Zakia M, Shalabi T, Hussein T, Hammam M, Youness E, El-Bassyouni H. T. Oxidative Stress, Neutrophil Elastaseand Vascular Endothelial Growth Factor in Obese Pregnant Women with Preeclampsia. Biomed Pharmacol J 2019;12(4).

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Manuscript received on :03-09-2019
Manuscript accepted on :05-11-2019
Published online on: 07-12-2019

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Moushira Zakia¹, Taghreed Shalabi², Tamer Hussein³, Mohamed Hammam⁴, Eman Youness^5* and Hala T. El-Bassyouni⁶

¹Biological Anthropology Department, Medical Research Division, National Research Centre,Egypt

²Prenatal Diagnosis and Fetal Medicine Department, Human Genetics and Genome Research Division, National Research Centre, Egypt

³Reproductive Health Research Department, Medical Research Division, National Research Centre, Egypt

⁴Obstetrics and Gynecology-Cairo University

⁵Medical Biochemistry Department, Medical Research Division, National Research Centre, Egypt

⁶Clinical Genetics Department,Human Genetics and Genome Research Division, National Research Centre, Giza, Egypt

DOI : https://dx.doi.org/10.13005/bpj/1819

Abstract

Oxidative stress, inflammation, and vascular endothelial proliferation and obesity are risk factors associated with preeclampsia (PE). Thepresent study aimed to investigate the levels of malondialdehyde (MDA) as a putative circulatory marker of oxidative stress, neutrophil Elastase (NE) as inflammatory marker andvascular endothelial growth factor (VEGF) as marker for vascular permeability-enhancing activities inobese women withpreeclampsia PE and compare withnormal pregnancy women. The study was carried out on 50 pregnant obese women with PE and 50 normal pregnant women.  The preeclampsia women were characterized with high blood pressure 160/110 mmHg and proteinuria. The gestational age ranged from ≥32 weeks to <37 weeks. Pre pregnancyweightwas recorded. Body mass index (BMI) was calculatedat delivery.SerumMDA, NEand VEGF were estimatedby ELISA. Significant higher levels of serum MAD,NE and VEGF were observed in obese PE patients as compared to normal controls. Our results suggested thatobesity;oxidative stress, NEandVEGFbiomarkers are risk factors for PE,emphasizing their role as feasible candidate risk markersfor cases withhigh blood pressure in early pregnancy.

Keywords

Malonaldehyde; Neutrophil Elastase; Preeclampsia; VEGF

Introduction

Hypertension and proteinuria are pregnancy-specific conditions characterize dpreeclampsia. Although its precise etiology is unknown,endothelial cell dysfunction might causematernal symptoms¹.The major cause of maternal and perinatal morbidity and mortality is preeclampsia, 10%of women had high blood pressure during pregnancy².

Moreover,preeclampsiamight lead to problems in the kidneys, liver, clotting system and brain in 2% to 8% of pregnancies, with premature andpoor and growth offspring.Although outcome is often good, preeclampsia can be harmful and life threatening.

Generally, preeclampsia and eclampsia are concomitant with direct maternal deaths  in 10% to 15% ³. The pathophysiology of preeclampsia has been implicated byneutrophils activation whichengaged binding and transmigration of neutrophils through the endothelium⁴ , through surface receptors on neutrophils and endothelium adhesion molecules.women with preeclampsia showed stimulated neutrophils which plays an important role in the vascular endothelium pathophysiology of this disorder⁵.Amplified numbers of neutrophils are notedfrom first to third trimesterin the maternal circulation, with elevated neutrophil count. Consequently,unfavorable pregnancy outcome might linked to excessive inflammatory neutrophil activation andincreased concentration of elastase discharged from neutrophil granules ⁶.Oxidative stress and oxidative damage in early gestation in early gestation influences the onset of these conditions later in pregnancy^7,8.  Increased oxidative stress markers perform significant role in the pathophysiology of preeclampsia⁹^9,10. Increase in the free radicalscauses overproduction of MDA which is the indicator of oxidativestress^6,7.

An important angiogenic factor was described to provoke the proliferation and migration of endothelial cells is vascular endothelial growth factor (VEGF), enhances vascular permeability, and modulates thrombogenicity. Consequently, it is implicated indevelopment of normal bloodvessel as well as in vascular pathologies¹¹.

The present study aimed to evaluate and compare the biomarker variables of oxidative stress, inflammatory and cytokine VEGF in preeclamptic women andin normal pregnant women.

Material and Methods

The blood samples were collected from 50 preeclamptic and 50 normal pregnant women at the department of obstetrics and gynecology, Cairo University and National Research Centre. The study was approved by the Ethical Committee form of National Research Centre, Egypt (number = 16361), in accordance with the World Medical Association’s Declaration of Helsinki.The age of the women ranged from 25-40 years, their mean age was 34.31 ± 8.83 andpre pregnancy BMI (kg/m²) was29.9 ± 6.91.

Circulating markers of oxidative stress MDA, neutrophil elastase and vascular endothelial growth factor (VEGF)were evaluatedamong women with and without preeclampsia.

A dipstick urine measurement for protein was performed on urine specimen collected from the patient on the clinic days. Testing was performed with multistix reagent strips (Bayer). Proteinuria was classified semi-quantitatively as absent if testing with a dipstick showed no protein or trace levels (level below 300 mg L-1); low grade if the dipstick showed a value of 1+ or 2+(level between 300 and 3000 mg L-1) and high grade if the dipstick showed a value of 3+ or 4+(level>3000 mg L-1).Proteinuria was observed with low grade in 46 % and with high grade in 54% of cases.

Statistical analyses

Statistical analyses were performed with SPSS software, version 19.0 (SPSS Inc., Chicago, IL, USA)taking level of significance to be p<0.05.Normal distributionof the data for each parameter was checked by Kolmogorov-Smirnov analysis. Percentage, mean, and standard deviationwere used to express normally distributed variables. An unpaired t-test was applied to determine the mean significant difference between normal and preeclamptic groups. Percentage distribution in preeclampsia women was done by using chi-square test.

Results

A total of 100 women were enrolled, 50 obese women with preeclampsia and 50 normotensive controls.The obstetric history shows that the mean gestational age at delivery was 33.54±5.68 in PE. The mean number of pregnancies was 3.69 ±1.932.The systolic blood pressures was 172.69 ± 12.85, diastolic blood pressure was 111.92 ± 9.02. PE showed significant higher BMI 32.94 ± 8.93 than normal controls. Moreover, the pre-pregnancy BMI was significantly higher in PE women. Proteinuria was observed in PE with low grade in 46 % and with high grade in 54 % and deliveries withprevious miscarriages was 92% in PE and 2% in normal controls(table 1).Statistically significant difference was observed between PE and controls in the mean levels of blood pressure and in frequency of previous miscarriages (p <0.05). Moreover, MDA levels were significantly higher among the preeclampsia patients (5.23 ± 2.58) as comparedto normal control group (0.91 ± 0.29)as well as NE in the preeclampsia patients(7.52 ± 2.60) compared tonormal control group (3.45 ± 1.23) and VEGF(122.68 ± 16.69) in PE compared to normal pregnancy(82.68 ± 10.14)(table 2) (P < 0.05).

Table 1: Clinical characteristic ofnormal controls and women with preeclampsia

* P ≤ 0.05: PE vs. healthy pregnant women

Table 2: Thelevels of malonaldehyde, neutrophil elastaseandVEGF in preeclampsia

* P ≤ 0.05: PE vs. healthy pregnant women

Discussion

PE is clinically detected after 20 weeks’ gestationand potentially life-threatening. It affects 5% of pregnancies and is characterized by hypertension and proteinuria in mild cases, and evenseizures, organ damage and maternal death in severe cases. In our study we found that the mean age was 34.31±8.835, not all of our cases were primigravida with the mean number of pregnancies 3.69±1.932.Similarly,  other study ¹² described preeclamptic women with maternal age31.0 ± 4.6. This report stated that the gestational age in their patients was 33.54±5.68 and the mean BMI was 32.94±8.93 this coincides with the findings of Sharma et al., 2006 and Wang et al., 2017who reported preeclamptic women with gestational age35.2 ± 3.6 and BMI 25.86 ± 2.82.Moreover,Sohlberg et al., 2012 elucidated that the high maternal body mass index increases the risk of preeclampsia. Likewise, inprevious studies done on extremely obese teenagers they detected that they were almost four times likely to develop preeclampsia and eclampsia compared with non-obese women. However, obesity elevated the risk for preeclampsia and eclampsia among all women in the study, teenagers were most at risk because of the compound effect of young age and obesity^8,9.

Magee et al., 2014 reported that ISSHP-definitionof pre-eclampsia occur whenthe systolic blood pressure is > 140 mmHg and diastolic blood pressure is > 90 mmHgdevelopingafter 20 weeksgestational age.

In our study the mean systolic blood pressure was 172.69±12.84 and the mean diastolic blood pressure 111.92±9.02 in women with preeclampsia which is higher than thenormal control pregnancy.Proteinuria (> 300 mg/day) occurs in preeclampsia and classified as low grade +1 or +2 which occurred in 46% of our cases and moderate and high grade in 54% of cases.

In PE, OS induced in the ischemic placenta producesthe release of cytotoxic factors into the maternal circulation, stimulating the inflammatory response and activating maternal endothelial cells ^6,15.During normal pregnancy, placental oxidative stress (OS) is present during all three trimestersand is necessary to obtain normal cell function. However, if OS reaches a certain level, pregnancy complications might develop^3,15. PE is related to an impaired endothelial function that accounts foractivation of the coagulation cascade,altered vascular reactivity and loss of vascular integrity. Impaired endothelial malondialdehyde levels were significantly higher as shown in the study done by ^16,17. Preeclampsia is a chronic inflammatory disease in pregnancy, which is associated with damaged maternal endothelium a potent stimulator for neutrophil activation¹⁸. Neutrophils are increased due to augmentedphysiologic stress and impaired neutrophilic apoptosis during pregnancy¹⁹. Elevated levels of VEGF in preeclamptic women compared to normal pregnant was reported in some studies^11,20. However, other studies delineated decreased level of serum VEGF in preeclamptic women ²¹.  The decrease in VEGF level becomes more significant with increasing PE severity, proposing that the decrease in VEGF synthesis and release may be an important factor in PEpathogenesis ²². The association between of preeclampsia and high BMI reported in our study is consistent with other studies^23,24.Pre-pregnancy obesity was observed in our study in agreement with previous studies reported association between re-pregnancy BMI and preeclampsia^25,26

Conclusion: Combination of obesity, elevated MDA, NE and VEGF biomarkers in the early third trimester may be important risk factors in PE pathogenesis and could predict cases at risk of high-normal blood pressure in early pregnancy.

References

1. Sharma JB, Sharma A, Bahadur A, Vimala N, Satyam A, Mittal S. Oxidative stress markers and antioxidant levels in normal pregnancy and pre‐eclampsia. Int J Gynecol Obstet. 2006;94(1):23-27.
2. Wright A, Wright D, Ispas CA, Poon LC, Nicolaides KH. Mean arterial pressure in the three trimesters of pregnancy: effects of maternal characteristics and medical history. Ultrasound Obstet Gynecol. 2015;45(6):698-706.
3. Duley L. The global impact of pre-eclampsia and eclampsia. In: Seminars in Perinatology. Vol 33. Elsevier; 2009:130-137.
4. Gupta AK, Hasler P, Holzgreve W, Gebhardt S, Hahn S. Induction of neutrophil extracellular DNA lattices by placental microparticles and IL-8 and their presence in preeclampsia. Hum Immunol. 2005;66(11):1146-1154.
5. Wang Y, Dong Q, Gu Y, Groome LJ. Up‐regulation of miR‐203 expression induces endothelial inflammatory response: Potential role in preeclampsia. Am J Reprod Immunol. 2016;76(6):482-490.
6. Sahay AS, Jadhav AT, Sundrani DP, et al. VEGF and VEGFR1 levels in different regions of the normal and preeclampsia placentae. Mol Cell Biochem. 2018;438(1-2):141-152.
7. Khoubnasabjafari M, Ansarin K, Jouyban A. Variations of malondialdehyde in pre-eclampsia. Hypertens pregnancy. 2016;35(3):346-349.
8. Cuffe JSM, Xu ZC, Perkins A V. Biomarkers of oxidative stress in pregnancy complications. Biomark Med. 2017;11(3):295-306.
9. Aksoy H, Ozkan A, Aktas F, Borekci B. Helicobacter pylori seropositivity and its relationship with serum malondialdehyde and lipid profile in preeclampsia. J Clin Lab Anal. 2009;23(4):219-222.
10. Aydemir B, Baykara O, Cinemre FBS, et al. LOX-1 gene variants and maternal levels of plasma oxidized LDL and malondialdehyde in patients with gestational diabetes mellitus. Arch Gynecol Obstet. 2016;293(3):517-527.
11. Tandon V, Hiwale S, Amle D, Nagaria T, Patra PK. Assessment of serum vascular endothelial growth factor levels in pregnancy-induced hypertension patients. J Pregnancy. 2017;2017.
12. Wang H, Gao B, Wu Z, Wang H, Dong M. Alteration of serum adropin level in preeclampsia. Pregnancy Hypertens An Int J Women’s Cardiovasc Heal. 2017;8:6-8.
13. Sohlberg S, Stephansson O, Cnattingius S, Wikström A-K. Maternal body mass index, height, and risks of preeclampsia. Am J Hypertens. 2012;25(1):120-125.
14. Magee LA, Pels A, Helewa M, et al. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary. J Obstet Gynaecol Canada. 2014;36(5):416-438.
15. Cohen JM, Beddaoui M, Kramer MS, Platt RW, Basso O, Kahn SR. Maternal antioxidant levels in pregnancy and risk of preeclampsia and small for gestational age birth: A systematic review and meta-analysis. PLoS One. 2015;10(8):e0135192.
16. Rani N, Dhingra R, Arya DS, Kalaivani M, Bhatla N, Kumar R. Role of oxidative stress markers and antioxidants in the placenta of preeclamptic patients. J Obstet Gynaecol Res. 2010;36(6):1189-1194.
17. Gupta A, Kant S, Gupta SK, et al. Serum FRAP levels and pre-eclampsia among pregnant women in a rural community of northern India. J Clin diagnostic Res JCDR. 2016;10(10):LC12.
18. Cho HY, Jung I, Kim SJ, Park YW, Kim YH, Kwon J. Increased delta neutrophil index in women with severe preeclampsia. Am J Reprod Immunol. 2017;78(3):e12705.
19. Hu Y, Li H, Yan R, et al. Increased Neutrophil Activation and Plasma DNA Levels in Patients with Pre-Eclampsia. Thromb Haemost. 2018;118(12):2064-2073.
20. Kupferminc MJ, Daniel Y, Englender T, et al. Vascular endothelial growth factor is increased in patients with preeclampsia. Am J Reprod Immunol. 1997;38(4):302-306.
21. Lyall F, Greer IA, Boswell F, Fleming R. Suppression of serum vascular endothelial growth factor immunoreactivity in normal pregnancy and in pre‐eclampsia. BJOG An Int J Obstet Gynaecol. 1997;104(2):223-228.
22. Ren Y, Wang H, Qin H, et al. Vascular Endothelial Growth Factor expression in peripheral blood of patients with pregnancy induced hypertension syndrome and its clinical significance. Pakistan J Med Sci. 2014;30(3):634.
23. Baeten JM, Bukusi EA, Lambe M. Pregnancy complications and outcomes among overweight and obese nulliparous women. Am J Public Health. 2001;91(3):436.
24. Fang R, Dawson A, Lohsoonthorn V, Williams MA. Risk factors of early and late onset preeclampsia among Thai women. Asian Biomed Res Rev news. 2009;3(5):477.
25. Baker AM, Haeri S. Estimating risk factors for development of preeclampsia in teen mothers. Arch Gynecol Obstet. 2012;286(5):1093-1096.
26. Ornaghi S, Tyurmorezova A, Algeri P, et al. Influencing factors for late-onset preeclampsia. J Matern Neonatal Med. 2013;26(13):1299-1302.