The role of the first trimester inflammation markers at early and late preeclampsia. Perinatal Journal 2014;22(4):128-132
- İzmir Tepecik Eğitim ve Araştırma Hastanesi, Perinatoloji Kliniği- İzmir TR
Cenk Gezer, İzmir Tepecik Eğitim ve Araştırma Hastanesi, Perinatoloji Kliniği- İzmir TR, [email protected]
Manuscript Received: January 24, 2014
Manuscript Accepted: April 30, 2014
Earlyview Date: April 30, 2014
Conflicts of Interest
No conflicts declared.
Our aim was to compare the difference between the levels of first trimester neutrophil/lymphocyte rate (NLR), platelet/lymphocyte rate (PLR), red blood distribution width (RDW), mean platelet volume (MPV) in patients developing early-onset or late-onset preeclampsia during their pregnancies.
In our clinic, 118 patients diagnosed as preeclampsia were evaluated retrospectively. The patients were separated into two groups as early-onset and late-onset preeclampsia. First trimester laboratory data were collected and the two groups were evaluated in terms of inflammation markers.
No significant difference was found among two groups in terms of inflammation markers. Birth week, mean birth weight and mean newborn percentile values (33.12±3.05 weeks, 1703±640 g and 11.15±15.54 percentile, respectively) of early preeclampsia group were found to be significantly lower than the late preeclampsia group (37.42±1.50 weeks, 2760±580 g and 29.16±30.36 percentile, respectively; p<0.001, p<0.001, p=0.002). The rate for delivery by cesarean section and the incidence for baby with growth retardation in the early preeclampsia group (100% and 64%, respectively) was significantly higher than the late preeclampsia group (86% and 37%, respectively; p=0.024, p=0.018).
High rate of growth retardation in early preeclampsia brings to mind that a placental pathology has a significant role in this group. We found no difference when we evaluate the systemic reflection of this pathology in terms of the inflammation markers in early weeks of gestation.
Inflammation, preeclampsia, platelet, neutrophil/lymphocyte rate, platelet/lymphocyte rate.
Preeclampsia (PE) is a disease characterized by hypertension (HT) appearing after 20 weeks of gestation in a pregnant women known to be previously normotensive and by accompanying proteinuria. This disease seen in 3-5% of pregnancies is responsible for 12% of maternal mortality seen worldwide.[1,2] When the appearance of the disease findings before 34 weeks of gestation is defined as early-onset PE, detecting them after 34 weeks of gestation is defined as late-onset PE.
Many pathological mechanisms have been asserted in order to explain preeclampsia. It was reported in the literature that defective trophoblastic invasion at first trimester caused PE. Another mechanism suggested is that the changes in the immune system of pregnant woman causes improper placentation due to increased inflammatory response and as a result, increase in permeability, microvascular thrombosis and increase in vascular tone.[4,5] In a study carried out on the rats, HT and proteinuria appeared only in the pregnant rats which were administered low dose endotoxin on the 14th day of pregnancy. This is significant for showing us that an inflammatory reaction during implantation and placentation may result with PE at further periods.
Inflammation has a role in HT pathogenesis seen non-pregnant patients, and in the onset and progression of cardiovascular system diseases (CVD).[7-9] Preeclampsia defined also as gestational proteinuric HT having similar characteristics with CVD which appears in non-pregnant patients brings to mind that both diseases may have a common pathological process based on increased systemic inflammation. In practice, the level of systemic inflammation in these diseases can be easily evaluated by using some blood parameters or formulas.
Recently, the studies carried out on the markers which shows systemic inflammation such as neutrophil/lymphocyte rate (NLR), platelet/lymphocyte rate (PLR) and red blood distribution width (RDW), and can be easily obtained by a simple full blood count (hemogram) have been drawn attention. It has been reported in these studies that high NLR is associated with increased cardiovascular risk and increased mortality in some malignancies.[7,11] PLR and mean platelet volume (MPV) which is an indicator of increased platelet activation were found to be associated with the onset and progression of atherosclerosis.[7,11] RDW was found to be associated with severity and presence of hypertension in non-pregnant patients and also with non-dipper hypertension.[12,13] There is limited number of studies in the literature researching PE patients for the first trimester level of NLR, PLR and RDW which are considered as the indicators of systemic inflammation and widely used clinically. In our study, it was aimed to compare the difference between first trimester NLR, PLR, MPV and RDW levels of the pregnant women diagnosed to have early and late preeclampsia.
One hundred and eighteen patients established with preeclampsia diagnosis at the Perinatology Department of Tepecik Training and Research Hospital between January 2010 and January 2013 were included in our study. The diagnosis of preeclampsia was established according to the criteria of ‘American College of Obstetrics and Gynecology’. All PE patients diagnosed were between 22 and 40 weeks of gestation and those diagnosed before 34 weeks were grouped as early preeclampsia and those diagnosed at or after 34 weeks were grouped as late preeclampsia. First trimester (7-14 weeks) hemogram values of all patients were screened and if there was more than one hemogram result, the values closest to the 7 weeks were accepted. When accessing delivery data of 92 patients, the data of 26 patients could not be reached since they delivered at an external center.
Patients which had any systemic disorder, acute or chronic inflammatory disease, any hematopoietic system disease history, malignancy history or any drug use that may affect blood condition were excluded from the study.
Demographic data, first trimester hemogram values, diagnosis week, delivery type of patients and sex, birth weight and percentile information of newborns were obtained by reviewing patient records retrospectively.
Coulter LH 750 device (Beckman Coulter, Brea, CA, USA) was used in the laboratory of our full blood count center. Neutrophil/lymphocyte rate was calculated by dividing absolute neutrophil by absolute lymphocyte number and PLR was calculated by dividing absolute platelet number by absolute lymphocyte number. Fetal percentile values were calculated by using Hadlock formula, and the values below 5 percentile were considered as small for gestational age (SGA).
The study group was evaluated in terms of the first trimester inflammation markers between early and late PE groups. The statistical analysis of data was done by using SPSS software, version 20.0 (SPSS, Inc., Chicago, IL, USA). Continuous variables were given as mean± standard deviation (SD). In the comparison of both groups, Mann-Whitney U and c2 tests were used. For all tests, p<0.05 was considered statistically significant.
Of 118 preeclampsia patients included in our study, 43 patients had early preeclampsia diagnosis and 75 patients had late preeclampsia diagnosis. The comparison of general characteristics of both groups is shown in the Table 1. While mean age value of early preeclampsia was 28.7 (range: 18-41), it was 28.6 (range: 17-43) in the late preeclampsia group. There was no difference between two groups in terms of age, pregnancy number and baby gender (p=0.868, p=0.595 and p=0.511, respectively). The diagnosis weeks of early and late preeclampsia groups were found as 29.57±2.62 and 36.69±1.55, respectively. Birth week, mean birth weight and mean newborn percentile values (33.12±3.05 weeks, 1703±640 g and 11.15±15.54 percentile, respectively) of early preeclampsia group were found to be significantly lower than the late preeclampsia group (37.42±1.50 weeks, 2760±580 g and 29.16±30.36 percentile, respectively; p<0.001, p<0.001, p=0.002). The rate for delivery by cesarean section and the incidence for SGA baby in the early preeclampsia group (100% and 64%, respectively) was significantly higher than the late preeclampsia group (86% and 37%, respectively; p=0.024, p=0.018). In terms of the duration between diagnosis and delivery, it was seen that the patients in early preeclampsia group was followed up for a longer period and that the period was significantly shorter in late preeclampsia group (14.05±20.07 days and 3.43±6.98 days, respectively; p<0.001).
When the patients were evaluated in terms of first trimester inflammation markers, mean white blood cell count (WBC), MPV, neutrophil, lymphocyte and platelet values were higher in early preeclampsia group; however, there was no significant difference compared to late preeclampsia group (p=0.792, p=0.678, p=0.954, p=0.689, and p=0.896, respectively). NLR, PLR and RDW as other inflammation markers were lower in early preeclampsia group; however, there was also no significant difference compared to late preeclampsia group (p=0.608, p=0.637, and p=0.498, respectively). The comparison of inflammation markers of both groups is shown in the Table 2.
It is seen that early- and late-onset preeclampsia differ by at some points in terms of clinical outcomes. It was reported that the newborns in early preeclampsia were shorter and weak, and the newborns in late preeclampsia might be weak as well as overweight. Both diseases having two different presentations in terms of fetal growth and early preeclampsia causing more apparent placental failure bring to mind that there may be some difference during implantation and placentation process.
It has been shown that some pathologies occurring during placentation and implantation processes in pregnant women cause changes in maternal peripheral blood values. Tzur et al. found in their studies that preeclamptic patients had higher first trimester platelet levels. This may associate with placental hypoxia increasing erythropoietin secretion and stimulating bone marrow and causing increase in megakaryocytes and platelets. Also, when preeclamptic and non-preeclamptic patients were compared in terms of platelet activation at early pregnancy period, it was seen that there was difference between two groups. It was shown that the platelets were active before preeclampsia begins clinically, and platelet activation was defined as an early marker for preeclampsia.[19-21] Another indicator of platelet activation is the MPV value in full blood count. Mean platelet volume also reflects inflammation and it was shown that it increases in chronic inflammatory diseases. Also, high MPV value is independent risk factor for hypertension and myocardial infarction and it is a poor prognosis marker for CVD.[23,24] There are controversial results in the studies researching the value of mean platelet volume for predicting preeclampsia. In the study of Altınbaş et al., it was expressed that MPV is insufficient to predict the development and severity of preeclampsia; in another study, higher MPV values were found in the preeclampsia group compared to the control group.[22,25]
NLR and PLR values though to be indicating systemic inflammation were studied in many diseases. It was reported that high NLP and PLR values indicate increased inflammation and associate with worsening renal functions in diabetic patients, increased mortality in malignancy patients and poor prognosis in CVD patients.[7,11,26,27] Increased neutrophil number in high NLR value is associated with increased inflammation and low lymphocyte number is associated with impairment in general health condition, increased cortisol levels and increased apoptosis due to physiological stress.[17,28] High NLR and PLR values were also found in non-dipper hypertension seen together with end organ damage and cardiovascular mortality. Organ damage in non-dipper hypertension depends on hypertension causing endothelial damage as in preeclampsia. There is limited number of studies on NLR and PLR in preeclampsia, and their results are controversial. Kurt et al. compared NLR in preeclampsia and control groups and also in severe and mild preeclampsia groups, but they could not find a significant difference; however, in the recent study made by Oylumlu et al., NLR was found to be significantly higher in preeclampsia group compared to the control group.[25,30]
RDW, another marker used in clinic, is a parameter showing the distribution of red blood cell volume in hemogram examinations. RDW values increase as a result of defective erythropoiesis, increased inflammation or hemolysis.[30,31] There are many conditions except anemia that red blood distribution width is associated clinically. Increased RDW values are associated with the presence and severity of hypertension and non-dipper hypertension.[12,13] It has also relationship with poor prognosis in cardiac diseases, cardiac failure and myocardial infarction, and it is considered that this relationship is related with chronic inflammation and increased inflammatory activity.[30,32] In pregnant women, RDW does not change much and remains stable between 16 and 34 weeks of gestation. In the study of Kurt et al. which is one of the rare publications analyzing RDW level in preeclampsia, the authors found RDW levels higher in preeclamptic pregnant women, particularly in severe preeclamptic pregnant women, and expressed that this may be associated with increased inflammation.
When we compared the data of the patients, we found that the incidence of SGA newborn was higher in early preeclampsia group. This condition which is also consistent with the literature shows that the pathology in early preeclampsia group causes more placental damage. No significant difference was found between two groups when evaluating early and late preeclampsia groups in terms of first trimester NLR, PLR, RDW and MPV. Although this seems to be inconsistent with the literature, analyzing the values at the week when preeclampsia diagnosis is established more than the first trimester values of the patients in other studies may explain this difference. While our results show that there is no difference between two groups in terms of systemic inflammation at first trimester, excluding normotensive control group from the study as a limitation as well does not show that there is no inflammation increase at first trimester generally in preeclampsia. For more clarification, more randomized prospective studies are required.
High rate of SGA in early preeclampsia brings to mind that a placental pathology has a significant role in this group. Not observing the systemic reflection of this pathology in inflammation markers of early weeks of gestation brings to mind that there are other factors not reflected in the blood values.
Conflicts of Interest: No conflicts declared.
1. Roberts JM, Cooper DW. Pathogenesis and genetics of pre-eclampsia. Lancet 2001;357:53-6.
2. World Health Organization Collaboration. The world health report: make every mother and child count. 2005. Department of Reproductive Health and Research, WHO. www.who.int/whr/2005/en/index.html (accessed Aug 2006).
3. von Dadelszen P, Magee LA, Roberts JM. Subclassification of preeclampsia. Hypertens Pregnancy 2003;22:143-8.
4. Pijnenborg R, Bland JM, Robertson WB, Brosens I. Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy. Placenta 1983;4:397-413.
5. Saito S, Shiozaki A, Nakashima A, Sakai M, Sasaki Y. The role of the immune system in preeclampsia. Mol Aspects Med 2007;28:192-209.
6. Faas MM, Schuiling GA, Baller JF, Visscher CA, Bakker WW. A new animal model for human preeclampsia: ultra-low-dose endotoxin infusion in pregnant rats. Am J Obstet Gynecol 1994;171:158-64.
7. Tamhane UU, Aneja S, Montgomery D, Rogers EK, Eagle KA, Gurm HS. Association between admission neutrophil to lymphocyte ratio and outcomes in patients with acute coronary syndrome. Am J Cardiol 2008;102:653-7.
8. Turak O, Ozcan F, Tok D, Işleyen A, Sökmen E, Taşoğlu I, et al. Serum uric acid, inflammation, and nondipping circadian pattern in essential hypertension. J Clin Hypertens 2013;15:7-13.
9. Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 1999;340:115-26.
10. Belo L, Santos-Silva A, Quintanilha A, Rebelo I. Similarities between pre-eclampsia and atherosclerosis: a protective effect of physical exercise? Curr Med Chem 2008;15:2223-9.
11. Tsiara S, Elisaf M, Jagroop IA, Mikhailidis DP. Platelets as predictor of vascular risk: is there a practical index of platelet activity? Clin Appl Thromb Hemost 2003;9:177-90.
12. Tanindi A, Topal FE, Topal F, Celik B. Red cell distribution width in patients with prehypertension and hypertension. Blood Press 2012;21:177-81.
13. Gunebakmaz O, Kaya MG, Duran M, Akpek M, Elcik D, Eryol NK. Red blood cell distribution width in ‘non-dippers’ versus ‘dippers’. Cardiology 2012;123:154-9.
14. American College of Obstetricians and Gynecologists. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. Obstet Gynecol 2002;99:159-67.
15. Hadlock FP, Harrist RB, Martinez-Poyer J. In utero analysis of fetal growth: a sonographic weight standard. Radiology 1991;181:129-33.
16. Rasmussen S, Irgens LM. Fetal growth and body proportion in preeclampsia. Obstet Gynecol 2003;101:575-83.
17. Tzur T, Sheiner E. Is there an association between platelet count during the first trimester and preeclampsia or other obstetric complications later in pregnancy? Hypertens Pregnancy 2013;32:74-82.
18. Troeger C, Holzgreve W, Ladewig A, Zhong XY, Hahn S. Examination of maternal plasma erythropoietin and activin A concentrations with regard to circulatory erythroblast levels in normal and preeclamptic pregnancies. Fetal Diagn Ther 2006;21:156-60.
19. Pijnenborg R, Dixon G, Robertson WB, Brosens I. Throphoblast invasion of human decidua from 8-18 weeks of pregnancy. Placenta 1980;1:3-19.
20. Zemel MB, Zemel PC, Berry S, Norman G, Kowalczyk C, Sokol RJ, et al. Altered platelet calcium metabolism as an early predictor of increased peripheral vascular resistance and preeclampsia in urban black women. N Engl J Med 1990;323:434-8.
21. Felfernig-Boehm D, Salat A, Vogl S, Murabito M, Felfernig M, Schmidt D, et al. Early detection of preeclampsia by determination of platelet aggregability. Thromb Res 2000;98:139-46.
22. Altınbas S, Toğrul C, Orhan A, Yücel M, Danısman N. Increased MPV is not a significant predictor for preeclampsia during pregnancy. J Clin Lab Anal 2012;26:403-6.
23. Bath P, Algert C, Chapman N, Neal B. Association of mean platelet volume with risk of stroke among 3134 individuals with history of CVD. Stroke 2004;35:622-6.
24. Kannel WB. Blood pressure as a cardiovascular risk factors: prevention and treatment. JAMA 1996;275:1571-6.
25. Oylumlu M, Ozler A, Yildiz A, Oylumlu M, Acet H, Polat N, et al. New inflammatory markers in pre-eclampsia: echocardiographic epicardial fat thickness and neutrophil to lymphocyte ratio. Clin Exp Hypertens 2014 Jan 16. [Epub ahead of print]
26. Azab B, Daoud J, Naeem FB, Nasr R, Ross J, Ghimire P, et al. Neutrophil-to-lymphocyte ratio as a predictor of worsening renal function in diabetic patients (3-year follow-up study). Ren Fail 2012;34:571-6.
27. Azab B, Shah N, Akerman M, McGinn JT Jr. Value of platelet/lymphocyte ratio as a predictor of all-cause mortality after non-STelevation myocardial infarction. J Thromb Thrombolysis 2012;34:326-34.
28. Gibson PH, Cuthbertson BH, Croal BL, Rae D, El-Shafei H, Gibson G, et al. Usefulness of neutrophil/lymphocyte ratio as predictor of new-onset atrial fibrillation after coronary artery bypass grafting. Am J Cardiol 2010;105:186-91.
29. Sunbul M, Gerin F, Durmus E, Kivrak T, Sari I, Tigen K, et al. Neutrophil to lymphocyte and platelet to lymphocyte ratio in patients with dipper versus non-dipper hypertension. Clin Exp Hypertens 2014;36:217-21.
30. Keskin Kurt R, Aras Z, Silfeler DB, Kunt C, Islimye M, Kosar O, et al. Relationship of red cell distribution width with the presence and severity of preeclampsia. Clin Appl Thromb Hemost 2013 May 31. [Epub ahead of print]
31. Means RT Jr. Free and easy? Red cell distribution width (RDW) and prognosis in cardiac disease. J Card Fail 2011;17:299-300
32. Ozcan F, Turak O, Durak A, Işleyen A, Uçar F, Giniş Z, et al. Red cell distribution width and inflammation in patients with non-dipper hypertension. Blood Press 2013;22:80-5.
The comparison of the general characteristics of the study group.
The comparison of inflammation markers in early- and late-onset preeclampsia groups.