Pre-eclampsia
Pre-eclampsia is a multi-system disorder specific to pregnancy, characterized by the new onset of high blood pressure and often a significant amount of protein in the urine or by the new onset of high blood pressure along with significant end-organ damage, with or without the proteinuria. When it arises, the condition begins after 20 weeks of pregnancy. In severe cases of the disease there may be red blood cell breakdown, a low blood platelet count, impaired liver function, kidney dysfunction, swelling, shortness of breath due to fluid in the lungs, or visual disturbances. Pre-eclampsia increases the risk of undesirable as well as lethal outcomes for both the mother and the fetus including preterm labor. If left untreated, it may result in seizures at which point it is known as eclampsia.
Risk factors for pre-eclampsia include obesity, prior hypertension, older age, and diabetes mellitus. It is also more frequent in a woman's first pregnancy and if she is carrying twins. The underlying mechanisms are complex and involve abnormal formation of blood vessels in the placenta amongst other factors. Most cases are diagnosed before delivery, and may be categorized depending on the gestational week at delivery. Commonly, pre-eclampsia continues into the period after delivery, then known as postpartum pre-eclampsia. Rarely, pre-eclampsia may begin in the period after delivery. While historically both high blood pressure and protein in the urine were required to make the diagnosis, some definitions also include those with hypertension and any associated organ dysfunction. Blood pressure is defined as high when it is greater than 140 mmHg systolic or 90 mmHg diastolic at two separate times, more than four hours apart in a woman after twenty weeks of pregnancy. Pre-eclampsia is routinely screened during prenatal care.
Recommendations for prevention include: aspirin in those at high risk, calcium supplementation in areas with low intake, and treatment of prior hypertension with medications. In those with pre-eclampsia, delivery of the baby and placenta is an effective treatment but full recovery can take days or weeks. The point at which delivery becomes recommended depends on how severe the pre-eclampsia is and how far along in pregnancy a woman is. Blood pressure medication, such as labetalol and methyldopa, may be used to improve the mother's condition before delivery. Magnesium sulfate may be used to prevent eclampsia in those with severe disease. Bed rest and salt intake are not useful for either treatment or prevention.
Pre-eclampsia affects 2–8% of pregnancies worldwide. Hypertensive disorders of pregnancy are one of the most common causes of death due to pregnancy. They resulted in 46,900 deaths in 2015. Pre-eclampsia usually occurs after 32 weeks; however, if it occurs earlier it is associated with worse outcomes. Women who have had pre-eclampsia are at increased risk of high blood pressure, heart disease and stroke later in life. Further, those with pre-eclampsia may have a lower risk of breast cancer.
Etymology
The word "eclampsia" is from the Greek term ἔκλᾰμψῐς. The first known description of the condition was by Hippocrates in the 5th century BC.An outdated medical term for pre-eclampsia is toxemia of pregnancy, a term that originated in the mistaken belief that the condition was caused by toxins.
Signs and symptoms
was originally considered an important sign for a diagnosis of pre-eclampsia. However, because edema is a common occurrence in pregnancy, its utility as a distinguishing factor in pre-eclampsia is not high. Pitting edema can be significant, and should be reported to a healthcare provider.Further, a symptom such as epigastric pain may be misinterpreted as heartburn. Standard features of pre-eclampsia, which are screened for during prenatal visits, include elevated blood pressure and excess protein in the urine. Additionally, some women may develop severe headaches as a sign of pre-eclampsia. In general, none of the signs of pre-eclampsia are specific, and even convulsions in pregnancy are more likely to have causes other than eclampsia in modern practice. Diagnosis depends on finding a coincidence of several pre-eclamptic features, the final proof being their regression within the days and weeks after delivery.
Causes
The cause of preeclampsia is not fully understood. It is likely related to factors such as:- Abnormal placentation
- Immunologic factors
- Prior or existing maternal pathologypre-eclampsia is seen more at a higher incidence in individuals with pre-existing hypertension, obesity, or antiphospholipid antibody syndrome, or those with a history of pre-eclampsia
- Dietary factors, e.g., calcium supplementation in areas where dietary calcium intake is low, have been shown to reduce the risk of pre-eclampsia
- Environmental factors, e.g. air pollution
- Infection, including at the time of conception.
Physiologically, research has linked pre-eclampsia to the following physiologic changes: alterations in the interaction between the maternal immune response and the placenta, placental injury, endothelial cell injury, altered vascular reactivity, oxidative stress, imbalance among vasoactive substances, decreased intravascular volume, and disseminated intravascular coagulation.
While the exact cause of pre-eclampsia remains unclear, there is strong evidence that a major cause predisposing a susceptible woman to pre-eclampsia is an abnormally implanted placenta. This abnormally implanted placenta may result in poor uterine and placental perfusion, yielding a state of hypoxia and increased oxidative stress and the release of anti-angiogenic proteins along with inflammatory mediators into the maternal plasma. A major consequence of this sequence of events is generalized endothelial dysfunction. The abnormal implantation may stem from the maternal immune system's response to the placenta, specifically a lack of established immunological tolerance in pregnancy. Endothelial dysfunction results in hypertension and many of the other symptoms and complications associated with pre-eclampsia. When pre-eclampsia develops in the last weeks of pregnancy or a multiple pregnancy, the causation may, in some cases, partly be due to a large placenta outgrowing the capacity of the uterus, eventually leading to the symptoms of pre-eclampsia.
Abnormal chromosome 19 microRNA cluster impairs extravillus trophoblast cell invasion to the spiral arteries, causing high resistance, low blood flow, and low nutrient supply to the fetus.
Genetic factors
Despite a lack of knowledge on specific causal mechanisms of pre-eclampsia, there is strong evidence to suggest it results from both environmental and heritable factors. A 2005 study showed that women with a first-degree relative who had a pre-eclamptic birth are twice as likely to develop it themselves. Furthermore, men related to someone with affected birth have an increased risk of fathering a pre-eclamptic pregnancy. Fetuses affected by pre-eclampsia have a higher chance of later pregnancy complications including growth restriction, prematurity, and stillbirth.The onset of pre-eclampsia is thought to be caused by several complex interactions between genetics and environmental factors. Our current understanding of the specifically heritable cause involves an imbalance of angiogenic factors in the placenta. Angiogenesis involves the growth of new blood vessels from existing vessels. An imbalance during pregnancy can affect the vascularization, growth, and biological function of the fetus. The irregular expression of these factors is thought to be controlled by multiple loci on different chromosomes. Research on the topic has been limited because of the heterogeneous nature of the disease. Maternal, paternal, and fetal genotypes play a role, as do complex epigenetic factors such as whether the parents smoke, maternal age, sexual cohabitation, and obesity. There is very little understanding of the mechanisms of these interactions. Due to the polygenic nature of pre-eclampsia, a majority of the studies that have been conducted thus far on the topic have utilized genome-wide association studies.
One known effector of pre-eclampsia is the fetal locus FLT1. Located on chromosome 13 in the q12 region, FLT1 codes for Fms-like tyrosine kinase 1, an angiogenic factor expressed in fetal trophoblasts. Angiogenic factors are crucial for vascular growth in the placenta. An FLT1 soluble isoform caused by a splice variant is sFLT1, which works as an antiangiogenic factor, reducing vascular growth in the placenta. A healthy, normotensive pregnancy is characterized by a balance between these factors. However, upregulation of this variant and overexpression of sFL1 can contribute to endothelial dysfunction. Reduced vascular growth and endothelial dysfunction manifest primarily in maternal symptoms such as kidney failure, swelling, and seizures. However, these factors can also lead to inadequate oxygen, nutrient, or blood supply to the fetus. Furthermore, in this locus region, several single-nucleotide polymorphisms have been observed to impact the overexpression of sFL1. Specifically, SNPs rs12050029 and rs4769613's risk alleles are linked with low red blood cell counts and carry an increased risk of late-onset pre-eclampsia.
Patau syndrome, or Trisomy 13, is also associated with the upregulation of sFLT1 due to the extra copy of the 13th chromosome. Because of this upregulation of an antiangiogenic factor, women with trisomy 13 pregnancies often experience reduced placental vascularization and are at higher risk for developing pre-eclampsia.
Beyond fetal loci, some maternal loci have been identified as effectors of pre-eclampsia. Alpha-ketoglutarate-dependent hydroxylase expression on chromosome 16 in the q12 region is also associated with pre-eclampsia. Specifically, allele rs1421085 heightens the risk of not just pre-eclampsia but also an increase in BMI and hypertension. This pleiotropy is one of the reasons why these traits are considered to be a risk factor. Furthermore, ZNF831 and its loci on chromosome 20q13 were identified as another significant factor in pre-eclampsia. The risk allele rs259983 is also associated with both pre-eclampsia and hypertension, further evidence that the two traits are possibly linked.
While the current understanding suggests that maternal alleles are the main hereditary cause of pre-eclampsia, paternal loci have also been implicated. In one study, paternal DLX5 was identified as an imprinted gene. Located on chromosome 7 in the q21 region, DLX5 serves as a transcription factor often linked with the developmental growth of organs. When paternally inherited, DLX5 and its SNP rs73708843 are shown to play a role in trophoblast proliferation, affecting vascular growth and nutrient delivery.
Besides specific loci, several important genetic regulatory factors contribute to the development of pre-eclampsia. Micro RNAs, or miRNAs, are noncoding mRNAs that downregulate posttranscriptional gene expression through RNA-induced silencing complexes. In the placenta, miRNAs are crucial for regulating cell growth, angiogenesis, cell proliferation, and metabolism. These placental-specific miRNAs are clustered in large groups, mainly on chromosomes 14 and 19, and irregular expression of either is associated with an increased risk of an affected pregnancy. For instance, miR-16 and miR-29 are vascular endothelial growth factors and play a role in upregulating sFLT-1. In particular, the overexpression of miRNA miR-210 has been shown to induce hypoxia, which affects spiral artery remodeling, an important part of the pathogenesis of pre-eclampsia.