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Dietary inflammatory index, inflammation biomarkers and preeclampsia risk: a hospital-based case–control study

Published online by Cambridge University Press:  18 May 2022

Yan-hua Liu
Affiliation:
Department of Nutrition, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, People’s Republic of China
Lu Zheng
Affiliation:
Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, No.601 Huangpu Road West, Guangzhou 510632, Guangdong, People’s Republic of China
Chen Cheng
Affiliation:
Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, No.601 Huangpu Road West, Guangzhou 510632, Guangdong, People’s Republic of China
Shu-na Li
Affiliation:
Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, No.601 Huangpu Road West, Guangzhou 510632, Guangdong, People’s Republic of China
Nitin Shivappa
Affiliation:
Cancer Prevention and Control Program, University of South Carolina, Columbia, USA; Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, USA; Connecting Health Innovations LLC, Columbia, USA
James R. Hebert
Affiliation:
Cancer Prevention and Control Program, University of South Carolina, Columbia, USA; Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, USA; Connecting Health Innovations LLC, Columbia, USA
Wen-jun Fu
Affiliation:
Department of Obstetrics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, People’s Republic of China
Xian-lan Zhao
Affiliation:
Department of Obstetrics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, People’s Republic of China
Yuan Cao
Affiliation:
The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, People’s Republic of China
Wei-feng Dou
Affiliation:
Department of Nutrition and Food Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450000, Henan, People’s Republic of China
Hua-nan Chen
Affiliation:
Department of Nutrition and Food Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450000, Henan, People’s Republic of China
Dan-dan Duan
Affiliation:
Department of Clinical Nutrition, Luoyang New Area People’s Hospital, Luoyang 471023, Henan, People’s Republic of China
Quan-jun Lyu
Affiliation:
Department of Nutrition, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, People’s Republic of China Department of Nutrition and Food Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450000, Henan, People’s Republic of China
Fang-fang Zeng*
Affiliation:
Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, No.601 Huangpu Road West, Guangzhou 510632, Guangdong, People’s Republic of China
*
* Corresponding author: Fang-fang Zeng, email zengffjnu@126.com
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Abstract

This study evaluated the association between inflammatory diets as measured by the Dietary Inflammatory index (DII), inflammation biomarkers and the development of preeclampsia among the Chinese population. We followed the reporting guidelines of the Strengthening the Reporting of Observational Studies in Epidemiology statement for observational studies. A total of 466 preeclampsia cases aged over 18 years were recruited between March 2016 and June 2019, and 466 healthy controls were 1:1 ratio matched by age (±3 years), week of gestation (±1 week) and gestational diabetes mellitus. The energy-adjusted DII (E-DII) was computed based on dietary intake assessed using a seventy-nine item semiquantitative FFQ. Inflammatory biomarkers were analysed by ELISA kits. The mean E-DII scores were −0·65 ± 1·58 for cases and −1·19 ± 1·47 for controls (P value < 0·001). E-DII scores positively correlated with interferon-γ (r s = 0·194, P value = 0·001) and IL-4 (r s = 0·135, P value = 0·021). After multivariable adjustment, E-DII scores were positively related to preeclampsia risk (P trend < 0·001). The highest tertile of E-DII was 2·18 times the lowest tertiles (95 % CI = 1·52, 3·13). The odds of preeclampsia increased by 30 % (95 % CI = 18 %, 43 %, P value < 0·001) for each E-DII score increase. The preeclampsia risk was positively associated with IL-2 (OR = 1·07, 95 % CI = 1·03, 1·11), IL-4 (OR = 1·26, 95 % CI = 1·03, 1·54) and transforming growth factor beta (TGF-β) (OR = 1·17, 95 % CI = 1·06, 1·29). Therefore, proinflammatory diets, corresponding to higher IL-2, IL-4 and TGF-β levels, were associated with increased preeclampsia risk.

Type
Research Article
Copyright
© The Author(s), 2022. Published by Cambridge University Press on behalf of The Nutrition Society

Preeclampsia is one of the gestational complications that leads to maternal and neonatal morbidity and mortality(Reference Farhat, Zafar and Sheikh1). It has been reported that approximately 2–8 % of first pregnancies are diagnosed with preeclampsia(Reference Valencia-Ortega, Zarate and Saucedo2). Pregnant woman with preeclampsia generally has a higher risk of adverse outcomes. For instance, respiratory distress syndrome and pneumonia in newborn infants have been reported in a Chinese large-prospective cohort study(Reference Tian, Wang and Ye3). In addition, there were about 2·57 times of odds of preterm birth in women with preeclampsia(Reference Omani-Samani, Ranjbaran and Amini4).

The aetiology of preeclampsia has not yet been fully clarified; however, the hypothesis is that a deficiency of restoring uterine spiral arteries from incomplete placental implantation is the primary causative factor of this disorder(Reference Valencia-Ortega, Zarate and Saucedo2). This disruption promotes placental ischaemia and contributes to more cellular oxidative stress, which is reflected by the release of soluble fms-like tyrosine kinase-1 and proinflammatory cytokine such as TNF-α. Moreover, studies found that the shift towards M1 phenotype leads to strong synthesis of proinflammatory cytokines that would enhance trophoblastic apoptosis(Reference Huppertz and Kingdom5). The overexpression of Th1 proinflammatory cytokines such as TNF-α, interferon gamma (IFN-γ) and IL-2 is associated with preterm delivery and intrauterine growth retardation(Reference Arababadi, Aminzadeh and Hassanshahi6,Reference Raghupathy, Alazemi and Azizieh7) . The upregulation of other proinflammatory cytokines, such as IFN-γ, IL-2 and IL-17, and the downregulation of anti-inflammatory cytokines, including IL-4, IL-10 and transforming growth factor beta (TGF-β), are eventually detected in preeclampsia(Reference Ribeiro, Romao-Veiga and Romagnoli8Reference Garcia, Mobley and Henson10).

More recent studies have focused on some interactions between nutrients and the possible impact of overall dietary habits on chronic systematic inflammation. Higher consumption of dietary fibre, vitamins (e.g. vitamin C, vitamin A and vitamin D), minerals (e.g. Ca, phosphorus, potassium and Mg) and MUFA and PUFA are examples of antioxidant nutrients(Reference Moosavian, Rahimlou and Saneei11), while SFA and cholesterol have some inflammation-promoting properties(Reference Rahimlou, Asadi and Banaei Jahromi12). Unfortunately, since we eat foods as a mixture of numerous nutrients, only focusing on some particular nutrients and diseases may miss much crucial information about their casual relationships. In fact, a systematic review and meta-analysis found that adequate vegetable and fruit intake could lower the risk of preeclampsia and reduce proteinuria(Reference Mi, Wen and Li13).

Based on the inflammatory properties of nutrients, the Dietary Inflammatory Index (DII) was first developed in 2014 by Shivappa et al. (Reference Shivappa, Steck and Hurley14) to evaluate the inflammatory properties of the diet from maximally anti- to proinflammatory by using a variety of dietary assessment tools such as 24-h recall, FFQ or 3-d food records(Reference Vadell, Brebring and Hulander15,Reference Shivappa, Steck and Hurley16) . SFA, retinol, processed meat, full-fat dairy, refined grain, sweets, desserts, carbonated beverages and sugar-sweetened beverages are examples of proinflammatory foods with a higher DII score(Reference Asadi, Yaghooti-Khorasani and Ghazizadeh17,Reference Bodén, Wennberg and Guelpen18) . Nuts, fruits, vegetables, whole grains, fish and olive oil are characterised as anti-inflammatory foods(Reference Asadi, Yaghooti-Khorasani and Ghazizadeh17). Higher DII scores and proinflammatory diets were reported to be associated with 2·12 times higher odds of miscarriage, with a corresponding increase in IL-6(Reference Vahid, Shivappa and Hekmatdoost19).

Recent studies have been published on the association between the DII and the risk of inflammatory-mediated noncommunicable chronic diseases as well as mortality(Reference Farazi, Jayedi and Shab-Bidar20). Based on our knowledge, however, no study has evaluated the potential of diets that are classified by the overall energy-adjusted dietary inflammatory index (E-DII) on the risk of preeclampsia. Therefore, this study aimed to explore the association between inflammatory diets as measured by the E-DII and the development of preeclampsia in a hospital-based population among the Chinese population in Henan province.

Methods

Study population and study design

This study was performed between March 2016 and June 2019 at the First Affiliated Hospital of Zhengzhou University, China. Full details about the study design have been published in previous studies(Reference Cao, Liu and Zhao21Reference Li, Liu and Luo23). In particular, a total of 466 cases with a ratio of 1:1 matched for case control were enrolled. The inclusion criteria were women aged over 18 years with at least 28 weeks of gestation with a singleton pregnancy. The presence of preeclampsia among the cases was defined on China’s ‘Diagnosis and treatment guideline of hypertensive disorders in pregnancy, 2015’ guideline(Reference Xiao, Fan and Zhu24). According to this guideline, cases of incident preeclampsia were identified as having systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg after the 20th week of pregnancy and met any of the following criteria: (1) urinary protein ≥ 0·3 g/24 h, urinary protein/creatinine ratio ≥ 0·3 or random urinary protein ≥ (+) (as the examination for quantitative urine protein cannot be carried out in pregnant women) and (2) nonalbuminuria but with damage to organs or systems such as the heart, lung, liver, kidney and other important organs, or abnormal changes in the blood system, digestive system, nervous system and placental–fetal involvement.

The controls recruited corresponding to the cases were women who were preparing for delivery, had never been diagnosed with hypertension or albuminuria and were matched with the cases for age (±3 years), week of gestation (±1 week) and gestational diabetes mellitus. The following exclusion criteria were applied to both groups: (1) being diagnosed with heart disease, malignancy, hyperthyroidism, immune system diseases, chronic renal insufficiency and other endocrine system diseases and (2) having epilepsy, depression and other mental or cognitive dysfunction.

Ethics

The study protocol including other study-related documents was run under the Declaration of Helsinki guidelines and was approved by the Ethics Committee of Scientific Research and Clinical Trials of the First Affiliated Hospital of Zhengzhou University. The informed consent form for participation in the study was signed by all participants before any epidemiological data and biological specimens were obtained. Data collection followed the reporting guidelines of the Strengthening the Reporting of Observational Studies in Epidemiology statement for observational studies.

Dietary assessment

A validate and reproducible seventy-nine item semiquantitative FFQ was used to collect information about the participants diet during the past 3 months prior to the study period(Reference Zhang and Ho25). The definition of the food groups has been described in detail in a previous study(Reference Zhang and Ho25). Each food item asked participants to report how often, on average, they had consumed it for frequency range from never, per day, per week and per month. A photobook with different food portion sizes was provided for more precisely estimating the quantity of food intake. Nutrients and energy analyses were derived by the China Food Composition Tables 2009, which includes the nutrient portion and energy of each food item(Reference Yuexin, Guangya and Xingchang26).

Dietary inflammatory index

To compute the DII score, we used the method described in Shivappa et al. (Reference Shivappa, Steck and Hurley14). Briefly, the literature published from 1950 to 2010 with 1943 articles determined the association of forty-five food parameters in total for at least one of six inflammatory factors. Scores of –1, +1 and 0 were assigned if the effects were significantly decreased, increased or nonsignificant changes, respectively, of inflammatory biomarkers including IL-1β, IL-6, TNF or C-reactive protein. E-DII scores were calculated using the nutrient density method in which all food parameters were converted to per 1000 kcal of nutrients. In this study, thirty-five available food parameters from the FFQ were used to calculate the E-DII score and included the following nutrients: energy, carbohydrate, protein, total fat, cholesterol, fatty acids, SFA, MUFA, PUFA, n-3 fats, n-6 fats, soluble fibre, carotene, β-carotene, total carotenoids, thiamin, riboflavin, niacin, vitamin C, vitamin A, vitamin E, vitamin D, vitamin B6, vitamin B12, folic acid, Mg, Fe, Zn, Se, total anthocyanidins, total flavonoids, total flavan-3-ol, total flavanones, total flavones and total flavonols. Higher E-DII scores indicate a more proinflammatory diet, whereas lower scores represent a more anti-inflammatory diet.

Laboratory evaluation

A 12-h overnight fasting blood sample was collected from all participants. The serum was obtained by centrifugation at 3000 rpm at 4°C for 15 min and stored at –80°C for further analysis(Reference Cakmak, Dincgez Cakmak and Abide Yayla27). Inflammatory biomarkers were measured in this study using ELISA kits, including TNF-α, IFN-γ, TGF-α and IL -2, -4, -10 and -17A. The Th1/Th2 and Th17/Treg ratios were also determined.

Assessment of covariates

Demographic characteristics included age, gestational age (weeks), education level (primary school or less, secondary/high school, college/university or above) and average monthly household income (≤ 2000, 2000–4000, 4000–6000 and > 6000 RMB). Lifestyle habits included passive smoking (yes or no), alcohol drinking status and dietary supplements used during the 3 months before pregnancy (yes or no) and physical activity (MET-h/d). Medical conditions, including pre-pregnancy BMI (kg/m2) and blood pressure (systolic blood pressure and diastolic blood pressure, mmHg), were collected via face-to-face interview of each case or control.

Statistical analysis

Descriptive statistics were used to summarise the characteristics of the participants. Continuous normally distributed variables are expressed as the mean ± sd . The Kolmogorov–Smirnoff test was used to test the normality of the data. Skewed distribution continuous variables are expressed as medians and interquartile ranges. Categorical variables are expressed as frequencies or percentages. The general characteristics of the cases and controls were compared using a paired t test for continuous variables with a normal distribution, whereas the Wilcoxon signed-ranks test was used for nonnormally distribution. The Pearson χ 2 test was applied to compare all categorical data. Tertiles of E-DII scores were calculated based on the distribution of E-DII among controls. For every distribution of the food groups, energy was adjusted prior to comparison across tertiles of the E-DII and the Kruskal–Wallis H test was used. The correlation among nutrients, E-DII and inflammatory biomarkers was performed by Spearman’s correlation coefficient. Binary logistic regression analysis was performed to estimate the association between inflammatory markers and preeclampsia risk. To determine the risk of preeclampsia, the E-DII was analysed as both a categorical and a continuous variable, and the OR and 95 % CI were estimated using conditional logistic regression with different models. The first model was adjusted for age. The second model was fully adjusted for age, gestational age (weeks), pre-pregnancy BMI (kg/m2), passive smoking (yes or no), alcohol drinking status and dietary supplements used during the 3 months before pregnancy (yes or no), physical activity (MET-h/d) and energy intake (kcal/d).

All tests were two-sided, and a P value < 0·05 was considered statistically significant. Data were analysed using SPSS version 2.0 (IBM Corp).

Results

The mean age was 30·88 ± 5·00 and 31·00 ± 4·85 in the case and control groups, respectively (Table 1). Cases had significantly higher E-DII scores than controls, of which the means and SD were −0·65 ± 1·58 and −1·19 ± 1·47, respectively (P value < 0·001) (Table 1). Cases with preeclampsia were statistically more likely to have a higher pre-pregnancy BMI, systolic pressure and diastolic pressure. Furthermore, compared with the controls, cases with preeclampsia were more likely to have primary school or less and were also passive smokers and active alcohol drinkers (Table 1).

Table 1. Characteristics of cases and controls

(Mean values and standard deviations)

Test for differences of case and control using a paired t test for normally distributed continuous variables; Wilcoxon signed-ranks test for skewed distributed continuous variables; χ 2 test for categorical variables; P value < 0·05 indicates significant difference.

Values are presented as mean (sd) for continuous variables; number (%) for categorical variables.

Drinking status refers to alcohol consumption during the 3 months before pregnancy.

Physical activities included daily occupational, leisure time and household chores, evaluated by metabolic equivalent (MET) hours per day.

With respect to the controls, subjects with preeclampsia had significantly higher IL-4 (2·05 ± 1·51 v. 1·64 ± 1·09, P value =0·008) and TGF-β (12·43 ± 7·77 v. 9·13 ± 4·72, P value = 0·004) levels (Table 2). Moreover, the Th1/Th2 ratios in preeclampsia were significantly higher than those in healthy pregnancy for both TNF-α/IL-10 ratios (1·99 ± 2·11 v. 0·68 ± 9·25, P value =0·039) and IL2/IL-10 ratios (1·95 ± 1·91 v. 0·59 ± 6·12, P value =0·035) (Table 2). The levels of proinflammatory cytokines, including TNF-α, IFN-γ, IL-2 and IL-17, were not significantly different between preeclampsia cases and controls (Table 2).

Table 2. Comparison of inflammatory biomarkers between cases and controls

(Mean values and standard deviations)

IQR, interquartile range; Th, helper T cells; Treg, regulatory T cells; IFN-γ, interferon gamma; TGF-β, transforming growth factor beta.

Test for differences of case and control using Wilcoxon signed-ranks test; P value < 0·05 indicates significant difference.

While the consumption of total grains significantly increased across tertiles, the consumption of leafy vegetables, starchy vegetables and fruits as well as fish and seafood was significantly decreased in the preeclampsia cases (P value < 0·001) (Table 3). Whole-grain consumption also decreased across the tertiles of E-DII scores; nevertheless, no significant difference was observed. Similar trends in the consumption of total grains across tertiles were found in the controls (P value < 0·001) (Table 2). In contrast to preeclampsia cases, with respect to the first tertiles of the E-DII scores, healthy pregnancy in the third tertiles of the E-DII scores had significantly lower whole-grain, poultry and red meat intake (P value < 0·001) (online Supplementary Table 1).

Table 3. Distribution of food groups across tertiles of energy-adjusted dietary inflammatory index (E-DII) for preeclampsia cases

(Median values and interquartile range, n 466)

IQR, interquartile range.

Comparison of food groups across tertiles of energy adjusted-dietary inflammatory index (E-DII) by using Kruskal–Wallis H test; P value < 0·05 indicates significant difference.

All foods groups were calculated by edible portions; total grains, whole grains, nuts and seeds were calculated by dry uncooked weights.

Dairy and products included fresh whole and skim cow’s milk, yogurt, butter, cheese and ice cream.

Regarding the controls, subjects with preeclampsia had significantly greater consumption of tubers, whereas consumption of leafy and starchy vegetables, nuts and seeds, fruits, dairy products, eggs, fish and seafood, poultry and red meat was significantly lower (all P values < 0·05) (online Supplementary Table 2). In addition, the lower levels of soluble fibre, protein, cholesterol, Ca, Mg, Fe, Zn, Se, β-carotene, vitamins A, C, D, E, B6 and B12, as well as folate and total flavonoids in preeclampsia were extremely significantly different from those in healthy pregnancies (all P values < 0·05) (online Supplementary Table 2).

The correlations among the E-DII score, inflammatory biomarkers, food groups and nutrients are shown in Supplementary Tables 3 and 4. E-DII scores showed a significant positive correlation with IFN-γ (r s = 0·194, P value = 0·001) and IL-4 (r s = 0·135, P value = 0·021). The correlation between E-DII scores and food groups revealed that while increasing intake of total grains provided significantly higher E-DII scores (P value < 0·001), whole grains, leaves and starchy vegetables, nuts and seeds, fruits, eggs, fish and seafood, poultry and red meat were significantly inversely correlated with the E-DII scores (P value < 0·001). In particular, total fat, SFA, MUFA, PUFA, Se and vitamin E presented significantly higher E-DII scores (all P values < 0·05). Th1 cytokine profiles such as TNF-α, IFN-γ, IL-2 and IL-17A were negatively correlated with leafy vegetables, fish and seafood, poultry, soluble fibre, Mg, β-carotene, vitamins A, C, B6, folate, total anthocyanidins and total flavonoids at a significant level (all P values < 0·05).

Participants whose E-DII belonged to the highest tertile, the most proinflammatory group, were 2·10 times more likely to have preeclampsia than those in the lowest tertiles, the most anti-inflammatory group (age-adjusted OR = 2·10, 95 % CI = 1·53, 2·89, P trend < 0·001) (Table 4). Similarly, when further adjusting was conducted for all possible covariances, there was a 2·18-fold risk of being preeclampsia for those in the highest tertile of E-DII compared with those in the lowest tertiles (full-adjusted OR = 2·18, 95 % CI = 1·52, 3·13, P trend < 0·001) (Table 4). Significant positive associations between the continuous E-DII score and preeclampsia risk in the age-adjusted model and full-adjusted model were simultaneously observed (age-adjusted OR = 1·26, 95 % CI = 1·16, 1·38, P value < 0·001; full-adjusted OR = 1·30, 95 % CI = 1·18, 1·43, P value < 0·001) (Table 4).

Table 4. OR and 95 % CI for association between the energy-adjusted dietary inflammatory index (E-DII) and the risk of preeclampsia

(Odd ratio and 95 % confidence intervals)

Crude and adjusted OR and 95 %CI were obtained from conditional logistic regression model by entering method; P value or P trend < 0·05 indicates significant difference.

Model 1 = Adjusted for age.

Model 2 = Fully adjusted for age, gestational age (weeks), pre-pregnancy BMI (kg/m2), education level (primary school or less, secondary/high school, college/university or above), passive smoking (yes or no), drinking status and dietary supplements used (e.g. vitamin D, Ca, Ca plus vitamin D, Fe, folic acid and multivitamin supplements) during the 3 months before pregnancy (yes or no), physical activity (MET-h/d) and energy intake (kcal/d).

The OR, 95 % CI and P values for the preeclampsia risk of inflammatory biomarkers are given in Table 5. After full adjustment for confounding factors, for every one-unit (mg/dl) increase in IL-2, IL-4 and TGF-β, there was a significant corresponding increase in the risk of developing preeclampsia by 7 % (95 % CI = 3 %, 11 %, P value = 0·001), 26 % (95 % CI = 3 %, 54 %, P value = 0·024) and 17 % (95 % CI = 6 %, 29 %, P value =0·002), respectively. However, TNF-α, IFN-γ, IL-10 and IL-17A were not associated with preeclampsia risk.

Table 5. Binary logistic regression analysis according to the association between the inflammatory biomarkers and preeclampsia

(Odd ratio and 95 % confidence intervals, n 466)

β, beta estimate; se, standard error; IFN-γ, interferon gamma; TGF-β, transforming growth factor beta; P value < 0·05 indicates significant difference.

All values adjusted for age, gestational age (weeks), pre-pregnancy BMI (kg/m2), education level (primary school or less, secondary/high school, college/university or above), passive smoking (yes or no), drinking status and dietary supplements used (e.g. vitamin D, Ca, Ca plus vitamin D, Fe, folic acid and multivitamin supplements) during the 3 months before pregnancy (yes or no), physical activity (MET-h/d) and energy intake (kcal/d).

The β estimate represents the change of each outcome per each 1-unit increase in inflammatory biomarkers.

Discussion

Our case–control study indicated a positive association between the E-DII, as well as inflammation markers (e.g. IL-2, IL-4 and TGF-β), and the risk of preeclampsia. Considering that the E-DII is a sensitive index for inflammatory markers, it can be inferred that lowering the intake of proinflammatory foods with high E-DII scores and increasing the consumption of anti-inflammatory foods with low-EDII scores would be negatively associated with the development of preeclampsia.

Recent studies found some relationship of different food types and intakes amount to pregnancy-related adverse outcomes(Reference Farazi, Jayedi and Shab-Bidar20). Our study is consistent with others that found when compared with the lowest quartile, participants who were more adherent to an unhealthy dietary pattern had a higher risk of preeclampsia, while those in the top quartile of adherence to a healthy dietary pattern had a decreased preeclampsia risk(Reference Hajianfar, Esmaillzadeh and Feizi28). In this study, an unhealthy dietary pattern was defined as consuming high amounts of processed meat, high GI foods, potatoes, legumes, high-fat dairy, whole-grain and soft drinks, whereas the healthy dietary pattern included more vegetables, poultry, red meat, eggs and unsaturated fat(Reference Hajianfar, Esmaillzadeh and Feizi28). A systematic review and meta-analysis showed that frequently consuming vegetables, fruits, legumes and whole-grains significantly reduced adverse pregnancy outcomes(Reference Kibret, Chojenta and Gresham29). Similarly, high plant-based food and vegetable oil consumption decreased preeclampsia risk, while processed meat, salty snacks and sweet drinks were positively correlated with the odds of preeclampsia in another study(Reference Brantsaeter, Haugen and Samuelsen30). Nevertheless, a cluster randomised controlled trial conducted in northwestern China concluded that only vegetable-type dietary patterns were inversely related to preeclampsia(Reference Mi, Wen and Li13).

All of these publications emphasised the relationship between diet and the development of preeclampsia through a crucial mediator called inflammation. Levels of serum inflammatory biomarkers such as C-reactive protein, IL-2, IL-4, IL-10 and IL-17A, TNF-α, transforming growth factor beta (TGF-β), interferon (IFN-γ), adiponectin, etc., are able to indicate the level of systematic inflammation and explain the pathogenesis of diseases(Reference Navarro, Shivappa and Hebert31).

The aetiology of preeclampsia is hypothesised to involve chronic immune activation or oxidative stress, which is attributed to impaired implantation, leading to an imbalance in the production of proinflammatory and regulatory cytokines. This imbalanced secretion during the gestational period might be the primary causative factor of preeclampsia. In general, regulatory T cell (Treg) proliferation triggered by TGF-β is induced by natural killer cells, resulting in increased maternal tolerance towards the fetus(Reference Cornelius32). In addition, M2 phenotype macrophages promote the releases of the Th2 cytokines TGF-β, IL-4 and IL-10, which occurs in successful pregnancy(Reference Cornelius32). In contrast, pregnancies with preeclampsia have limited trophoblast invasion that leads to narrow blood vessels, developing ischaemia and hypoxia in the placenta. Moreover, the activation of Th1 cells through the production of TNF-α, IL-6 and IFN-γ also occurs in preeclampsia(Reference Cornelius32). Apart from that, the expansion of Th1 and Th17 cells is responsible for triggering inflammation. Among women with a healthy pregnancy, Th1/Th17 activity is suppressed by the proliferation of Tregs; however, this activity seems to be higher in preeclampsia(Reference Saito, Nakashima and Shima33).

Previous studies, including a systematic and meta-analysis study, have observed associations between cytokines and the risk of preeclampsia, indicating women are at a higher risk of preeclampsia when their proinflammatory cytokines TNF-α, IFN-γ, IL-2 and IL-17 are elevated and their anti-inflammatory cytokine IL-4, IL-10 and TGF-β are depressed(Reference Aggarwal, Jain and Mittal34,Reference Nath, Cubro and Mccormick35) . These results might be attributed to the depletion of Th2 cells and Tregs in preeclampsia cases(Reference Zhang, Liu and Tian36). The decrease in Treg induces apoptosis in trophoblast cells, which limit the invasion of trophoblast cells and remodel the maternal spiral artery(Reference Nath, Cubro and Mccormick35). Placental ischaemia and hypoxia increase systematic oxidative stress and stimulate pro-inflammatory cytokine secretion as mentioned above.

Moreover, immune cell differentiation and proliferation are influenced by the presence of cytokines, for instance, the presence of IL-6 promoted Th17 cell differentiation while inhibiting Treg cells(Reference Bellos, Karageorgiou and Kapnias37). At the same time, the IL-17 cytokine produced by Th17 cells could increase the production of IL-6 cytokines(Reference Hosseini, Dolati and Hashemi38). These findings are partly in line with our study, which also showed a significant positive relationship between IL-2 and preeclampsia. However, the association between IL-4 and TGF-β and preeclampsia found in this study was inconsistent with other studies: increasing IL-4 and TGF-β significantly corresponded to an increase in preeclampsia. Since the serum levels of cytokines vary, depending on the condition of the pathology(Reference Clausen, Djurovic and Reseland39), these contradictory reports are probably due to differences in gestational age at sampling, differences in sample size, the severity of the condition, population diversities among studies and variations in blood collection and laboratory processing. Moreover, the half-life of the cytokines could also contribute to discrepancies among studies(Reference Cemgil Arikan, Aral and Coskun40).

To provide a further explanation for these findings, DII scores were adapted to explain the underlying strategies, since DII scores are based on dietary data sets collected from a dietary survey among the participants in that study, hence they could reflect the activation of oxidative stress and the inflammatory immune response related to specific food parameters(Reference Canto-Osorio, Denova-Gutierrez and Sanchez-Romero41). The production of TNF-α, IFN-γ, IL-2 and IL-6 is mediated by proinflammatory diets high E-DII foods, corresponding with higher intake of refined grains, dairy products, red meats, soft drinks, sweets and desserts and lower consumption of whole grains, vegetables and fruits(Reference Xu, Wan and Feng42Reference Esmaillzadeh, Kimiagar and Mehrabi44). Nevertheless, the consumption of red meat across tertiles E-DII among cases in this study was parallel. The effects of red meat and dairy products on inflammation are still controversial. A systematic review and meta-analysis of randomised controlled trials found that high dairy product intake significantly decreased TNF-α and IL-6 levels(Reference Moosavian, Rahimlou and Saneei11). Moreover, vegetables and fruits, low E-DII foods, contain antioxidant compounds such as β-carotene, polyphenols and vitamins C and E. High antioxidants content in these serum and placenta prevents hypoperfusion, thus protecting against preeclampsia development(Reference Grum, Hintsa and Hagos45). In addition, flavonoids and β-carotene inhibit the progression of inflammation through the reduction of free oxidative agents and IL-6 and TNF-α production(Reference Willcox, Ash and Catignani46,Reference Kim, Kim and Kim47) .

Some limitations need to be taken into account in the interpretation of our results. First, the present study is a case–control study, and a FFQ was used for dietary assessment in this study, so recall bias might exist. Second, since this study is a case–control study, selection bias is inevitable; however, we could reduce differences in socio-demographic information between two groups, ensure the comparability between two groups and reduce the risk of selection bias by recruiting cases and controls from the same referral hospital. Another limitation is that smaller samples with available inflammatory biomarkers were provided in our study; therefore, there is insufficient information about whether inflammation specifically mediates the association between a proinflammatory diet during pregnancy and preeclampsia. Our results indicate that E-DII scores were associated with greater IFN-γ, which supports the hypothesis that diets induce preeclampsia via systematic inflammation. However, the association between the E-DII and preeclampsia risk remains to be confirmed in prospective analysis.

Conclusion

Individuals with higher E-DII scores and higher IL-2, IL-4 and TGF-β cytokines were associated with increased preeclampsia risk. Additional prospective studies are recommended to confirm our results.

Acknowledgements

We are grateful to the staff at the First Affiliated Hospital of Zhengzhou University in China for technical and material support.

This study is funded by National Natural Science Foundation of China (Grant No. 81602852).

Y. L. and F. Z. contributed to conception and design of the study and manuscript revision. L. Z. wrote the manuscript; C. C. supervised the statistical analyses. S. L. performed data cleaning.  N. S. and J. H. performed E-DII scores. W. F., X. Z., Y. C., W. D., H. C., D. D. and Q. L. made a great contribution to the revised work. All authors have reviewed and approved the manuscript.

The authors have no conflicts of interest to declare.

Supplementary material

For supplementary material/s referred to in this article, please visit https://doi.org/10.1017/S0007114522001489

Footnotes

These authors contributed equally to this work

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Figure 0

Table 1. Characteristics of cases and controls(Mean values and standard deviations)

Figure 1

Table 2. Comparison of inflammatory biomarkers between cases and controls(Mean values and standard deviations)

Figure 2

Table 3. Distribution of food groups across tertiles of energy-adjusted dietary inflammatory index (E-DII) for preeclampsia cases(Median values and interquartile range, n 466)

Figure 3

Table 4. OR and 95 % CI for association between the energy-adjusted dietary inflammatory index (E-DII) and the risk of preeclampsia(Odd ratio and 95 % confidence intervals)

Figure 4

Table 5. Binary logistic regression analysis according to the association between the inflammatory biomarkers and preeclampsia(Odd ratio and 95 % confidence intervals, n 466)

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