycle phase was also unrelated to the occurrence of PONV during 0–24 h post-surgery (Figure 4 and Supplementary Table S3).

3.3 Secondary outcomes

The incidence of PONV during 25–120 h post-surgery was not significantly different between the non-luteal and luteal groups [51 (42.9%) vs. 61 (52.1%); adjusted OR 1.32 (95% CI: 0.75 to 2.31); adjusted P = 0.330; Table 2, Supplementary Table S1 and Figure 2].

The incidence of nausea during 0–24 h and 25–120 h post-surgery also did not significantly differ between the non-luteal and luteal groups [52 (43.7%) vs. 57 (47.1%); adjusted OR 1.15 (95% CI: 0.65 to 2.03); adjusted P = 0.631; 51 (42.9%) vs. 60 (51.3%); adjusted OR 1.27 )95% CI: 0.73–2.23); unadjusted P = 0.400; Table 2, Supplementary Table S1 and Figure 2].

The incidence of emetic episodes during both 0–24 h and 25–120 h post-surgery did not show significant differences between the non-luteal and luteal groups [31 (26.1%) vs. 23 (19.0%); adjusted OR 0.67 (95% CI: 0.35–1.30); adjusted P = 0.238; 30 (25.2%) vs. 33 (28.2%); adjusted OR 1.14 (95% CI: 0.62–2.10); adjusted P = 0.679; Table 2, Supplementary Table S1 and Figure 2].

Similarly, the use of postoperative antiemetic medications during 0–24 h and 25–120 h post-surgery did not significantly differ between the non-luteal and luteal groups [33 (27.7%) vs. 42 (34.7%); adjusted OR 1.24 (95% CI: 0.70–2.23); adjusted P = 0.461; 40 (33.6%) vs. 47 (38.8%); adjusted OR 1.18 (95% CI: 0.67–2.08); adjusted P = 0.558; Table 2, Supplementary Table S1 and Figure 2].

In the sensitivity analysis, the surgery-to-ovulation interval was not associated with the incidence of PONV during 25–120 h post-surgery, nor with the incidence of nausea, emetic episodes, or use of postoperative antiemetic medications during 0–24 h or 25–120 h post-surgery. Furthermore, no non-linear relationship was observed between this interval and secondary outcomes (Figure 3, Supplementary Table S2, Figure S1B–H). Moreover, when the menstrual cycle phase was categorized into three phases—follicular, ovulatory, and luteal, the menstrual cycle phase was also unrelated to the occurrence of these secondary outcomes (Figure 4 and Supplementary Table S3).

4 Discussion

Our findings indicate that the menstrual cycle phase does not exert any significant impact on the incidence of PONV, nausea, or emetic episodes, either within the first 0–24 h post-surgery or during the subsequent 25–120 h. As this retrospective study draws on data obtained from a prospective, randomized controlled trial, these sources are highly reliable and allow for detailed exploration of the potential correlation between menstrual cycle phases and the occurrence of PONV.

Previous studies have investigated the effects of diverse menstrual cycle phases on PONV and have yielded conflicting results. Honkavaara et al. enrolled 68 women with regular menstrual periods undergoing gynecological laparoscopy and reported that the highest incidence of PONV occurred during the luteal phase (21). Conversely, Simurina et al. included 111 women undergoing laparoscopic gynecological surgery and concluded that patients in the luteal phase might actually have a reduced risk of PONV (28). In a blinded prospective study, Sener et al. included 51 women undergoing laparoscopic gynecological surgery and identified that both the follicular and luteal phases contributed to an increased risk of PONV (29). Furthermore, both the study which enrolled 220 patients scheduled for gynecological endoscopic surgery by Zou et al. (30) and the study which investigated 195 pre-menopausal women undergoing third molar extractions by Ramsay et al. (31) suggested that female patients were particularly susceptible to PONV during the ovulation phase compared to the luteal and follicular phases. Moreover, two separate studies by Beattie et al. consistently showed a higher incidence of PONV in menstruating women undergoing laparoscopy compared to non-menstruating women, implying a greater risk during the early follicular phase (18, 19). Based on these observations, it becomes evident that a majority of previous research efforts were characterized by relatively small sample sizes. In contrast to these outcomes, our study recruited 240 women undergoing laparoscopic gastrointestinal surgery and did not uncover any significant correlation between the menstrual cycle phases and the incidence of PONV.

Several factors contribute to the varying results across these studies, such as different methods of categorizing menstrual cycles, varying surgical procedures and anesthesia methods, and approaches to PONV prevention. Inconsistent definitions of menstrual period across various studies, disparities in the duration of menstrual cycles among women, and potential inaccuracies in patients' recollections of their last menstruation or the duration of their menstrual cycles, may collectively contribute to the significant discrepancies in research outcomes. In this study, we excluded participants with irregular menstrual cycles and those unable to recall the precise onset of their last menstrual period, with the aim of classifying the menstrual cycle phase of each patient as accurately as possible. Furthermore, we conducted an exhaustive analysis, categorizing the menstrual cycle into distinct non-luteal and luteal phases, and further reinforced our findings through a comprehensive sensitivity analysis, ensuring the robustness and reliability of our conclusions. The sensitivity analysis directly examined the relationship between the surgery-to-ovulation interval and PONV outcomes and categorized patients into follicular, ovulatory, and luteal groups to assess their correlation. In addition, variations in surgical procedures, anesthesia protocols, and pharmacological PONV prevention methods can result in different frequencies of PONV (7, 8), contributing to divergent research findings and conclusions. Given that the patient population in this study originated from a previously conducted randomized controlled trial, the surgical interventions were exclusively confined to laparoscopic gastrointestinal surgery. Anesthesia was uniformly administered using TIVA with propofol and remifentanil, while PONV prevention strategies were randomly assigned as either triple or double therapy. In this context, the reduced potential for confounding bias strengthens the credibility of our results. Consistent with our results, a multicenter retrospective analysis by Gratz et al. (32) and a comprehensive systematic review by Eberhart et al. (33) concluded that the menstrual cycle phase had no significant impact on the occurrence of PONV.

Additionally, similar to the nausea and vomiting associated with chemotherapy (34), PONV can occur in either the early (0–24 h post-surgery) or delayed stages (beyond 24 h post-surgery) (35, 36). Previous studies have suggested that the mechanisms underlying the early and delayed stages may differ, with distinct risk factors contributing to each phase may also differ (35, 37). Paul et al. demonstrated that the incidence of delayed vomiting was not associated with the Apfel score (35), a widely accepted scoring tool for estimating PONV risk. Therefore, this study explored the influence of the menstrual cycle phase on both early and delayed PONV, finding no significant effect of the menstrual cycle phase on either.

PONV, as defined, is a composite outcome that includes nausea, vomiting, or both (3). The mechanisms underlying nausea and vomiting differ subtly (38). Furthermore, some medications have been shown to be more effective in preventing vomiting than nausea (39, 40). Consequently, this study not only assessed the influence of menstrual cycle phases on the composite PONV outcome but also examined their individual effects on nausea and vomiting episodes separately.

This study presented several limitations. First, ovulation was predicted based on the anticipated onset of the subsequent menstrual cycle rather than through the examination of circulating hormone levels, although only women with regular menstrual cycles were included to enhance prediction accuracy. Second, while not an explicit exclusion criterion in the parent trial, no participants in our analysis were using hormonal contraceptives or hormone replacement therapy. Therefore, the potential confounding effects of exogenous hormones on PONV risk were not assessed in this cohort. Finally, the study was limited to patients undergoing elective laparoscopic gastrointestinal surgery, necessitating further research to determine whether these findings are consistent across a broader range of surgical procedures.

5 Conclusions

In conclusion, the menstrual cycle phase did not significantly influence the incidence of PONV, nausea, emetic episodes, or the use of postoperative antiemetic medications in female patients undergoing laparoscopic gastrointestinal surgery, neither in the first 0–24 h post-surgery nor during the subsequent 25–120 h. This finding indicates that menstrual cycle phase need not be included in risk models for PONV.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fanes.2026.1872664/full#supplementary-material

The exposure-response curve relations of the surgery-to-ovulation interval with outcomes respectively. Restricted cubic splines A-H: the exposure-response relationship between the surgery-to-ovulation interval and the incidence of PONV (0-24h) (A), PONV (25-120h) (B), nausea (0-24h) (C), nausea (25-120h) (D), emetic episodes (0-24h) (E), emetic episodes (25-120h) (F), postoperative antiemetic medications (0-24h) (G) and postoperative antiemetic medications (25-120h) (H). The value of P for overall >0.05 represents that the exposure-response relationship between the surgery-to-ovulation interval and outcome did not reach the statistical significance. The value of P for overall >0.05 represents that there was no statistically significant exposure-response relationship between the surgery-to-ovulation interval and outcome. The value of P for nonlinear >0.05 represents that the nonlinear relationship between the surgery-to-ovulation interval and outcomes did not reach the statistical significance. Models were adjusted by age, body mass index, menstrual cycle length, smoking status, history of PONV and/or motion sickness, the Apfel score, administration of fosaprepitant, surgical site, utilization of neostigmine, and postoperative opioid consumption. PONV, postoperative nausea and vomiting. Supplementary material at the source

Supplementary material Supplementary material at the source

Supplementary material Supplementary material at the source

Supplementary material Supplementary material at the source

Footnotes

Edited by: Hong Liu, UC Davis Health, United States

Reviewed by: Liang Wang, Affiliated Hospital of Qinghai University, China

Zlatko Kirovakov, Prof. Assen Zlatarov University, Bulgaria

Abbreviations PONV, Postoperative nausea and vomiting; FSH, Follicle-stimulating hormone; LH, Luteinizing hormone; ASA, American Society of Aneshesiologists; TIVA, Total intravenous anesthesia; EPV, Event per variable; SD, Standard deviation; IQR, Interquartile range; OR, Odds ratio; CI, Confidence interval; BMI, Body mass index.