There is no definitive known cause of<unk> , though it is likely related to a number of factors. Some of these factors include: * Abnormal placentation (formation and development of the placenta) * Immunologic factors * Prior or existing maternal pathology—pre-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<unk>  * Dietary factors, e.g. calcium supplementation in areas where dietary calcium intake is low has been shown to reduce the risk of<unk>  * Environmental factors, e.g. air pollution Those with long term high blood pressure have a risk 7 to 8 times higher than those without. Physiologically, research has linked<unk>  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<unk>  remains unclear, there is strong evidence that a major cause predisposing a susceptible woman to<unk>  is an abnormally implanted placenta. This abnormally implanted placenta may result in poor uterine and placental<unk> rfusion, 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<unk> . Those with<unk>  may have a lower risk of breast cancer. Abnormal chromosome 19 microRNA cluster (C19MC) 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<unk> , 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<unk>  have a higher chance of later pregnancy complications including growth restriction, prematurity, and stillbirth. The onset of<unk>  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, and 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 all play a role as well as complex epigenetic factors such as whether the parents smoke, maternal age, sexual cohabitation, and obesity (Phipps et al., 2019). Currently, there is very little understanding behind the mechanisms of these interactions. Due to the polygenic nature of<unk> , a majority of the studies that have been conducted thus far on the topic have utilized genome-wide association studies. One known effector of<unk>  is the fetal loci 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 renal failure, edema, and seizures. However, these factors can also lead to inadequate oxygen, nutrient, or blood supply to the fetus. Furthermore, in this loci 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<unk> . 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<unk> . Beyond fetal loci, there have been some maternal loci identified as effectors of<unk> . Alpha-ketoglutarate-dependent hydroxylase expression on the 16th chromosome in the q12 region is also associated with<unk> . Specifically, allele rs1421085 heightens the risk of not just<unk>  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 (zinc finger protein 831) and its loci on chromosome 20q13 were identified as another significant factor in<unk> . The risk allele rs259983 is also associated with both<unk>  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<unk> , paternal loci have also been implicated. In one study, paternal DLX5 (Distal-Less Homeobox 5) 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<unk> . Micro RNAs, or miRNAs, are noncoding mRNAs that down-regulate 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 (VEGFs) 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<unk> . Risk factors Known risk factors for<unk>  include: * Having never previously given birth * Diabetes mellitus * Kidney disease * Chronic hypertension * Prior history of<unk>  * Family history of<unk>  * Advanced maternal age (>35 years) * Obesity * Antiphospholipid antibody syndrome * Multiple gestation * Having donated a kidney * Having sub-clinical hypothyroidism or thyroid antibodies * Placental abnormalities such as placental ischemia
Pre-eclampsia
Eclampsia
Early pregnancy bleeding
Hypertensive disease of pregnancy
Gestational hypertension
Gestational diabetes
Antepartum bleeding
Recurrent miscarriage