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Pre-eclampsia is a pregnancy-specific vascular disorder manifesting usually after twenty (20) weeks of gestation. Pre-eclampsia is identified by elevated blood pressure and proteinuria. There is a wide range of phenotypes from mild forms of pre-eclampsia to severe forms with extremely high blood pressure. Severe pre-eclampsia can lead to upper abdominal pain, visual disturbances, headache, changes in the liver, kidneys, brain and clotting abnormalities6,7. The foetus is also at risk and intrauterine growth restriction and prematurity are common consequences7. Most severe phase of pre-eclampsia is called eclampsia which is a rare condition. Eclampsia is characterized by occurrence of seizures, changes in the circulatory system and renal failure, and is associated with an increased risk of maternal death.
Pre-eclampsia belongs to a category of hypertensive disorders in pregnancy. Pre-eclampsia is defined as systolic blood pressure of at least 140 mmHg and/or diastolic blood pressure of at least 90 mmHg accompanied by proteinuria, first detected after 20 weeks of gestation8. Proteinuria is defined as the presence of at least 300 mg of protein in a 24 hour urine collection8. Hypertensive disorders in pregnancy can be classified in to 5 groups and details are given in table 19.
Table 1 : Classification of hypertensive disorders in pregnancy*
Chronic hypertension Blood pressure >140 mmHg systolic or 90 mmHg diastolic prior to pregnancy or before 20 weeks of gestation. Persists >12 weeks post-partum
Pre-eclampsia Blood pressure >140 mmHg systolic or 90 mmHg diastolic with proteinuria (>300 mg/24 hrs) after 20 of weeks gestation
Chronic hypertension with superimposed pre-eclampsia Newly onset proteinuria after 20 weeks of gestation in a woman with hypertension
Gestational hypertension Hypertension without proteinuria occurring after 20 weeks of gestation
Transient hypertension Retrospective diagnosis and normal blood pressure by 12 weeks post-partum
* Adapted from "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure" 9
3.1.3. Epidemiology of pre-eclampsia
Nearly 500 000 female deaths are reported each year from pregnancy related conditions, and about 99% of them live in low and middle income countries. Among the conditions that complicates of pregnancy and childbirth, pre-eclampsia is the main cause of death among women of reproductive age in low income countries10. Epidemiological studies have shown that around ten percent (10%) of women have high blood pressure during pregnancy, and pre-eclampsia complicates 2% to 8% of pregnancies. Overall, 10% to 15% of maternal deaths are directly associated with pre-eclampsia and eclampsia10. According to The World Health Report 2005, pre-eclampsia and eclampsia affected 2.8% of pregnancies in developing countries and 0.4% in developed countries respectively1.
Worldwide incidence of Pre-eclampsia and eclampsia1
Incidence % of live births -3.2%
Number of cases per year -4 152 000
Case-fatality rate (%) -1.7%
Maternal deaths in year 2000 -63 000
When the Sri Lankan situation is considered, Senevirathne HR (2009) has expressed that 6.7% of maternal deaths in Sri Lanka in year 2006 were attributed due to Pregnancy Induced Hypertension (PIH) and eclampsia11 by quoting the Maternal death investigation: (Results from 1999 - 2006) report by Family Health Bureau Ministry of Healthcare and Nutrition, Sri Lanka. Distribution of maternal deaths in Sri Lanka due to pre-eclampsia from year 1999 to 2006 is given in table 2.
Table 2 : Distribution of maternal deaths in Sri Lanka due to pre-eclampsia from year 1999 to 200611
Year 1999 2000 2001 2002 200312 200412 2005 2006
Percentage of maternal deaths due to PIH / Eclampsia (%) 12.50 7.40 16.50 17.50 19.11 17.24 10.40 6.70
Senevirathne HR, has further stated that "In Sri Lanka, deaths are purely due to eclampsia is absent from 2000" and this is mainly due to the "user friendly screening programs and prompt treatment" for PIH and eclampsia11.
Perinatal mortality is also very high following preeclampsia13. Ngoc NT et al have investigated the causes of stillbirths and early neonatal deaths in six developing countries, and have concluded that hypertensive disorders were among the most leading causes of perinatal death, which accounted for 26.3% of their dataset14.
3.1.4. Long term health effects for mother and child
Pre-eclampsia can have long term effects on mother and the child. Epidemiological data on long term health effects of pre-eclampsia indicate that affected women may be at increased risk of developing cerebrovascular and cardiovascular diseases such as ischemic heart disease, myocardial infarction, hypertension, and cerebrovacular accidents. Irgens HU (2001) has stated that the risk of death from cardiovascular causes among women with pre-eclampsia and preterm deliveries were 8-12 fold higher than normal15. More recent study on the same topic has identified that the history of hypertension in pregnancy as a risk factor for venous thromboembolic diseases and cerebrovascular events in patients taking oral contraceptives later in their life, and 60% more likely to have a non-pregnancy related ischemic stroke16. Some studies have pointed out a strong relationship between hypertensive pregnancy disorders with type 2 diabetes mellitus17.
Majority of the children from pre-eclamptic pregnancies are at risk of developing diseases later in their life. Perinatal outcome is strongly influenced by gestational age and the severity of hypertension irrespective of the underlying syndrome18. The main impact on the foetus is under nutrition, owing to the utero-placental vascular insufficiency18. Szymonowicz W and Yu V (1987) have studied on the effects of birth weight of infants of preeclamptic mothers and found that more infants were delivered before the onset of labour. These babies were small for dates and had a higher incidence of hyaline membrane disease, pulmonary air leak, hypotension and patent ductus arteriosus. They further mentioned that these babies had significantly differed low birth weight even at 2 years of age and had a significantly lower mean mental developmental index19.
3.1.5. Aetiology and pathophysiology
The pathogenesis of pre-eclampsia is a complex process. Several factors (genetic, immunological and environmental) interact with each other to produces the illness2. Pre-eclampsia is described as a two-stage disease. In the first stage, abnormal placental development during the first trimester results in placental insufficiency2. This also results in release of excessive amounts of placental materials into the maternal circulation2. First stage is asymptomatic but leads to the second, symptomatic stage2. In second stage, pregnant women develop all the signs and symptoms related to pre-eclampsia: hypertension, renal impairment, and proteinuria2. They are further at risk of developing the HELLP syndrome (Haemolysis, Elevated Liver function enzymes and Low Platelets), eclampsia, and other end organ damages2. Pathophysiologic process of the development of preeclampsia20 is shown in the figure 1.
Figure 1 : Pathophysiology of development of pre-eclampsia
3.1.6. Genetic aspect of pre-eclampsia
It is well known that preeclampsia has a familial component. There is a high risk of developing pre-eclampsia among sisters of women21 or has a mother13 with a previous pre-eclamptic pregnancy. Chappel S and Morgan L (2006)3 reviewed the genetic clues for the development of pre-eclampsia and showed the a connection between paternal genes and pre-eclampsia by stating that: "Only 1.3% of women who had not had pre-eclampsia in their first pregnancy developed pre-eclampsia in the second pregnancy. This risk was significantly increased if they had a new partner who had previously fathered a pre-eclamptic pregnancy."
Over the past years several attempts have been made to identify candidate genes by several researchers. Although candidate gene studies have failed to identify universally accepted susceptible genes, more than 50 candidate genes have been studied. Chappel S and Morgan L (2006) have described an extensive list22 of candidate genes. Some of the extensively studied genes are listed in OMIM23 database. Few such common genes related to PE are listed in table 3.
Table 3 : List of commonly studied candidate genes
Approved Symbol Approved Name Location
AGT angiotensinogen (serpin peptidase inhibitor, clade A, member 8) 1q41-qter
AGTR1 angiotensin II receptor, type 1 3q24
AGTR2 angiotensin II receptor, type 2 Xq22-q23
NOS3 nitric oxide synthase 3 (endothelial cell) 7q36
FLT1 fms-related tyrosine kinase 1 (vascular endothelial growth factor/vascular permeability factor receptor) 13q12
VEGFA vascular endothelial growth factor A 6p12
STOX1 storkhead box 1 10q22.1
MTHFR methylenetetrahydrofolate reductase (NAD(P)H) 1p36.3
TNF tumour necrosis factor 6p21.3
EPHX1 epoxide hydrolase 1, microsomal (xenobiotic) 1q42.1
GSTP1 glutathione S-transferase pi 1 11q13.2
EGF epidermal growth factor 4q25
TGFA transforming growth factor, alpha 2p13
F5 coagulation factor V (proaccelerin, labile factor) 1q23