Effect of different treatment protocols on in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) outcomes in adenomyosis women: a systematic review and meta-analysis.

OBJECTIVES: Pregnancy outcomes of different ovarian stimulation protocols for in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) in patients with adenomyosis are not explicit. This meta-analysis aimed to systematically evaluate the effects of different IVF/ICSI protocols on pregnancy outcomes. DESIGN: Meta-analysis. DATA SOURCES: PubMed, Web of Science and Cochrane library were searched up to October 2023. ELIGIBILITY CRITERIA: Comparative studies on IVF/ICSI outcomes in the adenomyosis population were eligible. Studies on preimplantation genetic testing, reviews, case reports and animal experiments were excluded. DATA EXTRACTION AND SYNTHESIS: Valid information was extracted by two independent authors according to a standard data format. All analyses were conducted using Review Manager (RevMan, V.5.3). RESULTS: Compared with the non-adenomyosis population, adenomyosis was responsible for a 26% reduction in clinical pregnancy rate (CPR; 42.47% vs 55.89%, OR: 0.74, 95% CI: 0.66 to 0.82, p<0.00001), a 35% reduction in live birth rate (LBR; 30.72% vs 47.77%, OR: 0.65, 95% CI: 0.58 to 0.73, p<0.00001) and a 1.9-fold increase in miscarriage rate (MR; 27.82% vs 13.9%, OR: 1.90, 95% CI: 1.56 to 2.31, p<0.00001). Subgroup analysis suggested that, in fresh embryo transfer (ET) cycles, the CPR (34.4% vs 58.25%) in the long/short/antagonist protocol group was poorer than that in the ultralong protocol group. In frozen ET (FET) cycles, there were no statistical differences in CPR ((GnRHa+FET) AM(adenomyosis) vs non-AM: 51.32% vs 43.48%, p=0.31; (non-GnRHa+FET) AM vs non-AM: 50.25% vs 60.10%, p=0.82), MR ((GnRHa+FET) AM vs non-AM:12.82% vs 12.50%, p=0.97; (non-GnRHa+FET) AM vs non-AM: 30.5% vs 15.54%, p=0.15) and LBR ((GnRHa+FET) AM vs non-AM:44.74% vs 36.96%, p=0.31; (non-GnRHa+FET) AM vs non-AM: 34.42% vs 50.25%, p=0.28). The MR in the adenomyosis group was high in the fresh ET and FET cycles. CONCLUSIONS: FET might be a better choice for women with adenomyosis, especially those pretreated with GnRHa. In fresh ET cycles, pregnancy outcomes of the long/short/antagonist protocols were poorer than those of the ultralong protocol. TRIAL REGISTRATION NUMBER: CRD42022340743.

Risk factors associated with monozygotic twinning in offspring conceived by assisted reproductive technology.

STUDY QUESTION: What are the factors influencing the occurrence of monozygotic (MZ) twins in offspring conceived by assisted reproductive technology (ART)? SUMMARY ANSWER: Parental ages, the transfer of fresh versus frozen embryos, and the grade of blastocysts are all related to MZ twinning in ART offspring. WHAT IS KNOWN ALREADY: Offspring conceived by ART have significantly increased risk of MZ twins, which may be due to the characteristics of the infertile population. The objective of this study was to explore the incidence of monozygotic (MZ) twins after ART and to clarify the risk factors for MZ twinning. STUDY DESIGN SIZE DURATION: A total of 255 monozygotic twins were enrolled in this cohort study, and then matched with singletons at a ratio of 1:4 randomly (with 1020 in the control group). All offspring were conceived by single embryo transfer. PARTICIPANTS/MATERIALS SETTING METHODS: The collected data were divided into the following three aspects for analysis: characteristics of the infertile population, gamete or embryo manipulations, and factors related to embryo development. MAIN RESULTS AND THE ROLE OF CHANCE: The incidence of MZ twins was 1.638% (255 out of 15 567 pregnancies after single embryo transfers). Compared to singleton births, a significantly lower rate of frozen embryo transfers (FET; 78.0% vs 86.1% P = 0.002) was seen amongst the MZ twins. Amongst fresh ETs, the rate of blastocyst transfers in the MZ twins group was higher compared to that in the control group (92.9% vs 75.4%, P = 0.005). We also found that certain grades of blastocysts in terms of trophectoderm (TE) development, inner cell mass + TE development and the classification of 'top-quality' embryos were associated with the incidence of MZ twinning (P = 0.025, P = 0.012, P = 0.020, respectively). Logistic regression analysis revealed that higher paternal age (odds ratio (OR) = 0.94, 95% CI = 0.89-1.00, P = 0.029) and FET (OR = 0.48, 95% CI = 0.33-0.68, P = 0.001) may be protective factors against MZ twinning. However, higher maternal age (OR = 1.07, 95% CI = 1.01-1.13, P = 0.027) and the transfer of blastocysts (OR = 4.31, 95% CI = 1.46-12.73, P = 0.008) appeared to be associated with an increased risk of MZ twinning. Amongst blastocyst transfers, a C grade TE may be protective factor against MZ twinning (B: OR = 1.90, 95% CI = 1.18-3.07, P = 0.009; A: OR = 1.58, 95% CI = 0.93-2.67, P = 0.089). LIMITATIONS REASONS FOR CAUTION: First, our definition of MZ twins was based on twins' birth after single embryo transfers (SET), rather than ultrasound examination during early pregnancy. Second, the parental characteristics of the two groups were homogenous, so it was difficult to find any associations between infertility factors and the incidence of MZ twins. WIDER IMPLICATIONS OF THE FINDINGS: This multifaceted analysis of the risk factors for MZ twinning provides some information for clinical interventions in high-risk populations. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the National Key Technology Research and Developmental Program of China (2022YFC2704404), CAMS Innovation Fund for Medical Sciences (2021-I2M-5-001), Taishan Scholars Program for Young Experts of Shandong Province (tsqn201909195), the Basic Science Center Program (31988101), and the Shandong Provincial Key Research and Development Program (2020ZLYS02). All authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Effects of duration of long-acting GnRH agonist downregulation on assisted reproductive technology outcomes in patients with adenomyosis: a retrospective cohort study.

Objectives: To elucidate the relationship between long-acting GnRH agonist (GnRHa) downregulation and assisted reproductive technology (ART) outcomes and identify the optimal duration of downregulation in patients with adenomyosis. Design: Retrospective cohort study. Participants: The study was designed to evaluate ART outcomes in adenomyosis patients with and without GnRHa downregulation between January 2016 and December 2020. A total of 374 patients with adenomyosis (621 cycles) were included with 281 cycles in downregulation group versus 340 cycles in non-downregulation group. After 1:1 propensity score matching (PSM), a sample size of 272 cycles in each group was matched. The matched downregulation group was further divided into 1-month (147 cycles), 2-months (72 cycles), and ≥3 months downregulation (53 cycles) subgroups. Stratification analysis was conducted on pregnancy outcomes in 239 fresh embryo transfer (ET) cycles and 305 frozen embryo transfer (FET) cycles. Results: The downregulation group had larger mean diameter of initial uterus and higher proportion of severer dysmenorrhea compared to non-downregulation group. The pregnancy-related parameters in GnRHa downregulation group were similar to those in non-downregulation group, except for higher late miscarriage rate (MR) (13.4% vs. 3.1%, P = 0.003). The subgroup comparisons in fresh ET cycles indicated that implantation rate (75.0% vs. 39.2%, P = 0.002), biochemical pregnancy rate (91.7% vs. 56.0%, P = 0.036) and clinical pregnancy rate (83.3% vs. 47.0%, P = 0.016) could be improved by prolonged GnRHa downregulation (≥3 months), whereas late MR was difficult to be reversed (30.0% vs. 3.2%, P = 0.017). In FET cycles, higher MR (53.6% vs. 29.9%, P = 0.029; 58.8% vs. 29.9%, P = 0.026) and lower live birth rate (18.8% vs. 34.1%, P = 0.023; 17.1% vs. 34.1%, P = 0.037) were observed in the 1-month and ≥3 months downregulation group, while no differences were found in the 2-months downregulation group compared to the non-downregulation group. Conclusion: In patients with severer adenomyosis, long-acting GnRHa downregulation might be correlated with improved ART outcomes. In fresh ET cycles, prolonged downregulation (≥3 months) might be beneficial to improve live birth rate, which needed to be verified by further study with larger sample. In FET cycles, the optimal duration of downregulation was not certain and still needed further exploration.

Effects of ovarian stimulation protocols on outcomes of assisted reproductive technology in adenomyosis women: a retrospective cohort study.

Objective: To evaluate the effects of different ovarian stimulation protocols on in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes in infertile women with adenomyosis. Methods: We carried out a retrospective cohort study among infertile women with adenomyosis receiving IVF/ICSI treatment, including 257 fresh embryo transfer (ET) cycles and 305 frozen embryo transfer (FET) cycles. In fresh ET cycles, ultra-long, long, short, and antagonist protocols were adopted. In FET cycles, patients received long-acting GnRH agonist (GnRHa) pretreatment or not. The primary outcome was clinical pregnancy rate (CPR), and the secondary outcomes included implantation rate (IR), miscarriage rate (MR), and live birth rate (LBR). Results: In fresh ET cycles, compared with ultra-long and long protocols, IR (49.7%, 52.1% versus 28.2%, P=0.001) and CPR (64.3%, 57.4% versus 35.6%, P=0.004) significantly decreased in the short protocol. Similarly, compared with ultra-long and long protocols, a decreased inclination of IR (49.7%, 52.1% versus 33.3%) and CPR (57.4%, 64.3% versus 38.2%) existed in the antagonist protocol, although no statistical significance was detected because of strict P adjustment of Bonferroni method (Padj=0.008). Compared with long protocol, LBR in short protocol decreased obviously (48.2% versus 20.3%, P<0.001). In FET cycles, no matter which origin of embryos, there were no statistical differences in IR, CPR, and LBR. For women ≥35 years receiving fresh ET, CPR was higher in ultra-long and long protocols (52.1%, 50.0% versus 20.0%, 27.5%, P=0.031) compared to antagonist and short protocols. For women ≥35 years receiving FET, compared with ultra-long and antagonist protocols, cycles with embryos originating from long and short protocols had higher proportions of long-acting GnRHa pretreatment (30.4%,30.00 versus 63.9%, 51.4%, P=0.009). IR (61.1%, 48.6% versus 32.6%, 25.0%, P=0.020) and CPR (58.3%, 48.6% versus 30.4%, 25.0%, P=0.024) in long and short protocols were higher than rates of ultra-long and antagonist protocols, but no statistical differences were supported because of strict Bonferroni method (Padj=0.008). Conclusion: In infertile women with adenomyosis, if a fresh embryo was planned for transfer, an ultra-long or long protocol might be beneficial. If antagonist and short protocols were used, whole embryos frozen followed by FET was recommended. In FET cycles, embryos derived from different protocols had no impact on pregnancy outcomes.

Systematical assessment of digit ratio in a female masculinization disease: polycystic ovary syndrome.

Background: In recent years, the right ratio of 2nd and 4th digit length (2D:4D) is regarded as an anatomical marker of prenatal testosterone exposure. Polycystic ovary syndrome (PCOS) is a female masculinized disease and is determined by prenatal testosterone exposure. Whether the ratio in the right hand of PCOS women is reduced or not compared with non-PCOS women is under debate. To further investigate the relationship between PCOS and digit ratio, we systematically measured all the digit ratios. Methods: We recruited 34 non-PCOS women, 116 PCOS women, and 40 men and systematically measured all the ratios of digit length (2D:3D, 2D:4D, 2D:5D, 3D:4D, 3D:5D, and 4D:5D) of right hands and left hands. Results: Left 2D:3D, 2D:4D, and 2D:5D in men were significantly lower than those in non-PCOS women. Significantly lower digit ratios of left 2D:3D and 2D:4D were observed in PCOS compared with non-PCOS women. In the subgroup analysis, the left ratio of digit length in 2D:3D and 2D:5D of the hyperandrogenism subgroup was lower than that of the non-hyperandrogenism subgroup without statistical significance. The logistic regression model of PCOS revealed that 2D:3D, 2D:4D, 2D:5D, and 3D:4D of left hands were statistically related to the diagnosis of PCOS among all the digit ratios. Conclusion: Not only 2D:4D but also other digit ratios, such as 2D:3D and 2D:5D, are a marker of prenatal testosterone exposure and may be an anatomical marker of PCOS. The majority of these significant differences included left 2D, with the following order: non-PCOS women > PCOS women > men.

The Nutritional Intervention Improves the Metabolic Profile of Overweight and Obese PCOS Along with the Differences in Gut Microbiota.

Previous studies had shown that the gut microbiota of polycystic ovary syndrome (PCOS) patients had significant differences from those of healthy individuals, which may play an important role in the pathogenesis of PCOS. Lifestyle intervention, such as nutritional intervention, could improve the metabolic profiles and PCOS-like phenotypes of PCOS patients. Meanwhile, nutritional intervention could rapidly alter and reshape the distribution of gut microbiota in individuals. Therefore, we sought to investigate the differences in gut microbiota in overweight and obese PCOS patients with or without nutritional intervention. Thirty-six overweight and obese PCOS patients were finally enrolled in the study. Eighteen individuals who refused nutritional intervention (RNI) were collected as the RNI group. Eighteen individuals who received the nutritional intervention were collected as the pre-NI group before the nutritional intervention. And they were also collected as the NI group after the nutritional intervention for 4-12 weeks. Significant decreases in BMI, FBG, TC, TG, APO A1, and APO B were observed when comparing the NI group with the pre-NI and RNI groups after the nutritional intervention for 4-12 weeks. Meanwhile, the differences in the phylum Firmicutes, Bacteroidetes, and the species Eubacterium rectale, Flavonifractor plautii, and Bacteroides vulgatus between the NI and the RNI groups were observed, which may be potentially linked to the improved inflammatory state and PCOS-like phenotypes of overweight and obese PCOS individuals.

Development and validation of a CT-based radiomics nomogram for preoperative prediction of tumor histologic grade in gastric adenocarcinoma.

OBJECTIVES: To develop and validate a radiomics nomogram for preoperative prediction of tumor histologic grade in gastric adenocarcinoma (GA). METHODS: This retrospective study enrolled 592 patients with clinicopathologically confirmed GA (low-grade: n=154; high-grade: n=438) from January 2008 to March 2018 who were divided into training (n=450) and validation (n=142) sets according to the time of computed tomography (CT) examination. Radiomic features were extracted from the portal venous phase CT images. The Mann-Whitney U test and the least absolute shrinkage and selection operator (LASSO) regression model were used for feature selection, data dimension reduction and radiomics signature construction. Multivariable logistic regression analysis was applied to develop the prediction model. The radiomics signature and independent clinicopathologic risk factors were incorporated and presented as a radiomics nomogram. The performance of the nomogram was assessed with respect to its calibration and discrimination. RESULTS: A radiomics signature containing 12 selected features was significantly associated with the histologic grade of GA (P<0.001 for both training and validation sets). A nomogram including the radiomics signature and tumor location as predictors was developed. The model showed both good calibration and good discrimination, in which C-index in the training set, 0.752 [95% confidence interval (95% CI): 0.701-0.803]; C-index in the validation set, 0.793 (95% CI: 0.711-0.874). CONCLUSIONS: This study developed a radiomics nomogram that incorporates tumor location and radiomics signatures, which can be useful in facilitating preoperative individualized prediction of histologic grade of GA.

Radiomic Nomogram for Pretreatment Prediction of Pathologic Complete Response to Neoadjuvant Therapy in Breast Cancer: Predictive Value of Staging Contrast-enhanced CT.

INTRODUCTION: The purpose of this study was to predict pathologic complete response (pCR) to neoadjuvant therapy in breast cancer using radiomics based on pretreatment staging contrast-enhanced computed tomography (CECT). PATIENTS AND METHODS: A total of 215 patients were retrospectively analyzed. Based on the intratumoral and peritumoral regions of CECT images, radiomic features were extracted and selected, respectively, to develop an intratumoral signature and a peritumoral signature with logistic regression in a training dataset (138 patients from November 2015 to October 2017). We also developed a clinical model with the molecular characterization of the tumor. A radiomic nomogram was further constructed by incorporating the intratumoral and peritumoral signatures with molecular characterization. The performance of the nomogram was validated in terms of discrimination, calibration, and clinical utility in an independent validation dataset (77 patients from November 2017 to December 2018). Stratified analysis was performed to develop a subtype-specific radiomic signature for each subgroup. RESULTS: Compared with the clinical model (area under the curve [AUC], 0.756), the radiomic nomogram (AUC, 0.818) achieved better performance for pCR prediction in the validation dataset with continuous net reclassification improvement of 0.787 and good calibration. Decision curve analysis suggested the nomogram was clinically useful. Subtype-specific radiomic signatures showed improved AUCs (luminal subgroup, 0.936; human epidermal growth factor receptor 2-positive subgroup, 0.825; and triple negative subgroup, 0.858) for pCR prediction. CONCLUSION: This study has revealed a predictive value of pretreatment staging-CECT and successfully developed and validated a radiomic nomogram for individualized prediction of pCR to neoadjuvant therapy in breast cancer, which could assist clinical decision-making and improve patient outcome.

A CT-based radiomics nomogram for prediction of human epidermal growth factor receptor 2 status in patients with gastric cancer.

OBJECTIVE: To develop and validate a computed tomography (CT)-based radiomics nomogram for predicting human epidermal growth factor receptor 2 (HER2) status in patients with gastric cancer. METHODS: This retrospective study included 134 patients with gastric cancer (HER2-negative: n=87; HER2-positive: n=47) from April 2013 to March 2018, who were then randomly divided into training (n=94) and validation (n=40) cohorts. Radiomics features were obtained from the CT images showing gastric cancer. Least absolute shrinkage and selection operator (LASSO) regression analysis was utilized for building the radiomics signature. A multivariable logistic regression method was applied to develop a prediction model incorporating the radiomics signature and independent clinicopathologic risk predictors, which were then visualized as a radiomics nomogram. The predictive performance of the nomogram was assessed in the training and validation cohorts. RESULTS: The radiomics signature was significantly associated with HER2 status in both training (P<0.001) and validation (P=0.023) cohorts. The prediction model that incorporated the radiomics signature and carcinoembryonic antigen (CEA) level demonstrated good discriminative performance for HER2 status prediction, with an area under the curve (AUC) of 0.799 [95% confidence interval (95% CI): 0.704-0.894] in the training cohort and 0.771 (95% CI: 0.607-0.934) in the validation cohort. The calibration curve of the radiomics nomogram also showed good calibration. Decision curve analysis showed that the radiomics nomogram was useful. CONCLUSIONS: We built and validated a radiomics nomogram with good performance for HER2 status prediction in gastric cancer. This radiomics nomogram could serve as a non-invasive tool to predict HER2 status and guide clinical treatment.

Deep Learning Features Improve the Performance of a Radiomics Signature for Predicting KRAS Status in Patients with Colorectal Cancer.

RATIONALE AND OBJECTIVES: We assess the performance of a model combining a deep convolutional neural network and a hand-crafted radiomics signature for predicting KRAS status in patients with colorectal cancer (CRC). MATERIALS AND METHODS: The primary cohort consisted of 279 patients with clinicopathologically confirmed CRC between April 2011 and April 2015. Portal venous phase computed tomographic images were analyzed to extract traditional hand-crafted radiomics features as well as deep learning features. A Wilcoxon rank sum test, the minimum redundancy maximum relevance algorithm, and multivariable logistic regression analysis were used to select features and build a radiomics signature. A combined model was then developed using multivariable logistic regression analysis. An independent validation cohort of 119 patients from May 2015 to April 2016 was used to confirm the combined model's predictive performance. RESULTS: The C-index of hand-crafted radiomics signature's discriminative ability was 0.719 (95% confidence interval, CI: 0.658-0.776) for the primary cohort and 0.720 (95% CI: 0.625-0.813) for the validation cohort. The C-index of the deep radiomics signature's discriminative ability was 0.754 (95% CI: 0.696-0.813) for the primary cohort and 0.786 (95% CI: 0.702-0.863) for the validation cohort. The combined model, which merged the hand-crafted radiomics features and deep radiomics features, achieve a C-index of 0.815 (95% CI: 0.766-0.868) for the primary cohort and 0.832 (95% CI: 0.762-0.905) for the validation cohort. CONCLUSION: This study presents a model that incorporates the hand-crafted and deep radiomics signature, which can be used for individualized preoperative prediction of KRAS mutations in patients with CRC.

CT-based Radiomics Signature to Discriminate High-grade From Low-grade Colorectal Adenocarcinoma.

RATIONALE AND OBJECTIVES: To develop and validate a computed tomography-based radiomics signature for preoperatively discriminating high-grade from low-grade colorectal adenocarcinoma (CRAC). MATERIALS AND METHODS: This retrospective study was approved by our institutional review board, and the informed consent requirement was waived. This study enrolled 366 patients with CRAC (training dataset: n = 222, validation dataset: n = 144) from January 2008 to August 2015. A radiomics signature was developed with the least absolute shrinkage and selection operator method in training dataset. Mann-Whitney U test was applied to explore the correlation between radiomics signature and histologic grade. The discriminative power of radiomics signature was investigated with the receiver operating characteristics curve. An independent validation dataset was used to confirm the predictive performance. We further performed a stratified analysis to validate the predictive performance of radiomics signature in colon adenocarcinoma and rectal adenocarcinoma. RESULTS: The radiomics signature demonstrated discriminative performance for high-grade and low-grade CRAC, with an area under the curve of 0.812 (95% confidence interval [CI]: 0.749-0.874) in training dataset and 0.735 (95%CI: 0.644-0.826) in validation dataset. Stratified analysis demonstrated that radiomics signature also showed distinguishing ability for histologic grade in both colon adenocarcinoma and rectal adenocarcinoma, with area under the curve of 0.725 (95%CI: 0.653-0.797) and 0.895 (95%CI: 0.838-0.952), respectively. CONCLUSIONS: We developed and validated a radiomics signature as a complementary tool to differentiate high-grade from low-grade CRAC preoperatively, which may make contribution to personalized treatment.

Foraging responses of sheep to plant spatial micro-patterns can cause diverse associational effects of focal plant at individual and population levels.

Multiple-scale foraging decisions by large herbivores can cause associational effects of focal plant individuals neighboured with different species. Spatial micro-patterns between the focal plant and its neighbouring species within patches can affect herbivore foraging selectivity at within- and between-patch scales, which may consequently lead to associational plant effects occurring at both plant individual and population levels. However, these associational effects have not been explored together in the plant-herbivore interaction studies. We aim to evaluate how plant spatial micro-pattern within different quality patches mediate herbivore foraging selectivity, thereby affecting the associational effects of focal plant individuals and population. Using sheep as the model herbivore and a medium preferred species as the focal plant, we conducted a manipulative experiment by allowing sheep grazing freely among three different quality patches, each of which consisted of preferred, unpreferred and focal plant species with different abundances forming spatially aggregated or dispersed micro-patterns. Results showed that, compared with the aggregated plant micro-pattern, dispersed plant micro-patterns within different quality patches increased sheep within-patch selectivity, and caused diverse associational effects of focal plant individuals. Focal plant individuals experienced neighbour contrast defence (i.e. got protection in the high quality patch) and associational defence (i.e. got protection in the low quality patch), respectively, when plants distributed dispersedly in the low and high quality patch. Focal plant individuals simultaneously experienced associational susceptibility (i.e. got damage in the high quality patch) and neighbour contrast susceptibility (i.e. got damage in the low quality patch) when plants distributed dispersedly in the medium quality patch. Furthermore, dispersed plant micro-patterns reduced sheep foraging selectivity between patches, and led to a lower consumption of focal plant population compared with the aggregated plant micro-pattern. Herbivores adopt different within- and between-patch foraging decisions to maintain a high intake of the preferred species in response to various plant micro-patterns, and consequently cause diverse associational effects of both focal plant individuals and population. These associational effects have important implications for understanding the species coexistence and plant community assembly in the grazing ecosystems.

Spatially complex neighboring relationships among grassland plant species as an effective mechanism of defense against herbivory.

Close spatial relationships between plant species are often important for defense against herbivory. The associational plant defense may have important implications for plant community structure, species diversity, and species coexistence. An increasing number of studies have focused on associational plant defense against herbivory at the scale of the individual plant and its nearest neighbors. However, the average neighborhood effects between plant species at the scale of whole plant communities have received almost no attention. The aims of this study were to determine patterns of spatial relationship between different plant species that can provide effective defense against herbivory. We conducted a manipulative experiment using sheep and three native plant species with different palatability. Consumption of palatable plants by herbivores was largest when the three plant species were isolated in three patches and independent of each other. A homogenous and spatially equal neighbor relationship between the three species did not reduce the risk of herbivory of palatable species compared to isolation of these species, but it reduced the total intake of all plant species. The palatable species was subject to less herbivory in a complex spatial neighborhood of several plant species. High complexity of spatial neighborhood resulted in herbivores passively reducing selectivity, thereby reducing the probability of damage to palatable species in the community, or making inaccurate judgments in foraging selectivity between and within patches, thereby reducing the vulnerability of palatable plants and even the whole plant community. We conclude that compelling herbivores to passively reduce the magnitude of foraging selectivity by establishing spatially complex neighborhoods between plant species is a compromise and optimal spatial strategy by plants to defend themselves again herbivory. This may contribute not only to maintenance of plant species diversity but also to a stable coexistence between herbivores and plants in grassland ecosystems.