In Malaysia, hypertension (HTN) is one of the most prevalent medical disorders (Lim et al., 2007; Malaysian Statistic on Medicine, 2005). HTN that occurs during pregnancy is known as hypertensive disorders of pregnancy (HDP). HDP can further be divided into gestational hypertension (GH), pre-eclampsia (PE), eclampsia, and superimposed PE. Annually; a huge amount of money has been allocated for management of these disorders (Mohamad Taha, 2003).
GH is the most frequent cause of HTN during pregnancy. GH can progress into PE and eclampsia. GH and PE occur in about 6-8 % and 2-8% (Walker, 2000; Sibai, 2003; Clarke & Nelson-Piercy, 2008) of all pregnancies respectively. Some studies revealed that the incidence was even higher in lower socioeconomic groups (Roberts & Gammill, 2005).
GH is an important obstetric problem as it may lead to both maternal and foetal morbidity and mortality (Jegasothy, 2002). Most of sudden maternal deaths were due eclampsia as a complications of untreated GH or PE. Many of the mortality cases occurred in less developed areas (Jegasothy, 2002). Maternal morbidity such as seizures, stroke, abruptio placenta and hepatic failure remains as the leading causes for admission of pregnant women to intensive care units (Walker, 2000; Sibai, 2006).
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Foetal mortality and morbidity are related to the effects of the disease on the foetus. These complications include prematurity, intra-uterine growth restriction (IUGR), increasing rate of neonatal intensive care unit (NICU) admission, and even death (Roberts & Gammill, 2005; Sibai, 2006).
Mortality and morbidity due to GH is alarming and have public health concern. Hence, early identification of GH cases is very essential and crucial. This is important for early intervention and management of the patients to ensure favorable outcome of the mother and the foetus.
1.1.2 Biomarkers in Medical Diagnosis
Biomarkers have been used for more than 100 years in medicine for prognostic and diagnostic purposes (Peck, 2007). The information gathered from the biomarkers facilitates the health practitioners for better understanding of the preclinical and clinical data (Lewin & Weiner, 2004). Disease specific biomarkers are able to enhance the probability of accurate diagnosis, which would be of great benefit, particularly in devastating diseases (Bakhtiar, 2008).
Recent studies have been focusing on the basis and underlying mechanisms that are responsible for development of GH and to identify the biomarkers that are responsible for disease progression. During normal pregnancy, a cluster of enzymes called Matrix Metalloproteinases (MMPs) and their tissue Inhibitors of MMPs (TIMPs) were noted to be involved in breakdown of uterine extracellular matrix (ECM), followed by trophoblastic invasion, vascular remodeling and angiogenesis. It was found that arterial invasiveness and growth were depending on successful ECM breakdown, which was abnormal in GH (Granger et al., 2001). Several MMPs and TIMPs particularly MMP-9, TIMP-1 and TIMP-2 were noted to be involved in development and progression of GH. Several studies showed these biomarkers were abnormal in GH and have potential roles in management of GH (Seval et al., 2004; Tayebjee et al., 2005; Sankaralingam et al., 2006; Palei et al., 2008; Raffetto & Khalil, 2008).
Further studies on these biomarkers are essential to confirm their potential role as novel biomarkers in GH.
1.1.3 Statement of Problems
Gestational hypertension (GH) is an important obstetric problem worldwide. It is an important precursor to preeclampsia (PE) and eclampsia, which results in reduced placental perfusion and subsequently causes maternal and foetal morbidity and mortality.
There are limited data on the biomarkers in GH that can be used to identify the high-risk group patients and to predict the risk of subsequent obstetric complications such as PE and eclampsia, as well as the outcomes of the pregnancy. The identification of such biomarkers is important to improve the management and prognosis of these problems.
Recently, extracellular matrix (ECM) turnover especially MMPs (including circulating levels of MMP-9, TIMP-1 and TIMP-2) were reported to play a major role in development of GH and its complications. Hence, MMPs have a potential role as candidate novel biomarkers in GH.
The aim of this study is to determine and compare the levels of these MMPs in GH and normotensive pregnant women. This study also aimed to provide baseline data for future studies.
1.1.4 Significant of the Study
The findings from this study will contribute towards enhancement of medical knowledge and understanding of the role of MMP-9 and TIMPs in the development and progression of GH and their potential use as novel biomarkers in identifying the high-risk groups and predicting the risks of subsequent PE, or eclampsia and pregnancy outcomes. Scientific data from this study will be useful for local baseline information as there's no similar study done on these biomarkers in Malaysian population.
1.2.1 General Objective
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The aim of this study is to determine the expression of MMP-9 and TIMPs in GH patients and to compare with normotensive pregnant women.
1.2.2 Specific Objectives
To identify socio-demographic and related clinical parameters distributions in the selected respondents i.e. GH and normotensive pregnant women.
To determine and compare the levels of MMP-9, TIMP-1 and TIMP-2 and MMP-9/TIMPs ratios (MMP-9: TIMP-1 and MMP-9: TIMP-2) in the studied groups i.e. GH (case) and normotensive (control) pregnant women.
To determine and compare the levels of MMP-9 and TIMPs in GH and control group based on parity status and to assess the effect of modification by controlling the effect of parity.
To identify association between MMP-9 and TIMPs with maternal age and gestational age.
To identify association between MMP-9 and TIMPs with blood pressure levels.
To determine outcome of the pregnancy among case and control groups.
To identify association between MMP-9 and TIMPs with maternal complications and foetal outcomes in GH.
There are significant differences in MMP-9, TIMP-1 and TIMP-2 levels between GH and the normotensive pregnant groups. There will be reduced in MMP-9 and increased in TIMP-1 and TIMP-2 in GH as compared to control group.
There are significant differences in the ratio between MMP-9 and TIMP-1 or TIMP-2 between GH and normotensive pregnant groups. There will be reduced in both MMP-9/TIMP-1 and MMP-9/TIMP-2 ratio in GH as compared to the control group.
Confounding factor such as parity might influence the outcome of the analyses. Thus, by controlling the effect of parity, the analyses is expected to demonstrate some differences.
There is association between MMP-9 and TIMPs with maternal and gestational age.
There is association between levels of MMP-9 and TIMPs with blood pressure levels.
There are differences in outcome of the pregnancies between GH and normotensive pregnancies.
There is a significant relationship between abnormal MMP-9 and TIMPs with maternal complications and foetal outcomes in GH.