Abstract
Objective: To investigate the correlation of serum vitamin A and vitamin E levels with the occurrence and severity of preeclampsia. Methods: The clinical data of 5,000 pregnant women in our hospital were retrospectively studied. Five hundred and sixty-five pregnant women with preeclampsia were divided into a mild group (259 cases) and a severe group (306 cases). The rest 4435 healthy pregnant women were classified as the healthy group. The concentrations of serum vitamin A and vitamin E in each group were compared to analyze the risk factors for preeclampsia. Results: The levels of vitamin A and vitamin E were negatively correlated with the severity of preeclampsia (P<0.001). The logistic regression analysis showed that older age (OR=1.674), vitamin A deficiency (OR=2.463) and vitamin E deficiency (OR=2.206) were independent risk factors for preeclampsia (all P<0.05). Conclusion: Older age, vitamin A deficiency and vitamin E deficiency are the risk factors for preeclampsia. The concentrations of vitamin A and vitamin E are negatively correlated with the severity of preeclampsia. Vitamin A and vitamin E deficiencies in preeclampsia can increase the risk of adverse pregnancy outcomes, which needs timely intervention.
Keywords: Vitamin A, vitamin E, pregnant woman, preeclampsia, correlation, pregnancy outcome
Introduction
Preeclampsia is a multi-organ and multi-system dysfunction syndrome that occurs after 20 weeks of pregnancy, manifested as hypertension, proteinuria and edema. It is an idiopathic disease during pregnancy, with an incidence of 2%-5% worldwide and about 9.4% in China [1,2]. Vitamin A and vitamin E are fat soluble vitamins, participating in the metabolic processes. They are also non-enzymatic strong antioxidants, which have a scavenging effect on oxygen free radicals [3]. At present, the pathogenesis of preeclampsia has not been fully elucidated. It is generally believed that preeclampsia is related to the insufficient uterine spiral artery remodeling, genetic factors and excessive oxidative stress [4,5]. Levels of vitamin A and E in preeclampsia patients have recent been found to be lower than those of healthy pregnant women. Therefore, it is speculated that vitamin A and vitamin E are closely related to the occurrence and development of preeclampsia [6,7]. Vitamin A and vitamin E play an important role in antioxidation. Deficiency of vitamin A and vitamin E may lead to oxidative stress response, which mediates the endothelial damage involved in the basic pathophysiological process of preeclampsia [8-10]. However, the relationship between vitamin A, vitamin E and preeclampsia and whether deficiency of vitamin A or vitamin E causes preeclampsia remain elusive. In this study, 5,000 pregnant women in the Department of Obstetrics at our hospital were enrolled, so as to compare the serum vitamin A and vitamin E concentrations in healthy pregnant women and those with preeclampsia, and to analyze the correlation of vitamin A and vitamin E concentrations with preeclampsia.
Materials and methods
General information
The clinical data of 5,000 pregnant women admitted to our hospital from December 2017 to December 2019 were retrospectively studied. Five hundred and sixty-five pregnant women with preeclampsia were divided into a mild group (259 cases) and a severe group (306 cases). The remaining 4,435 healthy pregnant women were classified as a healthy group.
Diagnostic criteria for preeclampsia: Pregnant women met the diagnostic criteria for preeclampsia in Obstetrics and Gynecology [11]; pregnant women had a normal basic blood pressure before pregnancy, but experienced hypertension after 20 weeks of gestation (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg); pregnant women experienced 24 h urine protein ≥0.3 g or random urine protein (+); pregnant women experienced no urine protein but abnormal changes of vital organs, nervous system, blood system, etc., affecting the placenta and fetus. Patients with one or more of the following conditions was considered to have severe preeclampsia: systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥110 mmHg; 24 h urine protein ≥5.0 g or random urine protein (++); new-onset central nervous system abnormalities or visual impairment; platelet <100×109/L; liver function damage; persistent epigastric pain; abnormal renal function; hypoproteinemia combined with pleural effusion or peritoneal effusion; fetal growth restriction or oligohydramnios; heart failure and pulmonary edema.
The inclusion criteria of preeclampsia group were: Pregnant women who were 18-40 years old; pregnant women whose serum vitamin A and vitamin E levels were detected at 12 weeks of gestation; pregnant women with a live singleton; pregnant women who underwent regular prenatal examination and delivery in our hospital; pregnant women who did not take multivitamins before enrollment; pregnant women without smoking or drinking history. The exclusion criteria of preeclampsia group were: pregnant women with gestational diabetes mellitus; pregnant women with combined with autoimmune diseases; pregnant women with a history of thrombosis; pregnant women with a history of malignant tumor; pregnant women combined with systemic acute and chronic infection; pregnant women combined with iron deficiency anemia. The inclusion criteria of healthy group were: pregnant women who were 18-40 years old; pregnant women whose serum vitamin A and vitamin E levels were detected at 12 weeks of gestation; pregnant women with a live singleton; pregnant women who underwent regular prenatal examination and delivery in our hospital; pregnant women who did not take multivitamins before enrollment; pregnant women without smoking or drinking history; pregnant women without other pregnancy complications. The exclusion criteria were: pregnant women with hypertension, diabetes, coronary heart disease, etc.; pregnant women with autoimmune diseases; pregnant women with a history of thrombosis; pregnant women with a history of malignant tumors; pregnant women with acute or chronic systemic infection. All selected candidates have signed the informed consent. This study was approved by the Ethics Committee of our hospital.
Methods
Detection of serum vitamin A and vitamin E concentrations
For all enrolled pregnant women, serum vitamin A and vitamin E concentrations were detected at 12-20 weeks of gestation. For pregnant women with preeclampsia, secondary detection of serum vitamin A and vitamin E concentrations were conducted after one month of treatment. The concentrations were detected by high performance liquid chromatography tandem mass spectrometry [12]. All subjects in the study were fasted for 8 hours before the blood collection. Fasting peripheral venous blood (3 mL) was collected, without anticoagulation treatment, and cryopreserved at -4°C. The blood sample was centrifuged at 3,000 rpm for 10 min with the centrifugation radius of 15 cm. The serum was collected, and the protein and impurities in the serum were removed. N-hexane was added to the sample, and the supernatant was collected and blown dry. The sample was added with methanol for re-dissolving. The concentrations of vitamin A and vitamin E were detected. The standard curve equation was made according to the instrument standard, with the relative standard deviation of <15%. The concentrations of vitamin A and vitamin E were calculated according to the standard curve equation, with the quality control range of x̅±2 standard deviation (sd).
Detection of urine protein and liver and kidney function
The morning urine was collected, and the urine protein was detected by the wet chemical method. Three milliliters of peripheral venous blood were collected to detect liver and kidney function by the wet chemical method.
Data collection
The age, body mass index (BMI), gestational weeks, times of pregnancy, times of labor and pregnancy outcome of the enrolled women were collected. BMI increase equals to prenatal BMI minus pre-pregnancy BMI.
Treatment methods
According to the treatment principle of preeclampsia, the pregnant women in the preeclampsia group were given conventional treatment such as antihypertensive treatment and sedation. For pregnant women combined with vitamin A and vitamin E deficiency, they were additionally treated with drug adjustment. The specific dosage regimens were as follows. Vitamin A (Sinopharm Xingsha Pharmaceutical (Xiamen) Co., Ltd., China) 2,500 U/d, oral, once a day; vitamin E (Qingdao Shuangjing Pharmaceutical Co., Ltd., China) 10~100 mg/time, oral, twice or three times a day.
Evaluation criteria
The reference range of serum vitamin A concentration is 3~7 mg/dL [13]. The reference range of serum vitamin E concentration is 50~200 mg/L. A vitamin concentration lower than the reference range is considered deficiency [14].
Statistical analysis
SPSS 25.0 statistical software was used for statistical analysis. The measurement data were expressed as x̅±sd and processed using t-test. Comparison for three or more groups was conducted using F test. The count data were expressed as percent, and conducted using chi-square test. Spearman rank correlation was used to analyze the correlation between vitamin A and vitamin E levels with preeclampsia. Univariate analysis was performed for each variable. The variables with statistical differences were entered into the multivariate logistic regression analysis. The test level is α=0.05. P<0.05 is considered statistically significant.
Results
Comparison of general information between the preeclampsia group and healthy group
There were significant differences in age and BMI increase between the preeclampsia group and healthy group (P<0.05). However, there were no significant differences in pregnancy times, labor times or gestational weeks between the two groups (all P>0.05). See Table 1.
Table 1.
Comparison of general information between the preeclampsia group and healthy group (x̅±sd, n (%))
| Factor | Preeclampsia group (n=565) | Healthy group (n=4435) | χ2/t | P | |
|---|---|---|---|---|---|
| Age (years old) | <35 | 396 (70.09) | 3902 (87.98) | 132.953 | <0.001 |
| ≥35 | 169 (29.91) | 533 (12.02) | |||
| Pregnancy times | 1 time | 186 (32.92) | 1,672 (37.70) | 5.909 | 0.052 |
| 2 times | 170 (30.09) | 1,313 (29.61) | |||
| ≥3 times | 209 (36.99) | 1,450 (32.69) | |||
| Labor times | 0 time | 315 (55.75) | 2,561 (57.75) | 0.901 | 0.637 |
| 1 time | 209 (36.99) | 1,553 (35.02) | |||
| ≥2 times | 41 (7.26) | 321 (7.24) | |||
| Gestational weeks | 14.3±0.7 | 14.2±0.6 | 0.718 | 0.473 | |
| BMI increase (kg/m2) | 6.03±1.55 | 5.34±1.53 | 10.081 | <0.001 | |
Note: BMI: body mass index.
Comparison of serum vitamin A and vitamin E levels among the preeclampsia groups with different degrees of severity and healthy groups
The levels of vitamin A and vitamin E in the severe group and mild group were lower than those in the healthy group, and the levels in the severe group were lower than those in the mild group before treatment (all P<0.001). With the exacerbation of preeclampsia, the levels of vitamin A and vitamin E showed decreasing trends. Spearman rank correlation analysis showed that the levels of vitamin A and vitamin E were negatively correlated with the severity of preeclampsia (vitamin A: r=-0.653, P<0.001; vitamin E: r=-1.105, P<0.001). The levels of vitamin A and vitamin E in two preeclampsia groups were increased after treatment (all P<0.001), but there was no significant difference between the mild group and severe group (both P>0.05). See Table 2 and Figure 1.
Table 2.
Comparison of serum vitamin A and vitamin E levels among the preeclampsia groups with different degrees of severity and healthy group (x̅±sd, mg/dL)
| Group | Vitamin A level | Vitamin E level | Vitamin A level after treatment | Vitamin E level after treatment |
|---|---|---|---|---|
| Healthy group (n=4,435) | 6.05±1.31 | 45.01±5.15 | - | - |
| Mild group (n=259) | 1.64±0.28*** | 35.96±4.92*** | 3.82±1.21ΔΔΔ | 39.15±6.31ΔΔΔ |
| Severe group (n=306) | 0.93±0.24***,### | 20.23±4.97***,### | 2.79±1.29ΔΔΔ | 38.52±5.69ΔΔΔ |
| F | 2639.752 | 3601.968 | 1.659 | 1.247 |
| P | <0.000 | <0.000 | 0.102 | 0.213 |
Note: Compared with the healthy group;
P<0.001.
Compared with the mild group;
P<0.001.
Compared with the same group before the treatment;
P<0.001.
Figure 1.
Comparison of serum vitamin A and vitamin E levels among the preeclampsia groups with different degrees of severity and healthy group. A: Vitamin A level; B: Vitamin E level. Compared with the healthy group, ***P<0.001; compared with the mild group, ###P<0.001; compared with the same group before treatment, ΔΔΔP<0.001.
Comparison of vitamin A and vitamin E deficiency rate among the preeclampsia group with different degrees of severity and healthy group
The deficiency rates of vitamin A and vitamin E in the mild group and severe group were higher than those in the healthy group, and were higher in the severe group than in the mild group (all P<0.05). See Table 3.
Table 3.
Comparison of vitamin A and vitamin E deficiency rate among the preeclampsia group with different degrees of severity and healthy group (n (%))
| Group | n | Vitamin A deficiency | Vitamin E deficiency | Vitamin A and E deficiency |
|---|---|---|---|---|
| Healthy group | 4,435 | 202 (4.55) | 126 (2.84) | 51 (1.15) |
| Mild group | 259 | 67 (25.87)* | 50 (19.31)* | 15 (5.79)* |
| Severe group | 306 | 125 (40.85)*,# | 77 (25.16)*,# | 32 (10.46)*,# |
| F | 641.232 | 412.289 | 149.918 | |
| P | <0.001 | <0.001 | <0.001 |
Note: Compared with the healthy group;
P<0.05.
Compared with the mild group;
P<0.05.
Logistic regression analysis of preeclampsia
Multivariate logistic regression analysis was performed with the occurrence of preeclampsia as the dependent variable, and with age, vitamin A deficiency, vitamin E deficiency and BMI increase as independent variables. For independent variables, αEntering=0.05 and αExiting=0.05. The result showed that older age (OR=1.674), vitamin A deficiency (OR=2.463) and vitamin E deficiency (OR=2.206) were independent risk factors for preeclampsia (all P<0.05), as shown in Table 4.
Table 4.
Logistic regression analysis of factors affecting preeclampsia
| Index | B | S.E. | Wald χ2 | P | OR | 95% CI | |
|---|---|---|---|---|---|---|---|
|
| |||||||
| Upper limit | Lower limit | ||||||
| Older age | 14.739 | 0.091 | 11.226 | 0.002 | 1.674 | 1.332 | 3.795 |
| Vitamin A deficiency | 25.033 | 0.032 | 61.139 | 0.007 | 2.463 | 1.554 | 12.049 |
| Vitamin E deficiency | 10.276 | 0.041 | 46.227 | 0.013 | 2.206 | 1.146 | 9.267 |
| BMI increase | 0.122 | 0.117 | 1.269 | 0.105 | 0.794 | 0.428 | 0.862 |
Comparison of pregnancy outcomes among the preeclampsia group with different degrees of severity and healthy group
The incidences of neonatal asphyxia, fetal distress and preterm birth in pregnant women with vitamin A or vitamin E deficiency in each group were higher than those with normal vitamin A and vitamin E levels in each group, and the neonatal body weight and the neonatal Apgar score in pregnant women with vitamin A and vitamin E deficiencies were lower than those with normal vitamin A and vitamin E levels (all P<0.05). See Table 5.
Table 5.
Comparison of pregnancy outcomes among the preeclampsia group with different degrees of severity and healthy group (x̅±sd, n (%))
| Group | n | Neonatal asphyxia | Fetal distress | Premature delivery | Neonatal body weight (kg) | Neonatal Apgar score (scores) | |
|---|---|---|---|---|---|---|---|
| Healthy group | Normal vitamin A and vitamin E | 4056 | 51 (1.26) | 63 (1.55) | 192 (4.73) | 3.69±0.52 | 9.30±0.59 |
| Vitamin A deficiency | 202 | 10 (4.95) | 15 (7.43) | 20 (9.90) | 3.57±0.50 | 9.13±0.51 | |
| Vitamin E deficiency | 126 | 6 (4.76) | 12 (9.52) | 13 (10.32) | 3.60±0.53 | 9.09±0.56 | |
| Vitamin A and E deficiency | 51 | 6 (11.76) | 9 (17.65) | 10 (19.61) | 3.49±0.51 | 9.01±0.54 | |
| χ2/F | 57.220 | 119.760 | 38.241 | 6.795 | 14.010 | ||
| P | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | ||
| Mild group | Normal vitamin A and vitamin E | 127 | 5 (3.94) | 8 (6.30) | 9 (7.09) | 3.41±0.40 | 9.02±0.47 |
| Vitamin A deficiency | 67 | 10 (14.93) | 12 (17.91) | 11 (16.42) | 3.13±0.37 | 8.79±0.45 | |
| Vitamin E deficiency | 50 | 7 (14.00) | 11 (22.00) | 9 (18.00) | 3.15±0.39 | 8.82±0.43 | |
| Vitamin A and E deficiency | 15 | 3 (20.00) | 5 (33.33) | 4 (26.67) | 3.02±0.35 | 8.63±0.49 | |
| χ2/F | 9.819 | 15.461 | 8.850 | 12.082 | 6.425 | ||
| P | 0.020 | 0.002 | 0.031 | <0.001 | <0.001 | ||
| Severe group | Normal vitamin A and vitamin E | 72 | 8 (11.11) | 9 (12.50) | 10 (13.89) | 3.05±0.31 | 8.38±0.46 |
| Vitamin A deficiency | 125 | 22 (17.60) | 25 (20.00) | 29 (23.20) | 2.87±0.26 | 8.02±0.41 | |
| Vitamin E deficiency | 77 | 13 (16.88) | 18 (23.38) | 17 (22.08) | 2.89±0.29 | 8.06±0.43 | |
| Vitamin A and E deficiency | 32 | 12 (37.50) | 13 (40.62) | 13 (40.62) | 2.76±0.33 | 7.87±0.44 | |
| χ2/F | 10.649 | 10.800 | 9.119 | 9.228 | 15.264 | ||
| P | 0.014 | 0.013 | 0.028 | <0.001 | <0.001 |
Discussion
Vitamin A and vitamin E are microelements required to maintain the body’s normal metabolism and physiological function, and they also serve as antioxidants. Vitamin A has the function of maintaining normal embryonic development and antioxidation and plays an important role in the growth and reproduction of normal cells [15]. In addition to the role of vitamins, vitamin E can also scavenge oxygen free radicals, play an antioxidant role and maintain the body’s oxidative stress balance [16].
Foreign researchers conducted a comprehensive analysis of the oxidative stress markers and antioxidant status of preeclampsia, including 2,953 cases of patients with preeclampsia and 3,621 healthy pregnant women as the controls [17]. The study found that the vitamin E level in women with preeclampsia decreased significantly. Another researcher investigated 2,824 pregnant women and found that the abnormal rate of serum vitamin A concentrations was 12.3% [18]. A study found that vitamin E had a protective effect against preeclampsia. In the study, 400 IU/d vitamin E supplementation was given to pregnant women (within 20-40 weeks) with risk factors for preeclampsia. The results showed that the incidence of preeclampsia was 5.0%, lower than 17.5% in the control group without vitamin E supplementation [19]. The results of this study showed that the levels of vitamin A and vitamin E in the severe group and mild group were lower than those in the healthy group, and the deficiency rates of vitamin A and vitamin E in severe group and mild group were higher than those in healthy group, similar to the results reported above. After preeclampsia treatment, the levels of vitamin A and vitamin E increased in patients with preeclampsia. Further correlation analysis showed that the levels of vitamin A and E were negatively correlated with the severity of preeclampsia. Our results showed that the levels of vitamin A and E in patients with preeclampsia decreased significantly, and the levels of vitamin A and E were closely related to the severity of preeclampsia. The levels of vitamin A and E in patients with severe preeclampsia decreased more significantly than those with mild preeclampsia. It is speculated that the patients with preeclampsia consume a lot of antioxidants due to oxidative stress reaction, resulting in the decrease of vitamin A and vitamin E levels [20]. Vitamin A and vitamin E supplementation can improve the status of vitamin A and vitamin E deficiencies in patients with preeclampsia.
We have shown that older age (OR=1.674), vitamin A deficiency (OR=2.463) and vitamin E deficiency (OR=2.206) were independent risk factors for preeclampsia. Yi et al. found that older age and vitamin A and vitamin E deficiencies were independent risk factors for preeclampsia through logistic regression analysis, which was consistent with the results of this study [21]. The possible reasons are listed as follows. (1) Older age. With the increase of age, the metabolic function of pregnant women over 35 years old changes, and there is a trend of metabolic disorder. The production of free radicals increases. The lower content of vitamin A and vitamin E leads to the relative increase of free radical content, leading to placental aging and vascular endothelial damage, thus increasing the incidence of preeclampsia [22,23]. (2) Vitamin A and vitamin E deficiencies. During pregnancy, placental ischemia-hypoxia-reperfusion injury response stimulates the release of oxidative factors, leading to the damage of vascular endothelial cells, promoting inflammatory response and eventually leading to the development of preeclampsia [24]. Vitamin A and vitamin E not only participate in the body’s normal metabolism and physiological function as essential microelements, but also maintain the body’s oxidative stress balance as a non-enzymatic strong antioxidant, playing the role of antioxidant and scavenging oxygen free radicals. Vitamin A and vitamin E deficiencies can easily cause the imbalance of oxidative stress, increase the free radicals, cause endothelial damage, and increase the risk of preeclampsia [25,26].
In addition, the results showed that for comparison within groups, the incidences of neonatal asphyxia, fetal distress and preterm birth in pregnant women with vitamin A and vitamin E deficiencies were higher than those with normal vitamin A and vitamin E levels, and the neonatal body weight and the neonatal Apgar score in pregnant women with vitamin A and vitamin E deficiency were lower than those with normal vitamin A and vitamin E levels. It suggests that in patients with preeclampsia, vitamin A and E deficiencies are more likely to develop adverse pregnancy outcomes such as neonatal asphyxia, fetal distress and premature delivery as well as lower neonatal body weight and neonatal Apgar score.
This is a retrospective study based on hospital cases from a single-center study. The sample size is small and the follow-up time is short, so there may be case selection bias. In the future, we will do a multi-center study with expanded sample size and extended follow-up time, to further confirm the reliability of the research results. At the same time, we did not supplement pregnant women with different doses according to the degree of vitamin A and E deficiency in this study. There is no clinical research report on the supplement doses related to different vitamin deficiency levels. This is also a shortcoming of this study. The study will be further improved in the next step.
In conclusion, older age, vitamin A deficiency and vitamin E deficiency are risk factors for preeclampsia. The concentrations of vitamin A and vitamin E are negatively correlated with the severity of preeclampsia. Vitamin A deficiency and vitamin E deficiency in pregnant women with preeclampsia will increase the risk of adverse pregnancy outcomes. Therefore, during pregnancy, the levels of vitamin A and vitamin E should be closely monitored, and reasonable dietary guidance and nutritional supplements should be provided should vitamin A and vitamin E deficiencies occur, so as to avoid adverse pregnancy outcomes as of preeclampsia.
Acknowledgements
This work was supported by the National Health Commission Medical and Health Technology Development Research Center (W2016CWSD02).
Disclosure of conflict of interest
None.
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