Association between embryo transfer season and the risks of hypertensive disorders of pregnancy and gestational diabetes mellitus.

Purpose To explore the impact of seasonal variations on the risks of hypertensive disorders of pregnancy (HDP) and gestational diabetes mellitus (GDM) in women who undergo in vitro fertilization (IVF) treatment.

We retrospectively included a total of 21,469 women who achieved singleton delivery during their first cycles of IVF, the risks of HDP and GDM were compared in different seasonal groups according to the time of embryo transfer and the time of oocyte retrieval.

After adjustment via multivariable logistic regression, women who underwent embryo transfer in spring with the expected date of confinement in winter had a higher risk of HDP (4.9% vs. 3.8%; adjusted odds ratio (aOR), 1.34; 95% confidence interval (CI), 1.09–1.64; P = 0.005) than those underwent embryo transfer in winter with the expected date of confinement in autumn. There were no seasonal variations in the risk of HDP according to the time of oocyte retrieval or in the risk of GDM regardless of the time of embryo transfer or the time of oocyte retrieval. After subgroup analysis, the seasonal variations in the risk of HDP remained in frozen embryo transfer (FET) cycles but not in fresh embryo transfer (FreET) cycles.

The risk of HDP was increased in women who underwent embryo transfer in spring compared to those who underwent embryo transfer in winter. The risk of HDP is more likely to be affected by the season at the time of embryo transfer in FET cycles compared to FreET cycles. Supplementary Information The online version contains supplementary material available at 10.1007/s10815-025-03426-4.

Season, Hypertensive disorder of pregnancy, In vitro fertilization, Embryo transfer

Human birth rates vary across seasons, with the underlying mechanisms remain unclear [1, 2]. Although behavioral or cultural factors may influence couples’ pregnancy attempts, seasonal exposure may also affect their fecundity. It has been suggested that the rates of pregnancy loss, preterm delivery, and ectopic pregnancy vary seasonally [3–6]. Seasonal variations in the prevalence of maternal cardiometabolic disorders (CMDs) [7], such as hypertensive disorders of pregnancy (HDP) and gestational diabetes mellitus (GDM), were also observed in the general population, possibly due to seasonal variations in ambient temperature and humidity, daylight length, and daylight-related serum vitamin D levels [8–10]. The molecular and pathophysiological mechanisms of HDP and GDM are largely unknown, but are likely to originate from poor placentation early in pregnancy [11–13]. The combination and interaction of placental factors and maternal factors ultimately result in the clinical manifestations of HDP or GDM [11, 14], during which the environmental exposures may be of critical etiological importance. Although the use of in vitro fertilization (IVF) benefits many couples around the world, women who conceive via IVF are more likely to present an increased risk of CMDs, such as HDP [15] and GDM [16], compared to those who conceive spontaneously. Moreover, compared to fresh embryo transfer (FreET), frozen embryo transfer (FET) results in an increased risk of HDP [17]. Both HDP and GDM contribute to significantly increased risks of maternal and perinatal morbidity and mortality, and affected women and their offspring are at increased risk of future CMDs, which poses a substantial risk to their long-term health and well-being [18–20]. Thus, understanding any possible risk factors for maternal CMDs in IVF clinical practice is critical. Several studies have explored the association between seasonal variations and the efficacy of fertility treatment. It has been suggested that there are seasonal variations in the rates of fertilization and high-quality embryos in women who undergo IVF [21, 22], and the season at the time of oocyte retrieval impacts the rates of pregnancy and live birth in subsequent FreET and FET cycles [23–25]. However, the season at the time of FET has been shown to have no seasonal associations with live birth [26, 27]. Although there are significant seasonal variations in blood pressure and blood glucose levels [28–30], whether the season at the time of oocyte retrieval or embryo transfer affects maternal risks of HDP and GDM, in women who undergo IVF has rarely been explored. Temperature seems to be the most important season-related factor that influences natural conception [31]. Accumulated evidences have shown that extreme high and low temperatures are associated with altered uterine blood flow and adverse pregnancy outcomes of natural reproduction [32–34]. The temperature exposure in women undergoing IVF treatment is more complicated due to containing different stages of treatment, including oocyte retrieval, embryo transfer, and pregnancy period. Recently, it has been suggested that ambient temperatures result in a lower rate of live birth and a higher rate of pregnancy loss in IVF cycles [35]. However, the impact of ambient temperatures on the risks of HDP and GDM after IVF treatment remains unclear. In this study, we performed a retrospective study on a relatively large IVF population, aiming to explore whether there are seasonal variations in the risks of HDP and GDM for women who undergo IVF treatment. To be more precise, the impact of month and temperature exposure on maternal risks of HDP and GDM has also been evaluated.

Patients This was a retrospective study conducted in Jinan, Shandong Province, China, where features a Northern Hemisphere temperate continental-monsoon climate with four distinct seasons. A total of 21,469 embryo transfer cycles from 21,469 different women who achieved singleton delivery at the Center for Reproductive Medicine of Shandong University from January 2016 to June 2021 were included for analysis. All women were aged 20 to 40 years and underwent their first cycles of IVF with or without intracytoplasmic sperm injection (ICSI). The following participants were excluded: women who were diagnosed with pregestational diabetes mellitus, chronic hypertension, polycystic ovary syndrome (PCOS), or other ovulation disorders; women who were recipients of donor oocytes; women who underwent preimplantation genetic testing cycles; or women who had vanishing twins. The study protocol was approved by the Institutional Ethics Committee of the Center for Reproductive Medicine of Shandong University (Ethical Review No. 66, 2023). All patients signed informed consent forms. Seasonality parameters We grouped the 12 months of the year into 3-month intervals and defined “seasons” as follows: spring = Mar-May, summer = Jun-Aug, autumn = Sep-Nov, and winter = Dec-Feb. This grouping is largely consistent with climate change in Shandong Province. The daily mean temperature in Jinan, Shandong Province, China, was collected from historical data on the American National Centers for Environmental Information website (www.ncei.noaa.gov). The weather on the day of embryo transfer was categorized into three categories by the 25th to 75th percentile range of the mean daily temperature for each day during the study period and was defined as cold, comfortable, or hot weather: 25.00 °C, respectively. Similarly, the weather on the day of delivery was defined as cold, comfortable, or hot weather with tiles of 25.11 °C, respectively. Controlled Ovarian Stimulation (COS) and embryo procedures A gonadotropin-releasing hormone (GnRH) agonist protocol or a GnRH antagonist protocol was used for ovarian stimulation as previously reported [36, 37]. The determination of FreET or FET was based on whether patients were concomitant with medical conditions (such as risk of ovarian hyperstimulation syndrome, premature elevation of progesterone, or infection) and patients’ preferences. Women who underwent FET were those with medical conditions that were not suitable for FreET and those who failed in FreET. In the FreET group, cleavage-stage embryos or blastocyst embryos were transferred on the 3rd or 5th day, respectively, after the retrieval of oocytes. For women who underwent FET, embryos were transferred on the 3rd or 5th day after ovulation (natural ovulation or ovulation induction regimen for endometrial preparation) or after progesterone initiation (artificial regimen for endometrial preparation). Up to two embryos were transferred for all patients. The temperature and humidity in the operating theatre and embryology laboratory conditions were strictly controlled, and there was no seasonal or monthly variation. If successfully conceived, luteal phase support was continued until 11 weeks of gestation. Obstetrical complications were obtained from telephone follow-up at the time of delivery by trained nurses, and the diagnosis was generally based on the obstetric discharge records. Due to timely follow-up and specialized medical record data management, outcome data were integrated for all 21,469 patients in our study. Clinical outcomes The primary outcomes were the rates of HDP and GDM. Secondary outcomes included placental abruption, placenta previa, and preterm delivery. HDP was defined as a sustained blood pressure ≥ 140/90 mmHg after 20 weeks, including gestational hypertension, preeclampsia (PE), eclampsia, and no prior history of hypertension [11]. Gestational hypertension was defined as a sustained blood pressure ≥ 140/90 mmHg at or after 20 weeks of gestation in the absence of features of PE. PE was defined as a sustained blood pressure > 140/90 mmHg after 20 weeks of gestation accompanied by proteinuria or other maternal organ dysfunction, including features such as renal or liver involvement, neurological or hematological complications, or uteroplacental dysfunction [38]. GDM was defined as one or more of the 75 g OGTT glucose level indexes above the following cutoff values screened between 24 and 28 weeks of gestation after excluding pregestational diabetes mellitus: fasting plasma glucose ≥ 5.1 mmol/L; 1 h plasma glucose ≥ 10.0 mmol/L; and 2 h plasma glucose ≥ 8.5 mmol/L [39]. Statistical analysis For continuous variables, normality was tested by the graphical use of histograms, Q–Q plots, and the Kolmogorov–Smirnov test. Variables were presented as mean ± standard deviation (SD) if they were normally distributed and as the median (25th percentile to 75th percentile) if they were nonnormally distributed. For categorical variables, they were expressed as the number of cases (n) and percentage of occurrence (%). Continuous variables were assessed with the use of the one-way ANOVA test or the Kruskal–Wallis test. Categorical variables were examined by the chi–square test or Fisher’s exact test. The adjusted odds ratios (aORs) and 95% confidence intervals (CIs) of the outcomes were calculated by multivariable logistic regression to assess the risk of HDP and GDM according to season, month, and temperature at the time of embryo transfer. Potential confounding covariates, including maternal age, body mass index (BMI), number of oocyte retrieved, endometrial thickness before embryo transfer, stage of embryo transfer, number of embryo transfer, and type of embryo transfer, were included directly in the adjusted regression models. Potential non-linear relationships between months and HDP risk were examined using restricted cubic splines (RCSs) (knot = 4). All the statistical analyses in this study were performed with the Statistical Package for Social Sciences (SPSS) version 26.0 or the R program version 4.0.3. A value of P < 0.05 was considered statistically significant.

Baseline characteristics A total of 21,469 women who underwent their first cycles of IVF and achieved singleton delivery were included in the analysis and were assigned to four seasonal groups: the spring (N = 5986), summer (N = 5700), autumn (N = 5664), and winter (N = 4119) group. As illustrated in Table 1, the four groups exhibited similar maternal and paternal ages, BMIs, infertility causes, fertilization methods, and ratio of using donor sperm. There were less oocytes retrieved from the summer group than from the winter group (11.00 (8.00–15.00) vs. 12.00 (8.00–16.00), P = 0.018)). The proportion of cleavage-stage embryos was lower in the spring group compared to that in the summer (25.4% vs. 31.1%, P < 0.001) and autumn group (25.4% vs. 29.4%, P < 0.001). The spring group had the highest proportion of single embryo transfer, while the summer group had the highest rate of FreET, among the four seasonal groups. As expected, most patients delivered three seasons after embryo transfer. Table 1. | Spring (N = 5986) | Summer (N = 5700) | Autumn (N = 5664) | Winter (N = 4119) | P-value | | |---|---|---|---|---|---| | Maternal age (years) | 30.00 (28.00–33.00) | 30.00 (28.00–33.00) | 30.00 (28.00–33.00) | 30.00 (28.00–33.00) | 0.739 | | Paternal age (years) | 31.0 (28.0–34.0) | 31.0 (28.0–34.0) | 31.0 (28.0–34.0) | 31.0 (28.0–34.0) | 0.102 | | BMI (kg/m2) | 22.77 (20.70–25.3) | 22.75 (20.70–25.2) | 22.66 (20.67–25.2) | 22.67 (20.69–25.2) | 0.597 | | Infertility causes | 0.372 | |||| | Tube factors, n (%) | 3333 (55.7%) | 3266 (57.3%) | 3239 (57.2%) | 2338 (56.8%) | | | Endometriosis, n (%) | 198 (3.3%) | 168 (2.9%) | 185 (3.3%) | 134 (3.3%) | | | Male factor, n (%) | 906 (15.1%) | 867 (15.2%) | 894 (15.8%) | 593 (14.4%) | | | Other factors, n (%) | 203 (3.4%) | 194 (3.4%) | 185 (3.3%) | 145 (3.5%) | | | Mixed factors, n (%) | 1346 (22.5%) | 1205 (21.1%) | 1161 (20.5%) | 909 (22.1%) | | | Fertilization methods | 0.127 | |||| | IVF, n (%) | 4427 (74.0%) | 4196 (73.6%) | 4135 (73.0%) | 3065 (74.4%) | | | ICSI, n (%) | 1351 (22.6%) | 1295 (22.7%) | 1280 (22.6%) | 887 (21.5%) | | | Half IVF and half ICSI, n (%) | 208 (3.5%) | 209 (3.7%) | 249 (4.4%) | 167 (4.1%) | | | Donor sperm, n (%) | 411 (6.9%) | 384 (6.7%) | 364 (6.4%) | 276 (6.7%) | 0.814 | | Number of oocytes retrieved | 12.00 (8.00–15.00) | 11.00 (8.00–15.00) c | 12.00 (8.00–15.00) | 12.00 (8.00–16.00) | 0.016 | | Endometrial thickness before embryo transfer (mm) | 10.00 ± 2.40a,b | 10.21 ± 2.10 | 10.16 ± 2.23 | 10.01 ± 2.29a,b | < 0.001 | | Stage of embryo transfer | < 0.001 | |||| | Cleavage embryo, n (%) | 1522(25.4%)a,b | 1775 (31.1%)c | 166 (29.4%) | 1114 (27.0%) | | | Blastocyst embryo, n (%) | 4464 (74.6%)a,b | 3925 (68.9%)c | 3998 (70.6%) | 3005 (73.0%) | | | Number of embryo transfer | < 0.001 | |||| | 1, n (%) | 4468 (74.6%)a,b,c | 3906 (68.5%)c | 3985 (70.4%) | 2972 (72.2%) | | | 2, n (%) | 1518 (25.4%)a,b,c | 1794 (31.5%)c | 1679 (29.6%) | 1147 (27.8%) | | | Type of embryo transfer | 0.002 | |||| | FreET, n (%) | 2242 (37.5%)a | 2314 (40.6%)b,c | 2159 (38.1%) | 1547 (37.6%) | | | FET, n (%) | 3744 (62.5%)a | 3386 (59.4%)b,c | 3505 (61.9%) | 2572 (62.4%) | | | Endometrial preparation regimen | 0.272 | |||| | Natural ovulation regimen, n (%) | 2350/3744 (62.8%) | 2142/3386 (63.3%) | 2185/3505 (62.3%) | 1559/2572 (60.6%) | | | Artificial regimen, n (%) | 1111/3744 (29.7%) | 1008/3386 (29.8%) | 1048/3505 (29.9%) | 828/2572 (32.2%) | | | Ovulation induction regimen, n (%) | 283/3744 (7.6%) | 236/3386 (7.0%) | 272/3505 (7.8%) | 185/2572 (7.2%) | | | Season at the time of delivery | < 0.001 | |||| | Spring, n (%) | 3(0.1%) | 4687 (82.2%) | 1077 (19.0%) | 1 (0.0%) | | | Summer, n (%) | 0 (0.0%) | 2 (0.0%) | 4586 (81.0%) | 1189 (28.9%) | | | Autumn, n (%) | 1233 (20.6%) | 1 (0.0%) | 1 (0.0%) | 2929 (71.1%) | | | Winter, n (%) | 4750 (79.4%) | 1010 (17.7%) | 0 (0.0%) | 0 (0.0%) | BMI body mass index, IVF in vitro fertilization, ICSI intracytoplasmic sperm injection, FreET fresh embryo transfer, FET frozen embryo transfer aSignificantly different from summer bSignificantly different from autumn cSignificantly different from winter Clinical outcomes The rate of HDP was higher in the spring group compared to that in the autumn group (4.9% vs. 3.6%, P = 0.001) (Table 2). The spring group exhibited a trend toward a higher rate of HDP compared to the winter group, though this difference did not reach statistical significance. Both the spring group and the summer group were associated with a higher rate of gestational hypertension compared to the autumn group (3.4% vs. 2.4%, P = 0.001 for spring group vs. autumn group; 3.2% vs. 2.4%, P = 0.006 for summer group vs. autumn group). We did not observe significant differences in the rates of PE, GDM, preterm delivery, placental abruption, and previa placenta across the four seasonal groups. Table 2. | Spring (N = 5986) | Summer (N = 5700) | Autumn (N = 5664) | Winter (N = 4119) | P-value | | |---|---|---|---|---|---| | HDP, n (%) | 291 (4.9%)a | 244 (4.3%) | 202 (3.6%) | 156 (3.8%) | 0.003 | | PE, n (%) | 88 (1.5%) | 61 (1.1%) | 68 (1.2%) | 47 (1.1%) | 0.226 | | Gestational hypertension, n (%) | 203 (3.4%)a | 183 (3.2%)a | 134 (2.4%) | 109 (2.6%) | 0.004 | | GDM, n (%) | 492 (8.2%) | 454 (8.0%) | 476 (8.4%) | 307 (7.5%) | 0.358 | | Preterm delivery, n (%) | 372 (6.2%) | 341 (6.0%) | 359 (6.3%) | 255 (6.2%) | 0.887 | | Placental abruption, n (%) | 10 (0.2%) | 17 (0.3%) | 20 (0.4%) | 8 (0.2%) | 0.175 | | Previa placenta, n (%) | 54 (0.9%) | 64 (1.1%) | 58 (1.0%) | 36 (0.9%) | 0.545 | HDP hypertensive disorders of pregnancy, PE preeclampsia, GDM gestational diabetes mellitus aSignificantly different from autumn After adjustment for the confounding factors including maternal age, BMI, number of oocyte retrieved, endometrial thickness before embryo transfer, stage of embryo transfer, number of embryo transfer, and type of embryo transfer (Table 3), the spring group had higher risks of HDP (adjusted odds ratio (aOR), 1.34; 95% confidence interval (CI), 1.09–1.64; P = 0.005) and gestational hypertension (aOR, 1.32; 95% CI, 1.04–1.68; P = 0.023) compared to winter group. There were still no significant differences in the rates of PE and GDM among the four seasonal groups. Table 3. | Spring vs. Winter | Summer vs. Winter | Autumn vs. Winter | |||| |---|---|---|---|---|---|---| | aOR (95% CI) | P-value | aOR (95% CI) | P-value | aOR (95% CI) | P-value | | | HDP | 1.34 (1.09–1.64) | 0.005 | 1.17 (0.95–1.44) | 0.141 | 0.95 (0.76–1.18) | 0.623 | | PE | 1.36 (0.95–1.96) | 0.091 | 0.99 (0.67–1.45) | 0.948 | 1.07 (0.73–1.56) | 0.737 | | Gestational hypertension | 1.32 (1.04–1.68) | 0.023 | 1.25 (0.98–1.60) | 0.073 | 0.90 (0.70–1.17) | 0.440 | | GDM | 1.12 (0.96–1.31) | 0.132 | 1.08 (0.93–1.26) | 0.311 | 1.16 (1.00–1.35) | 0.057 | HDP hypertensive disorders of pregnancy, PE preeclampsia, GDM gestational diabetes mellitus, aOR adjusted odds ratio, CI confidence interval. Analyses were adjusted for maternal age, BMI, number of oocytes retrieved, endometrial thickness before the embryo transfer, stage of embryo transfer, number of embryo transfer, and type of embryo transfer Moreover, we also compared the impact of season at the time of oocyte retrieval on the risk of pregnancy complications, with results showing there were no differences in the risks of HDP, gestational hypertension, and other complications such as PE and GDM among the four seasonal groups divided by the time at oocyte retrieval (Supplementary Table 1). To further narrow the high-risk duration of the year for embryo transfer, we compared the risk of HDP among months at the time of embryo transfer and observed the highest risk of HDP in May (late spring) and June (early summer) (Fig. 1). However, the risk of HDP was comparable as the months at the time of oocyte retrieval changed (Supplementary Fig. 1A). Considering that temperature varies most dramatically with season, we further explored the associations between cold, comfortable, and hot weather and the risk of HDP after adjustment for confounding factors, including maternal age, BMI, number of oocyte retrieved, endometrial thickness before embryo transfer, stage of embryo transfer, number of embryo transfer, and type of embryo transfer. The forest map showed that women who had embryos transferred during comfortable and hot weather had a greater risk of HDP compared to those who had embryos transferred during cold weather (Fig. 2A) and women who delivered during comfortable and hot weather had a lower risk of HDP compared to those who delivered during cold weather (Fig. 2B). Subgroup analysis We also compared pregnancy complications after FreET and FET among the four seasonal groups based on the time of embryo transfer (Table 4). For women who underwent FreET cycles, no significant differences were observed in the rates of HDP, PE, gestational hypertension, or GDM among the four seasonal groups. For women who underwent FET cycles, the spring group had a higher rate of HDP compared to the autumn group (5.3% vs. 3.8%, P = 0.002). We also observed a higher risk of gestational hypertension in the spring group (3.6% vs. 2.5%, P = 0.008) and the summer group (3.8% vs. 2.5%, P = 0.002) compared to that in the autumn group. After adjustment by multivariable logistic regression, women who underwent FET in spring were associated with higher risks of HDP (aOR, 1.37; 95% CI, 1.07–1.75; P = 0.013), PE (aOR, 1.58; 95% CI, 1.02–2.44; P = 0.041), and GDM (aOR, 1.23; 95% CI, 1.01–1.49; P = 0.039), compared to those underwent FET in winter (Table 5). However, there were no associations between pregnancy complications and season at the time of oocyte retrieval in either FreET or FET cycles (Supplementary Table 2). Table 4. | Spring (N = 5986) | Summer (N = 5700) | Autumn (N = 5664) | Winter (N = 4119) | P-value | | |---|---|---|---|---|---| | HDP | ||||| | FreET, n (%) | 92 (4.1%) | 75 (3.2%) | 68 (3.1%) | 51 (3.3%) | 0.278 | | FET, n (%) | 199 (5.3%) a | 169 (5.0%) | 134 (3.8%) | 105 (4.1%) | 0.008 | | PE | ||||| | FreET, n (%) | 22 (1.0%) | 20 (0.9%) | 21 (1.0%) | 16 (1.0%) | 0.955 | | FET, n (%) | 66 (1.8%) | 41 (1.2%) | 47 (1.3%) | 31 (1.2%) | 0.155 | | Gestational hypertension | ||||| | FreET, n (%) | 70 (3.1%) | 55 (2.4%) | 47 (2.2%) | 35 (2.3%) | 0.175 | | FET, n (%) | 133 (3.6%) a | 128 (3.8%) a | 128 (2.5%) | 74 (2.9%) | 0.008 | | GDM | ||||| | FreET, n (%) | 172 (7.7%) | 186 (8.0%) | 186 (8.6%) | 123 (8.0%) | 0.711 | | FET, n (%) | 320 (8.5%) | 268 (7.9%) | 290 (8.3%) | 184 (7.2%) | 0.225 | HDP hypertensive disorders of pregnancy, PE preeclampsia, GDM gestational diabetes mellitus, FreET fresh embryo transfer, FET frozen embryo transfer aSignificantly different from autumn Table 5. | Spring vs. Winter | Summer vs. Winter | Autumn vs. Winter | |||| |---|---|---|---|---|---|---| | aOR (95% CI) | P-value | aOR (95% CI) | P-value | aOR (95% CI) | P-value | | | HDP | |||||| | FreET | 1.26 (0.89–1.80) | 0.192 | 1.01 (0.70–1.46) | 0.954 | 0.96 (0.66–1.39) | 0.808 | | FET | 1.37 (1.07–1.75) | 0.013 | 1.26 (0.98–1.62) | 0.077 | 0.94 (0.72–1.23) | 0.647 | | PE | |||||| | FreET | 0.95 (0.50–1.81) | 0.872 | 0.86 (0.45–1.68) | 0.664 | 0.95 (0.49–1.82) | 0.867 | | FET | 1.58 (1.02–2.44) | 0.041 | 1.05 (0.66–1.70) | 0.828 | 1.13 (0.71–1.80) | 0.614 | | Gestational hypertension | |||||| | FreET | 1.40 (0.93–2.12) | 0.110 | 1.08 (0.70–1.66) | 0.734 | 0.96 (0.62–1.50) | 0.855 | | FET | 1.27 (0.95–1.71) | 0.109 | 1.34 (1.00–1.81) | 0.051 | 0.87 (0.63–1.20) | 0.390 | | GDM | |||||| | FreET | 0.97 (0.76–1.24) | 0.814 | 1.03 (0.81–1.30) | 0.824 | 1.10 (0.87–1.40) | 0.434 | | FET | 1.23 (1.01–1.49) | 0.039 | 1.13 (0.92–1.38) | 0.241 | 1.21 (0.99–1.47) | 0.059 | HDP hypertensive disorders of pregnancy, PE preeclampsia, GDM gestational diabetes mellitus, FreET fresh embryo transfer, FET frozen embryo transfer, aOR adjusted odds ratio, CI confidence interval. Analyses were adjusted for maternal age, BMI, number of oocytes retrieved, endometrial thickness before embryo transfer, stage of embryo transfer, number of embryo transfer, and type of embryo transfer Our study showed a high risk of HDP in FET cycles compared to that in FreET cycles in all months (Fig. 1B and Supplementary Fig. 1B). While the risk of HDP in FreET cycles remained low as the month of embryo transfer changed, the risk of HDP in FET cycles was highest in women who had their embryos transferred in May (late spring) and June (early summer) (Fig. 1B). When the month at the time of oocyte retrieval was considered, the risk of HDP in FreET cycles remained low, and the risk of HDP was comparable across the year in FET cycles (Supplementary Fig. 1B). It has been suggested that the regimens used for endometrial preparation before FET are associated with altered risks of HDP [40–53]. In consisted with previous studies, our study showed higher rates of HDP, PE, and gestational hypertension in women who underwent artificial regimen for endometrium preparation before FET compared to both women who underwent natural ovulation regimen and women who underwent ovulation induction regimen for endometrium preparation before FET (Supplementary Table 3). We further conducted subgroup analysis by different endometrium preparation protocols in women who underwent FET in Supplementary Table 4. For women who underwent natural ovulation regimen for endometrium preparation before FET, the rate of HDP was higher in the spring group compared to both the autumn (3.8% vs. 2.5%, P = 0.011) and the winter group (3.8% vs. 2.4%, P = 0.020). Similarly, the rate of HDP was higher in the summer group compared to both the autumn (3.7% vs. 2.5%, P = 0.016) and the winter group (3.7% vs. 2.4%, P = 0.027). There was a trend towards these above differences in artificial regimen and ovulation induction regimen for endometrium preparation before FET, though this difference did not reach statistical significance.

In this study, we found significantly increased risks of HDP and gestational hypertension in women whose embryos were transferred in spring with the expected date of confinement in winter compared to those whose embryos were transferred in winter with the expected date of confinement in autumn. In subgroup analysis, women who underwent FET in spring were associated with higher risks of HDP, PE, and GDM compared to those who underwent FET in winter. We did not observe seasonal variations in the risks of HDP and GDM in FreET cycles. There were no significant differences in the risk of preterm delivery, placental abruption, and previa placenta across the four seasonal groups. Evidence from systematic reviews and specific individual studies has revealed seasonal variation in the risk of HDP in women who conceived spontaneously [8, 10, 54–60]. A study conducted in a single center in Denmark included 50,665 women with singleton pregnancies and reported the highest risk of HDP in women with the estimated date of conception in June and August (summer) [59]. Another Danish cohort study based on registry data included 555,459 singleton deliveries and reported that pregnancies conceived in spring and summer presented the highest risk of HDP, whereas no seasonal variation in other placenta-mediated complications was detected [10]. Morikawa and coworkers studied Japanese women and reported the highest rate of HDP among women conceived in March and April (spring) and the lowest rate of HDP among women conceived in November and December (late autumn and early winter) [57]. In line with these studies suggesting that the rate of HDP is highest with conceptions in spring and summer in temperate regions, our study focused on the IVF population and revealed an increased risk of HDP in women whose embryos were transferred in spring compared to those whose embryos were transferred in winter. However, the impact of seasonal exposure at the time of embryo transfer and seasonal exposure during gestation on the risk of HDP can be difficult to distinguish due to collinearity issues. Given our current understanding of HDP, especially PE, as a two-stage disease [11, 61], it is biologically plausible that both first- and third-trimester seasonal-associated exposures could be of critical etiological importance. Temperatures vary most significantly with seasons. Previous studies have suggested that the ambient temperature has an effect on the risk of HDP. A Canadian study by Auger et al. reported that the risk of PE was higher for hot temperatures at conception and cold temperatures during late pregnancy [62]. A study by Xiong and coworkers conducted in a Chinese national cohort revealed that cold exposure during the first half of pregnancy decreased the risk of HDP, whereas heat exposure increased the risk of HDP [63]. Similarly, our study revealed increased risks of HDP in women whose embryos were transferred in hot and comfortable weather and in women who delivered in cold weather. Interestingly, heat exposure during early pregnancy and cold exposure during late pregnancy are associated with an increased risk of HDP. A plausible explanation is that heat exposure disturbs the dissipation of internal heat due to increased metabolism during early pregnancy [64]. It has been suggested that heat exposure during the first half of pregnancy impairs fetal growth [65]. Thus, heat exposure may interfere with early placentation and maternal adoption. Furthermore, exposure to cold weather in the second and third trimesters could activate the sympathetic nervous system, the renin-angiotensin system, and the systemic inflammatory response [66], and trigger the manifestations of HDP. Thus, the impact of seasonal exposure on HDP after IVF treatment may be partially mediated by temperatures. Additionally, some other factors that vary with season may also contribute to seasonal variation in the risk of HDP. For example, exercise during pregnancy is beneficial for preventing HDP [67, 68]. Both hot weather in summer and cold weather in winter make exercise challenging for pregnant women. Moreover, it is difficult to obtain sufficient vitamin D doses in winter in a northern latitude region due to reduced outdoor activity, hiding from layers of clothing, and inadequate daily doses of solar ultraviolet radiation [69]. Furthermore, seasonal variation in infectious diseases, asthma epidemics, dietary habits, sleep quality, and environmental pollution may affect maternal physiology and placental development, thus contributing to the development of HDP [59]. Individual behavior and societal practices may also interfere with the development of HDP. We observed the highest risk of HDP in women whose embryos were transferred in May (late spring) and June (early summer) in the present study, suggesting a possible role of exposure associated with the summer holiday during early pregnancy. Interestingly, our study showed that the impact of season at the time of embryo transfer on the risk of HDP was more obvious in patients who underwent FET than in patients who underwent FreET. It has been well established that FET results in an increased risk of HDP compared to FreET, which may be due to epigenetic and metabolic alterations in embryos during the cryopreservation process [70, 71] and the absence of endogenous corpus luteum formation in artificial regimens for endometrium preparation [72]. Thus, women who undergo FET may be more sensitive to temperature changes because of seasonal variations and are thus more susceptible to HDP in cold seasons. Furthermore, the stratified analyses showed that the rate of HDP was higher in women whose embryos were transferred in spring and summer compared to women whose embryos were transferred in autumn and winter in natural ovulation regimen for endometrium preparation before FET. Similarly, there was a trend towards these above differences in artificial regimen for endometrium preparation before FET. Our study adds additional evidence to the increased risk of HDP in artificial regimen compared to other regimens [40–53] and suggests the seasonal impact on the risk of HDP in IVF cycles may be concealed by use of artificial regimen for endometrium preparation. We did not observe seasonal variation in the risk of HDP in ovulation induction regimen, which may be due to the small sample size. These findings may be particularly relevant for patients planning FET. It has been suggested that seasonal exposure has an impact on oocyte development and/or maturation and ultimately embryo development and subsequent live birth rates [25]. Our study observed no association between the season at the time of oocyte retrieval and the risk of HDP. It has been suggested that extreme weather leads to reduced rate of pregnancy and live birth [24, 35]; thus, the association between season at the time of oocyte retrieval and the risk of HDP may be concealed. The impact of seasonal exposure on oocyte and early embryo development needs to be further studied. In addition, previous studies have explored the association between seasonal changes and the development of GDM and have reached contradictory conclusions [9, 73–75]. In the present study, there were no seasonal variations in the risk of GDM in the overall IVF population. However, the risk of GDM was higher in women who underwent FET in spring compared to those who underwent FET in winter. Further studies are needed to explore the seasonal impact on GDM. One of the strengths of our study was the large sample size and data integrity, which enabled us to investigate the risks of pregnancy complications associated with seasonality. Another advantage was that we excluded women who were diagnosed with pregestational diabetes mellitus, chronic hypertension, PCOS, or other ovulation disorders, which are potential confounding factors between the risk of CMDs and seasonal variations. We acknowledge that this study has several limitations. First, our study is limited by its retrospective observational nature. Although we performed adjustment with multivariable logistic regression, we still cannot rule out the possible effects of confounders and biases. Second, as a regional clinic center in Jinan city, most patients in our center reside in the surrounding regions; due to the unavailability of the detailed address of patients, we used the temperature of Jinan city of Shandong province to represent the temperature of all patients’ residence address. Third, women with pre-existing risk factors (including twin pregnancies, pregestational diabetes mellitus, chronic hypertension, and PCOS) for HDP and GDM were excluded from our study, and whether the results could be extrapolated to high-risk populations warrants further study. Furthermore, other factors related to season and temperature that we have not considered may confound the observed associations and need to be further studied. For example, seasonal variations in maternal hormone levels, infectious diseases, immune status, healthcare access, nutrition, sleep quality, and environmental pollution may also be associated with the risk of pregnancy complications, including HDP and GDM.

We found that compared to those who underwent embryo transfer in winter, women who underwent embryo transfer in spring had an increased risk of HDP. The risk of HDP is more likely to be affected by the season at the time of embryo transfer in FET cycles compared to FreET cycles. Further studies are warranted to confirm our findings and explore the underlying mechanisms. Supplementary Information Below is the link to the electronic supplementary material.

The authors thank the patients and staff of the State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, for their cooperation and support. Author contribution Y.L. conceived and designed the project; Y.N., Y.W., GG.OY., HY.X., and CD.L collected and analyzed the data; Y.N. and Y.W., and XW.H. wrote the manuscript; Y.L. critically revised the manuscript. All authors have been involved in interpreting the data and approved the final version. Funding This study was supported by grants from the National Key Research and Development Program of China (2024YFC2706700), the National Natural Science Foundation of China (82471719, 82101784), and the Taishan Scholars Program for Young Experts of Shandong Province (tsqn202408396). Data availability The corresponding authors can be contacted on reasonable data request. Code availability The corresponding authors can be contacted on reasonable code request. Declarations Ethics approval All methods in this study were carried out in accordance with the guidelines and regulations in the Declaration of Helsinki. The Institutional Ethics Committee of the Center for Reproductive Medicine of Shandong University approved the study (Ethical Review No. 66, 2023). Consent to participate Written informed consent was obtained from all patients before treatment, and the patients consented to the use of their retrospective data in scientific publications. Consent for publication Not application. Conflict of interest The authors declare no competing interests. Footnotes Yue Niu and Yue Wang should be regarded as joint first authors. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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