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Difference of Serum MMP9 and TNF Level in Preterm and Term Premature Rupture of Membranes

PROM can be categorized based on the time of occurrence. Breakage of fetal membranes before contractions begin in term pregnancy is called PROM at term, whereas rupture occurring during preterm pregnancy is called preterm PROM. The proportion of PROM ranges from 3% to 18% of all pregnancies. Approximately 30‐40% of preterm deliveries are caused by PROM. The proportion of PROM at term cases in Sanglah Hospital was 12.92% out of 2113 deliveries in 2005 whereas the proportion of preterm PROM cases was 16.77% out of 328, including those who went through de‐ livery and conservative hospitalization.3‐5


INTRODUCTION
Premature rupture of membranes (PROM) is an important matter in obstetrics in relation to complications of pregnancy in the form of prematurity, chorioamnionitis infection, and sepsis, which increases perinatal morbidity and mortality for both mother and baby. Currently, the incidence of PROM is still high, with ten percent of deliveries being preceded by PROM. 1,2 PROM can be categorized based on the time of occurrence. Breakage of fetal membranes before contractions begin in term pregnancy is called PROM at term, whereas rupture occurring during preterm pregnancy is called preterm PROM. The proportion of PROM ranges from 3% to 18% of all pregnancies. Approximately 30-40% of preterm deliveries are caused by PROM. The proportion of PROM at term cases in Sanglah Hospital was 12.92% out of 2113 deliveries in 2005 whereas the proportion of preterm PROM cases was 16.77% out of 328, including those who went through delivery and conservative hospitalization. [3][4][5] pression of MMP-9 in human amniotic epithelial (hAE) cells. This is partially consistent with previous reports stating that in-vitro TNF-triggers the secretion of MMP-9 in human amnion and trophoblast. 6

METHODS
This research was conducted in dr. Moewardi Hospital of Surakarta. The population of this research were patients with the diagnosis of PROM, either at term or preterm who gave birth in the hospital from July to August 2012 and were willing to provide informed consent as requirement for sample collection.
This research employed observational, crosssectional design and clinical test approach on the female clients with either preterm PROM or PROM at term. All of our subjects had to fulfill the following inclusion criteria, pregnant women aged 20 up to 35 years old who had delivery in the delivery room of dr. Moewardi Hospital of Surakarta with either preterm PROM or PROM at term case, no abnormality of the baby, and willing to participate in the research by signing an informed consent form.
The minimum number of sample needed to confirm a difference between preterm PROM and PROM at term was 35. The levels of MMP-9 and TNF-for both groups were assessed using ELISA method. Venous blood sample was collected from the subjects, which was then processed in Prodia Laboratory in Jakarta. The concentrations of MMP-9 and TNF-in both groups were compared using t-test. All statistical analysis was conducted using SPSS version 17.0 for Windows.

RESULTS
The subjects of this research were 70 pregnant women who were gave birth in dr. Moewardi Hospital of Surakarta with PROM. They were divided into 2 groups, 35 women with preterm PROM and 35 women with PROM at term. The characteristics of research subjects are presented in Table 1.
The normality of the samples was tested using Kolmogorov-Smirnov test. There was no significant difference in terms of age of the subjects and average gestational age between the preterm PROM and PROM at term group.
The average serum MMP-9 concentration in the preterm PROM group (2860.68 K 627.32 ng/ml) is higher than that in the PROM at term group (2549.74 K 657.15 ng/ml) as shown in Table 2 below.

Indones J 16 Wibowo et al Obstet Gynecol
The difference in the average serum concentration of MMP-9 between the preterm PROM group and the PROM at term group is found to be statistically significant (p=0.04).
The MMP-9 level of both sample groups is homogenous, as indicated by the Kolmogorov-Smirnov normality test, the p-value generated for each respective group was 0.994 for the preterm PROM group and 0.495 for the PROM at term group.
The average serum TNFconcentration in preterm PROM (12,086.60 K 5,384.51 pg/ml) is higher than that in PROM at term (6,422.51 K 2,645.32 pg/ml) as shown in Table 3 below.
Serum TNF-concentration is homogenously distributed in both groups. This is verified by the p-value obtained by Kolmogorov-Smirnov test, with p=0.495 for the preterm PROM group and p=0.497 for the PROM at term group. The average serum TNF-concentration of the preterm PROM group is significantly different from the PROM at term group, as verified by independent samples ttest analysis (p=0.00).

DISCUSSION
Inflammatory cytokines (IL-1, IL-6, and TNF-) have been found in higher concentrations in the amniotic fluid of pregnant women with PROM. However, TNF-is the cytokine with the most distinct characteristic out of the cytokines, which seems to influence the family of MMP during preg-nancy. This member of the pro-inflammatory cytokines have been proven to trigger the expression of MMP in various tissues in such a way that it causes the active release of MMP-9 from the fetal membrane and triggers apoptosis in the fetal membrane. The activation of MMP-9 will eventually lead to PROM. 7,8 Demographic characteristics of the preterm PROM group and the PROM at term group are presented in Table 1 and it was discovered that there was no siginificant difference between the groups for the variables of education level, parity, occupation, age, and gestational age. Thus, we can conclude that the two groups are comparable in terms of demographics.
Kolmogorov-Smirnov Z tests for MMP-9 and TNF-in both groups provided p-value more than 0.05. Therefore, we can conclude that the distribution of values in all of the groups are normally distributed.
From results of independent t-test, the level of MMP-9 is significantly higher in preterm PROM than PROM at term (p-value=0.04). This result is in line with findings by Romero et al conducted in 2002 in which the concentration of MMP-9 is significantly higher in preterm PROM than that in premature delivery (p=0.035). However, the research did not compare two groups with PROM although we can see similar findings that there is an increase in the level of MMP-9 in PROM cases. [9][10][11]  The average concentration of TNF-in preterm PROM is almost twice the average concentration in PROM at term. The difference in the level of TNFbetween that in preterm PROM and that in PROM at term was found to be significant (p=0.00). A similar research was conducted by Sabarudin in dr. Hasan Sadikin Hospital of Bandung and network hospitals in Bandung from May up to November 2009. It is generally claimed that gestational age from 28 up to 34 weeks bear greater risk to undergo PROM. As has been stated by Noriko et al, TNF-in human chorionic cells has been verified to promote the production of MMP-9 and Prostaglandin E2 and suppress the tissue inhibitor of metalloproteinase (TIMP). Thus, TNF-has the tendency to cause weakening and rupture of membranes through degrading extracellular collagen matrix. [12][13][14] CONCLUSION There is a significant difference in the levels of MMP-9 and TNF-between preterm PROM and PROM at term, in which the levels of MMP-9 and TNF-in preterm PROM are greater than PROM at term. This verifies that the role of MMP-9 and TNFin the occurrence of preterm PROM is higher than that in PROM at term.