Mortality rate

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Mortality_rate

Mortality rate of countries, deaths per thousand

Mortality rate, or death rate, is a measure of the number of deaths (in general, or due to a specific cause) in a particular population, scaled to the size of that population, per unit of time. Mortality rate is typically expressed in units of deaths per 1,000 individuals per year; thus, a mortality rate of 9.5 (out of 1,000) in a population of 1,000 would mean 9.5 deaths per year in that entire population, or 0.95% out of the total. It is distinct from "morbidity", which is either the prevalence or incidence of a disease, and also from the incidence rate (the number of newly appearing cases of the disease per unit of time).

An important specific mortality rate measure is the crude death rate, which looks at mortality from all causes in a given time interval for a given population. As of 2020, for instance, the CIA estimates that the crude death rate globally will be 7.7 deaths per 1,000 people in a population per year. In a generic form, mortality rates can be seen as calculated using ${\displaystyle (d/p)\cdot {10}^n}$, where d represents the deaths from whatever cause of interest is specified that occur within a given time period, p represents the size of the population in which the deaths occur (however this population is defined or limited), and ${\displaystyle {10}^n}$is the conversion factor from the resulting fraction to another unit (e.g., multiplying by ${\displaystyle {10}^3}$to get mortality rate per 1,000 individuals).

Crude death rate, globally

The crude death rate is defined as "the mortality rate from all causes of death for a population," calculated as the "[t]otal number of deaths during a given time interval" divided by the "[m]id-interval population", per 1,000 or 100,000; for instance, the population of the U.S. was around 290,810,000 in 2003, and in that year, approximately 2,419,900 deaths occurred in total, giving a crude death (mortality) rate of 832 deaths per 100,000. As of 2020, the CIA estimates the U.S. crude death rate will be 8.3 per 1,000, while it estimates that the global rate will be 7.7 per 1,000.

According to the World Health Organization, the ten leading causes of death, globally, in 2016, for both sexes and all ages, were as presented in the table below.

Crude death rate, per 100,000 population

1. Ischaemic heart disease, 126
2. Stroke, 77
3. Chronic obstructive pulmonary disease, 41
4. Lower respiratory infections, 40
5. Alzheimer's disease and other dementias, 27
6. Trachea, bronchus, and lung cancers, 23
7. Diabetes mellitus, 21
8. Road injury, 19
9. Diarrhoeal diseases, 19
10. Tuberculosis, 17

Mortality rate is also measured per thousand. It is determined by how many people of a certain age die per thousand people. Decrease of mortality rate is one of the reasons for increase of population. Development of medical science and other technologies has resulted in the decrease of mortality rate in all the countries of the world for some decades. In 1990, the mortality rate of children under 5 years of age was 144 per thousand, but in 2015 the child mortality rate was 38 per thousand.

Related measures of mortality

Other specific measures of mortality include:

Measures of mortality

Name	Typical definition
Perinatal mortality rate	The sum of fetal deaths (stillbirths) past 22 (or 28) completed weeks of pregnancy plus the number of deaths among live-born children up to 7 completed days of life, divided by number of births.
Maternal mortality rate	Number of deaths of mothers assigned to pregnancy-related causes during a given time interval, divided by the number of live births during the same time interval.
Infant mortality rate	Number of deaths among children <1 year of age during a given time interval divided by the number of live births during the same time interval.
Child mortality rate (also known as 'Under-five mortality rate')	Number of deaths of children less than 5 years old, divided by number of live births.
Standardized mortality ratio (SMR)	The ratio of the number of deaths in a given (index) population to the number of deaths expected, a form of indirectly (as opposed to directly) standardized rates, where the categories are usually "defined by age, gender and race or ethnicity". The numerator is calculated as ${\displaystyle \sum n_i{R}_i}$, where "${\displaystyle n_i}$ is the number of persons in category ${\displaystyle i}$ of the index population and ${\displaystyle R_i}$ is the corresponding category-specific event rate in a standard population." It has also been described as a proportional comparison to the numbers of deaths that would have been expected if the population had been of a standard composition in terms of age, gender, etc.
Age-specific mortality rate (ASMR)	The total number of deaths per year at a specific age, divided by the number of living persons at that age (e.g. age 62 at last birthday)
Cause-specific death rate	Number of deaths assigned to a specific cause during a given time interval divided by the mid-interval population
Cumulative death rate	The incidence proportion of death, that is, the proportion of a [defined] group that dies over a specified time interval,  whether in reference to all deaths over the time inverval, to "to deaths from a specific cause or causes". It has also been described as a measure of the (growing) proportion of a group that die over a specified period (often as estimated by techniques that account for missing data by statistical censoring).
Case fatality rate (CFR)	The proportion of diagnosed cases of a particular medical condition that lead to death.
Infection fatality rate (IFR)	The proportion of infected cases of a particular medical condition that lead to death. Similar to CFR, but adjusted for asymptomatic and undiagnosed cases.

For any of these, a "sex-specific mortality rate" refers to "a mortality rate among either males or females", where the calculation involves both "numerator and denominator... limited to the one sex".

Use in epidemiology

In most cases there are few if any ways to obtain exact mortality rates, so epidemiologists use estimation to predict correct mortality rates. Mortality rates are usually difficult to predict due to language barriers, health infrastructure related issues, conflict, and other reasons. Maternal mortality has additional challenges, especially as they pertain to stillbirths, abortions, and multiple births. In some countries, during the 1920s, a stillbirth was defined as "a birth of at least twenty weeks' gestation in which the child shows no evidence of life after complete birth". In most countries, however, a stillbirth was defined as "the birth of a fetus, after 28 weeks of pregnancy, in which pulmonary respiration does not occur".

Census data and vital statistics

Ideally, all mortality estimation would be done using vital statistics and census data. Census data will give detailed information about the population at risk of death. The vital statistics provide information about live births and deaths in the population. Often, either census data and vital statistics data is not available. This is common in developing countries, countries that are in conflict, areas where natural disasters have caused mass displacement, and other areas where there is a humanitarian crisis. 

Household surveys

Household surveys or interviews are another way in which mortality rates are often assessed. There are several methods to estimate mortality in different segments of the population. One such example is the sisterhood method, which involves researchers estimating maternal mortality by contacting women in populations of interest and asking whether or not they have a sister, if the sister is of child-bearing age (usually 15) and conducting an interview or written questions about possible deaths among sisters. The sisterhood method, however, does not work in cases where sisters may have died before the sister being interviewed was born.

Orphanhood surveys estimate mortality by questioning children are asked about the mortality of their parents. It has often been criticized as an adult mortality rate that is very biased for several reasons. The adoption effect is one such instance in which orphans often do not realize that they are adopted. Additionally, interviewers may not realize that an adoptive or foster parent is not the child's biological parent. There is also the issue of parents being reported on by multiple children while some adults have no children, thus are not counted in mortality estimates.

Widowhood surveys estimate adult mortality by responding to questions about the deceased husband or wife. One limitation of the widowhood survey surrounds the issues of divorce, where people may be more likely to report that they are widowed in places where there is the great social stigma around being a divorcee. Another limitation is that multiple marriages introduce biased estimates, so individuals are often asked about first marriage. Biases will be significant if the association of death between spouses, such as those in countries with large AIDS epidemics.

Sampling

Sampling refers to the selection of a subset of the population of interest to efficiently gain information about the entire population. Samples should be representative of the population of interest. Cluster sampling is an approach to non-probability sampling; this is an approach in which each member of the population is assigned to a group (cluster), and then clusters are randomly selected, and all members of selected clusters are included in the sample. Often combined with stratification techniques (in which case it is called multistage sampling), cluster sampling is the approach most often used by epidemiologists. In areas of forced migration, there is more significant sampling error. Thus cluster sampling is not the ideal choice.

Mortality statistics

For worldwide statistics, see List of sovereign states and dependent territories by mortality rate.

Causes of death vary greatly between developed and less developed countries; see also list of causes of death by rate for worldwide statistics.

World historical and predicted crude death rates (1950–2050)
UN, medium variant, 2012 rev.

Years	CDR	Years	CDR
1950–1955	19.1	2000–2005	8.4
1955–1960	17.3	2005–2010	8.1
1960–1965	16.2	2010–2015	8.1
1965–1970	12.9	2015–2020	8.1
1970–1975	11.6	2020–2025	8.1
1975–1980	10.6	2025–2030	8.3
1980–1985	10.0	2030–2035	8.6
1985–1990	9.4	2035–2040	9.0
1990–1995	9.1	2040–2045	9.4
1995–2000	8.8	2045–2050	9.7

Scatter plot of the natural logarithm (ln) of the crude death rate against the natural log of per capita GDP. The slope of the trend line is the elasticity of the crude death rate with respect to per capita income. It indicates that as of the date of the basis data set, an increase in per capita income tends to be associated with a decrease in the crude death rate. Source: World Development Indicators.

According to Jean Ziegler (the United Nations Special Rapporteur on the Right to Food for 2000 to March 2008), mortality due to malnutrition accounted for 58% of the total mortality in 2006: "In the world, approximately 62 million people, all causes of death combined, die each year. In 2006, more than 36 million died of hunger or diseases due to deficiencies in micronutrients".

Of the roughly 150,000 people who die each day across the globe, about two thirds—100,000 per day—die of age-related causes. In industrialized nations, the proportion is much higher, reaching 90%.

Economics

Scholars have stated that there is a significant relationship between a low standard of living that results from low income; and increased mortality rates. A low standard of living is more likely to result in malnutrition, which can make people more susceptible to disease and more likely to die from these diseases. A lower standard of living may lead to as a lack of hygiene and sanitation, increased exposure to and the spread of disease, and a lack of access to proper medical care and facilities. Poor health can in turn contribute to low and reduced incomes, which can create a loop known as the health-poverty trap. Indian economist and philosopher Amartya Sen has stated that mortality rates can serve as an indicator of economic success and failure.

Historically, mortality rates have been adversely affected by short term price increases. Studies have shown that mortality rates increase at a rate concurrent with increases in food prices. These effects have a greater impact on vulnerable, lower-income populations than they do on populations with a higher standard of living.

In more recent times, higher mortality rates have been less tied to socio-economic levels within a given society, but have differed more between low and high-income countries. It is now found that national income, which is directly tied to standard of living within a country, is the largest factor in mortality rates being higher in low-income countries.

Preventable mortality

These rates are especially pronounced for children under 5 years old, particularly in lower-income, developing countries. These children have a much greater chance of dying of diseases that have become mostly preventable in higher-income parts of the world. More children die of malaria, respiratory infections, diarrhea, perinatal conditions, and measles in developing nations. Data shows that after the age of 5 these preventable causes level out between high and low-income countries.

NMDA receptor antagonist

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/NMDA_receptor_antagonist 

Ketamine, one of the most popular NMDA receptor antagonists.

NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for human and non-human animals; the state of anesthesia they induce is referred to as dissociative anesthesia.

Several synthetic opioids function additionally as NMDAR-antagonists, such as pethidine, levorphanol, methadone, dextropropoxyphene, tramadol, and ketobemidone.

Some NMDA receptor antagonists, such as ketamine, dextromethorphan (DXM), phencyclidine (PCP), methoxetamine (MXE), and nitrous oxide (N₂O), are sometimes used as recreational drugs, for their dissociative, hallucinogenic, and euphoriant properties. When used recreationally, they are classified as dissociative drugs.

Uses and effects

NMDA receptor antagonists induce a state called dissociative anesthesia, marked by catalepsy, amnesia, and analgesia. Ketamine is a favored anesthetic for emergency patients with unknown medical history and in the treatment of burn victims because it depresses breathing and circulation less than other anesthetics. Dextrorphan, a metabolite of dextromethorphan (one of the most commonly used cough suppressants in the world), is known to be an NMDA receptor antagonist.

Numerous detrimental symptoms are linked to depressed NMDA receptor function. For example, NMDA receptor hypofunction that occurs as the brain ages may be partially responsible for memory deficits associated with aging. Schizophrenia may also have to do with irregular NMDA receptor function (the glutamate hypothesis of schizophrenia). Increased levels of another NMDA antagonist, kynurenic acid, may aggravate the symptoms of schizophrenia, according to the "kynurenic hypothesis". NMDA receptor antagonists can mimic these problems; they sometimes induce "psychotomimetic" side effects, symptoms resembling psychosis. Such side effects caused by NMDA receptor inhibitors include hallucinations, paranoid delusions, confusion, difficulty concentrating, agitation, alterations in mood, nightmares, catatonia, ataxia, anesthesia, and learning and memory deficits.

Because of these psychotomimetic effects, NMDA receptor antagonists, especially phencyclidine, ketamine, and dextromethorphan, are used as recreational drugs. At subanesthetic doses, these drugs have mild stimulant effects and, at higher doses, begin inducing dissociation and hallucinations, though these effects and the strength thereof vary from drug to drug.

Most NMDA receptor antagonists are metabolized in the liver. Frequent administration of most NMDA receptor antagonists can lead to tolerance, whereby the liver will more quickly eliminate NMDA receptor antagonists from the bloodstream.

NMDA receptor antagonists are also under investigation as antidepressants. Ketamine has been demonstrated to produce lasting antidepressant effects after administration in a clinical setting. In 2019, esketamine, an NMDA antagonist enantiomer of ketamine, was approved for use as an antidepressant in the United States. In 2022, Auvelity was approved by the FDA for the treatment of depression. This combination medication contains dextromethorphan, an NMDA receptor antagonist.

Neurotoxicity

Main article: Olney's lesions

Olney's lesions involve mass vacuolization of neurons observed in rodents. However, many suggest that this is not a valid model of human use, and studies conducted on primates have shown that use must be heavy and chronic to cause neurotoxicity. A 2009 review found no evidence of ketamine-induced neuron death in humans. However, temporary and permanent cognitive impairments have been shown to occur in long-term or heavy human users of the NMDA antagonists PCP and ketamine. A large-scale, longitudinal study found that current frequent ketamine users have modest cognitive deficits, while infrequent or former heavy users do not. Many drugs have been found that lessen the risk of neurotoxicity from NMDA receptor antagonists. Centrally acting alpha 2 agonists such as clonidine and guanfacine are thought to most directly target the etiology of NMDA neurotoxicity. Other drugs acting on various neurotransmitter systems known to inhibit NMDA antagonist neurotoxicity include: anticholinergics, diazepam, barbiturates, ethanol, 5-HT_2A serotonin receptor agonists, anticonvulsants, and muscimol.

Potential for treatment of excess excitotoxicity

Since NMDA receptor overactivation is implicated in excitotoxicity, NMDA receptor antagonists have held much promise for the treatment of conditions that involve excitotoxicity, including benzodiazepine withdrawal, traumatic brain injury, stroke, and neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's. This is counterbalanced by the risk of developing Olney's lesions, and studies have started to find agents that prevent this neurotoxicity. Most clinical trials involving NMDA receptor antagonists have failed due to unwanted side effects of the drugs; since the receptors also play an important role in normal glutamatergic neurotransmission, blocking them causes side-effects. These results have not yet been reproduced in humans, however. Mild NMDA receptor antagonists like amitriptyline have been found to be helpful in benzodiazepine withdrawal.

Mechanism of action

Simplified model of NMDAR activation and various types of NMDAR blockers.

The NMDA receptor is an ionotropic receptor that allows for the transfer of electrical signals between neurons in the brain and in the spinal column. For electrical signals to pass, the NMDA receptor must be open. To remain open, glutamate and glycine must bind to the NMDA receptor. An NMDA receptor that has glycine and glutamate bound to it and has an open ion channel is called "activated."

Chemicals that deactivate the NMDA receptor are called antagonists. NMDAR antagonists fall into four categories: Competitive antagonists blocks, binding to neurotransmitter glutamate sites; glycine antagonists blocks, binding to glycine sites; noncompetitive antagonists inhibits, binding to NMDARs allosteric sites; and uncompetitive antagonists blocks, binding to a site within the ion channel.

Examples

Competitive antagonists

• AP5 (APV, R-2-amino-5-phosphonopentanoate).
• AP7 (2-amino-7-phosphonoheptanoic acid).
• CGP-37849
• CPPene (3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid).
• Selfotel: an anxiolytic, anticonvulsant but with possible neurotoxic effects.

Uncompetitive channel blockers

• 3-MeO-PCP: an analogue of PCP
• 8A-PDHQ: a high affinity PCP structural analogue.
• Amantadine: used for treating Parkinson's disease, influenza, and Alzheimer's disease.
• Atomoxetine: a norepinephrine reuptake inhibitor used in the treatment of ADHD.
• AZD6765.
• Agmatine: Blocks NMDA receptors and other cation ligand-gated channels. Can also potentiate opioid analgesia.
• Argiotoxin: polyamine toxins produced by the orb-weaver spider (Araneus gemma and Argiope lobata)
• Chloroform: an early anesthetic.
• Cyclopropane: an early anesthetic.
• Delucemine: also an SSRI with neuroprotective properties.
• Desflurane: an inhalational anesthetic.
• Dextrallorphan: a more potent analogue of dextromethorphan.
• Dextromethorphan: an antitussive found in OTC cough medicines.
• Dextrorphan: active metabolite of dextromethorphan.
• Dextromethadone: (S)-enantiomer of the drug methadone that has low affinity for opioid receptors and exhibits rapid antidepressant effects in animal models.
• Diphenidine: a designer drug and PCP analogue sold on the internet.
• Dizocilpine (MK-801): an experimental drug used in scientific research.
• Ethanol: also known as alcohol, a widely used intoxicant.
• Eticyclidine: a slightly more potent dissociative anesthetic than phencyclidine but with greater nausea/unpleasant taste, that was discontinued early in its development due to these digestive complaints.
• Gacyclidine: an experimental drug developed for neuroprotection and is being studied for the treatment of tinnitus.
• Halothane: an inhalational anesthetic.
• Isoflurane: an inhalational anesthetic.
• Ketamine: a dissociative hallucinogen with antidepressant properties used as an anesthetic in humans and animals, a possible treatment in bipolar disorder patients with treatment-resistant depression, and used recreationally for its effects on the CNS.
• Magnesium.
• Memantine: treatment for Alzheimer's disease.
• Methoxetamine: a novel designer drug sold on the internet.
• Methoxydine: 4-MeO-PCP.
• Minocycline.
• Neramexane: a memantine analogue with nootropic, antidepressant properties. Also a nicotinic acetylcholine antagonist.
• Nitromemantine: a novel memantine derivative.
• Nitrous oxide: used for anesthesia, particularly in dentistry.
• PD-137889: Potent NMDA receptor antagonist with roughly 30 times the potency of ketamine. Substitutes for PCP in animal studies.
• Phencyclidine: a dissociative anesthetic previously used in medicine, but its development was discontinued in the 1960s in favor of its successor ketamine due to its relatively high incidence of psychotomimetic effects. Abused recreational and legally controlled in most countries.
• Remacemide: a low affinity antagonist also a sodium-channel blocker.
• Rolicyclidine: a less potent analogue of phencyclidine, but seems to be seldom, if ever, abused.
• Sevoflurane: an inhalational anesthetic.
• Tenocyclidine: an analogue of phencyclidine that is more potent.
• Tiletamine: an animal anesthetic.
• Eliprodil: an anticonvulsant drug with neuroprotective properties.
• Etoxadrol: a potent dissociative similar to PCP.
• Dexoxadrol: similar to etoxadrol.
• WMS-2539: potent fluorinated derivative of dexoxadrol.
• NEFA: a moderate affinity antagonist.

Non-competitive antagonists

• Aptiganel (Cerestat, CNS-1102): binds the Mg²⁺ binding site within the channel of the NMDA receptor.
• HU-211: an enantiomer of the potent cannabinoid HU-210 which lacks cannabinoid effects and instead acts as a potent non-competitive NMDA antagonist.
• Huperzine A.
• Dipeptide D-Phe-L-Tyr. weakly inhibit NMDA/Gly-induced currents possibly by ifenprodil-like mechanism.
• Ibogaine: a naturally-occurring alkaloid found in plants of the family Apocynaceae. Has been used, albeit with limited evidence, to treat opioid and other addictions.
• Remacemide: principle metabolite is an uncompetitive antagonist with a low affinity for the binding site.
• Rhynchophylline an alkaloid, found in Kratom and Rubiaceae.
• Gabapentin: a calcium α₂δ ligand that is commonly used in diabetic neuropathy.

Glycine antagonists

These drugs act at the glycine binding site:

• Rapastinel (GLYX-13) (weak partial agonist; IA = ~20%).
• NRX-1074 (weak partial agonist).
• 7-Chlorokynurenic acid.
• 4-Chlorokynurenine (AV-101) (prodrug for 7-chlorokynurenic acid).
• 5,7-Dichlorokynurenic acid.
• Kynurenic acid (a naturally occurring antagonist).
• TK-40 (competitive antagonist at the GluN1 glycine binding site).
• 1-Aminocyclopropanecarboxylic acid (ACPC).
• L-Phenylalanine. a naturally occurring amino acid (equilibrium dissociation constant (K_B) from Schild regression is 573 μM).
• Xenon: an anesthetic.

See also: NMDA receptor modulator

Pre-eclampsia

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Pre-eclampsia

 

Pre-eclampsia
Other names	Preeclampsia toxaemia (PET)
A micrograph showing hypertrophic decidual vasculopathy, a finding seen in gestational hypertension and pre-eclampsia. H&E stain.
Specialty	Obstetrics
Symptoms	High blood pressure, protein in the urine
Complications	Red blood cell breakdown, low blood platelet count, impaired liver function, kidney problems, swelling, shortness of breath due to fluid in the lungs, eclampsia
Usual onset	After 20 weeks of pregnancy
Risk factors	Obesity, prior hypertension, older age, diabetes mellitus
Diagnostic method	BP > 140 mmHg systolic or 90 mmHg diastolic at two separate times
Prevention	Aspirin, calcium supplementation, treatment of prior hypertension
Treatment	Delivery, medications
Medication	Labetalol, methyldopa, magnesium sulfate
Frequency	2–8% of pregnancies
Deaths	46,900 hypertensive disorders in pregnancy (2015)

Pre-eclampsia is a multi-system disorder specific to pregnancy, characterized by the onset of high blood pressure and often a significant amount of protein in the urine. 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. When delivery becomes recommended depends on how severe the pre-eclampsia 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 have not been found to be useful for either treatment or prevention.

Pre-eclampsia affects 2–8% of pregnancies worldwide. Hypertensive disorders of pregnancy (which include pre-eclampsia) 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 for lightning. The first known description of the condition was by Hippocrates in the 5th century BC.

Signs and symptoms

Edema (especially in the hands and face) 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 (unusual swelling, particularly of the hands, feet, or face, notable by leaving an indentation when pressed on) can be significant, and should be reported to a health care provider.

Further, a symptom such as epigastric pain may be misinterpreted as heartburn. Common features of pre-eclampsia which are screened for during pre-natal visits include elevated blood pressure and excess protein in the urine. Additionally, some women may develop severe headache 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

There is no definitive known cause of pre-eclampsia, 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 pre-eclampsia
• Dietary factors, e.g. calcium supplementation in areas where dietary calcium intake is low has been shown to reduce the risk of pre-eclampsia
• 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 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 in 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 (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 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, 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. Currently, there is very little understanding behind 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 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 (SNPs) 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, there have been some maternal loci 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 (zinc finger protein 831) 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 (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 pre-eclampsia. 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 pre-eclampsia.

Risk factors

Known risk factors for pre-eclampsia include:

• Having never previously given birth
• Diabetes mellitus
• Obesity
• Advanced maternal age (>35 years)
• Kidney disease
• Untreated hypertension
• Prior history of pre-eclampsia
• Family history of pre-eclampsia
• Antiphospholipid antibody syndrome
• Multiple gestation
• Having donated a kidney
• Having sub-clinical hypothyroidism or thyroid antibodies
• Placental abnormalities such as placental ischemia
• Socioeconomics play a large role in the prevalence of these risk factors, and, like other processes, each risk factor plays a role in the likelihood of increased consequences (morbidity) to, and the complexity of care for, the hospitalized patient

Pathogenesis

Although much research into mechanism of pre-eclampsia has taken place, its exact pathogenesis remains uncertain. Pre-eclampsia is thought to result from an abnormal placenta, the removal of which ends the disease in most cases. During normal pregnancy, the placenta vascularizes to allow for the exchange of water, gases, and solutes, including nutrients and wastes, between maternal and fetal circulations. Abnormal development of the placenta leads to poor placental perfusion. The placenta of women with pre-eclampsia is abnormal and characterized by poor trophoblastic invasion. It is thought that this results in oxidative stress, hypoxia, and the release of factors that promote endothelial dysfunction, inflammation, and other possible reactions.

In normal early embryonic development, the outer epithelial layer contains cytotrophoblast cells, a stem cell type found in the trophoblast that later differentiates into the fetal placenta. These cells differentiate into many placental cells types, including extravillous trophoblast cells. Extravillous trophoblast cells are an invasive cell type which remodel the maternal spiral arteries by replacing the maternal epithelium and smooth muscle lining the spiral arteries, thus causing and maintaining spiral artery dilation. This prevents maternal vasoconstriction in the spiral arteries and allows for continued blood and nutrient supply to the growing fetus with low resistance and high blood flow.

The clinical manifestations of pre-eclampsia are associated with general endothelial dysfunction, including vasoconstriction and end-organ ischemia. Implicit in this generalized endothelial dysfunction may be an imbalance of angiogenic and anti-angiogenic factors. Both circulating and placental levels of soluble fms-like tyrosine kinase-1 (sFlt-1) are higher in women with pre-eclampsia than in women with normal pregnancy. sFlt-1 is an anti-angiogenic protein that antagonizes vascular endothelial growth factor (VEGF) and placental growth factor (PIGF), both of which are proangiogenic factors. Soluble endoglin (sEng) has also been shown to be elevated in women with pre-eclampsia and has anti-angiogenic properties, much like sFlt-1 does.

Both sFlt-1 and sEng are upregulated in all pregnant women to some extent, supporting the idea that hypertensive disease in pregnancy is a normal pregnancy adaptation gone awry. As natural killer cells are intimately involved in placentation and placentation involves a degree of maternal immune tolerance for a foreign placenta, it is not surprising that the maternal immune system might respond more negatively to the arrival of some placentae under certain circumstances, such as a placenta which is more invasive than normal. Initial maternal rejection of the placental cytotrophoblasts may be the cause of the inadequately remodeled spiral arteries in those cases of pre-eclampsia associated with shallow implantation, leading to downstream hypoxia and the appearance of maternal symptoms in response to upregulated sFlt-1 and sEng.

Oxidative stress may also play an important part in the pathogenesis of pre-eclampsia. The main source of reactive oxygen species (ROS) is the enzyme xanthine oxidase (XO) and this enzyme mainly occurs in the liver. One hypothesis is that the increased purine catabolism from placental hypoxia results in increased ROS production in the maternal liver and release into the maternal circulation that causes endothelial cell damage.

Abnormalities in the maternal immune system and insufficiency of gestational immune tolerance seem to play major roles in pre-eclampsia. One of the main differences found in pre-eclampsia is a shift toward Th₁ responses and the production of IFN-γ. The origin of IFN-γ is not clearly identified and could be the natural killer cells of the uterus, the placental dendritic cells modulating responses of T helper cells, alterations in synthesis of or response to regulatory molecules, or changes in the function of regulatory T cells in pregnancy. Aberrant immune responses promoting pre-eclampsia may also be due to an altered fetal allorecognition or to inflammatory triggers. It has been documented that fetal cells such as fetal erythroblasts as well as cell-free fetal DNA are increased in the maternal circulation in women who develop pre-eclampsia. These findings have given rise to the hypothesis that pre-eclampsia is a disease process by which a placental lesion such as hypoxia allows increased fetal material into the maternal circulation, that in turn leads to an immune response and endothelial damage, and that ultimately results in pre-eclampsia and eclampsia.

One hypothesis for vulnerability to pre-eclampsia is the maternal-fetal conflict between the maternal organism and fetus. After the first trimester trophoblasts enter the spiral arteries of the mother to alter the spiral arteries and thereby gain more access to maternal nutrients. Occasionally there is impaired trophoblast invasion that results in inadequate alterations to the uterine spiral arteries. It is hypothesized that the developing embryo releases biochemical signals that result in the woman developing hypertension and pre-eclampsia so that the fetus can benefit from a greater amount of maternal circulation of nutrients due to increased blood flow to the impaired placenta. This results in a conflict between maternal and fetal fitness and survival because the fetus is invested in only its survival and fitness while the mother is invested in this and subsequent pregnancies.

Another evolutionary hypothesis for vulnerability to pre-eclampsia is the idea of ensuring pair-bonding between the mother and father and paternal investment in the fetus. Researchers posit that pre-eclampsia is an adaptation for the mother to terminate investment in a fetus that might have an unavailable father, as determined by repeated semen exposure of the father to the mother. Various studies have shown that women who frequently had exposure to partners' semen before conception had a reduced risk of pre-eclampsia. Also, subsequent pregnancies by the same father had a reduced risk of pre-eclampsia while subsequent pregnancies by a different father had a higher risk of developing pre-eclampsia.

In pre-eclampsia, abnormal expression of chromosome 19 microRNA cluster (C19MC) in placental cell lines reduces extravillus trophoblast migration. Specific microRNAs in this cluster which might cause abnormal spiral artery invasion include miR-520h, miR-520b, and 520c-3p. This impairs extravillus trophoblast cells invasion to the maternal spiral arteries, causing high resistance and low blood flow and low nutrient supply to the fetus. There is tentative evidence that vitamin supplementation can decrease the risk.

Immune factors may also play a role.

Diagnosis

Pre-eclampsia laboratory values
Shorthand for laboratory values commonly used in pre-eclampsia. LDH=Lactate dehydrogenase, Uric acid=Uric acid, AST=Aspartate aminotransferase, ALT=Alanine aminotransferase, Plt=Platelets, Cr=Creatinine.
Reference range	LDH: 105–333 IU/L Uric Acid: 2.4–6.0 mg/dL AST: 5–40 U/L ALT: 7–56 U/L Plt: 140–450 x 109/L Cr: 0.6–1.2 mg/dL
MeSH	D007770
LOINC	Codes for pre-eclampsia

Testing for pre-eclampsia is recommended throughout pregnancy via measuring a woman's blood pressure.

Diagnostic criteria

Pre-eclampsia is diagnosed when a pregnant woman develops:

• Blood pressure ≥140 mmHg systolic or ≥90 mmHg diastolic on two separate readings taken at least four to six hours apart after 20 weeks' gestation in an individual with previously normal blood pressure.
• In a woman with essential hypertension beginning before 20 weeks' gestational age, the diagnostic criteria are an increase in systolic blood pressure (SBP) of ≥30 mmHg or an increase in diastolic blood pressure (DBP) of ≥15 mmHg.
• Proteinuria ≥ 0.3 grams (300 mg) or more of protein in a 24-hour urine sample or a SPOT urinary protein to creatinine ratio ≥0.3 or a urine dipstick reading of 1+ or greater (dipstick reading should only be used if other quantitative methods are not available).

Suspicion for pre-eclampsia should be maintained in any pregnancy complicated by elevated blood pressure, even in the absence of proteinuria. Ten percent of individuals with other signs and symptoms of pre-eclampsia and 20% of individuals diagnosed with eclampsia show no evidence of proteinuria. In the absence of proteinuria, the presence of new-onset hypertension (elevated blood pressure) and the new onset of one or more of the following is suggestive of the diagnosis of pre-eclampsia:

• Evidence of kidney dysfunction (oliguria, elevated creatinine levels)
• Impaired liver function (noted by liver function tests)
• Thrombocytopenia (platelet count <100,000/microliter)
• Pulmonary edema
• Ankle edema (pitting type)
• Cerebral or visual disturbances

Pre-eclampsia is a progressive disorder and these signs of organ dysfunction are indicative of severe pre-eclampsia. A systolic blood pressure ≥160 or diastolic blood pressure ≥110 and/or proteinuria >5g in a 24-hour period is also indicative of severe pre-eclampsia. Clinically, individuals with severe pre-eclampsia may also present epigastric/right upper quadrant abdominal pain, headaches, and vomiting. Severe pre-eclampsia is a significant risk factor for intrauterine fetal death.

A rise in baseline blood pressure (BP) of 30 mmHg systolic or 15 mmHg diastolic, while not meeting the absolute criteria of 140/90, is important to note but is not considered diagnostic.

Predictive tests

There have been many assessments of tests aimed at predicting pre-eclampsia, though no single biomarker is likely to be sufficiently predictive of the disorder. Predictive tests that have been assessed include those related to placental perfusion, vascular resistance, kidney dysfunction, endothelial dysfunction, and oxidative stress. Examples of notable tests include:

• Doppler ultrasonography of the uterine arteries to investigate for signs of inadequate placental perfusion. This test has a high negative predictive value among those individuals with a history of prior pre-eclampsia.
• Elevations in serum uric acid (hyperuricemia) is used by some to "define" pre-eclampsia, though it has been found to be a poor predictor of the disorder. Elevated levels in the blood (hyperuricemia) are likely due to reduced uric acid clearance secondary to impaired kidney function.
• Angiogenic proteins such as vascular endothelial growth factor (VEGF) and placental growth factor (PIGF) and anti-angiogenic proteins such as soluble fms-like tyrosine kinase-1 (sFlt-1) have shown promise for potential clinical use in diagnosing pre-eclampsia, though evidence is insufficient to recommend a clinical use for these markers.

A recent study, ASPRE, known to be the largest multi-country prospective trial, has reported a significant performance in identifying pregnant women at high risk of pre-eclampsia yet during the first trimester of pregnancy. Utilizing a combination of maternal history, mean arterial blood pressure, intrauterine Doppler and PlGF measurement, the study has shown a capacity to identify more than 75% of the women that will develop pre-eclampsia, allowing early intervention to prevent development of later symptoms. This approach is now officially recommended by the International Federation of Gynecologists & Obstetricians (FIGO), However this model particularly predict pre-eclampsia with onset before 34 weeks' of gestation, while prediction of pre-eclampsia with later onset remains challenging.

• Recent studies have shown that looking for podocytes (specialized cells of the kidney) in the urine has the potential to aid in the prediction of pre-eclampsia. Studies have demonstrated that finding podocytes in the urine may serve as an early marker of and diagnostic test for pre-eclampsia.

Differential diagnosis

Pre-eclampsia can mimic and be confused with many other diseases, including chronic hypertension, chronic renal disease, primary seizure disorders, gallbladder and pancreatic disease, immune or thrombotic thrombocytopenic purpura, antiphospholipid syndrome and hemolytic-uremic syndrome. It must be considered a possibility in any pregnant woman beyond 20 weeks of gestation. It is particularly difficult to diagnose when pre-existing conditions such as hypertension are present. Women with acute fatty liver of pregnancy may also present with elevated blood pressure and protein in the urine, but differ by the extent of liver damage. Other disorders that can cause high blood pressure include thyrotoxicosis, pheochromocytoma, and drug misuse.

Prevention

Preventive measures against pre-eclampsia have been heavily studied. Because the pathogenesis of pre-eclampsia is not completely understood, prevention remains a complex issue. Some currently accepted recommendations are:

Diet

Supplementation with a balanced protein and energy diet does not appear to reduce the risk of pre-eclampsia. Further, there is no evidence that changing salt intake has an effect.

Supplementation with antioxidants such as vitamin C, D and E has no effect on pre-eclampsia incidence; therefore, supplementation with vitamins C, E, and D is not recommended for reducing the risk of pre-eclampsia.

Calcium supplementation of at least 1 gram per day is recommended during pregnancy as it prevents pre-eclampsia where dietary calcium intake is low, especially for those at high risk. Higher selenium level is associated with lower incidence of pre-eclampsia. Higher cadmium level is associated with higher incidence of pre-eclampsia.

Aspirin

Taking aspirin is associated with a 1 to 5% reduction in pre-eclampsia and a 1 to 5% reduction in premature births in women at high risk. The World Health Organization recommends low-dose aspirin for the prevention of pre-eclampsia in women at high risk and recommends it be started before 20 weeks of pregnancy. The United States Preventive Services Task Force recommends a low-dose regimen for women at high risk beginning in the 12th week. Benefits are less if started after 16 weeks. Since 2018 the American College of Obstetricians and Gynecologists has recommended low-dose aspirin therapy as standard preventive treatment for pre-eclampsia. There is a reported problem of its efficacy when combined with paracetamol. Supplementation of aspirin with L-Arginine has shown favourable results.

The study ASPRE, besides its efficacy in identifying women suspected to develop pre-eclampsia, has also been able to demonstrate a strong drop in the rate of early pre-eclampsia (-82%) and preterm pre-eclampsia (-62%). The efficacy of aspirin is due to screening to identify high risk women, adjusted prophylaxis dosage (150 mg/day), timing of the intake (bedtime) and must start before week 16 of pregnancy.

Physical activity

There is insufficient evidence to recommend either exercise or strict bedrest as preventive measures of pre-eclampsia.

Smoking cessation

In low-risk pregnancies, the association between cigarette smoking and a reduced risk of pre-eclampsia has been consistent and reproducible across epidemiologic studies. High-risk pregnancies (those with pregestational diabetes, chronic hypertension, history of pre-eclampsia in a previous pregnancy, or multifetal gestation) showed no significant protective effect. The reason for this discrepancy is not definitively known; research supports speculation that the underlying pathology increases the risk of pre-eclampsia to such a degree that any measurable reduction of risk due to smoking is masked. However, the damaging effects of smoking on overall health and pregnancy outcomes outweighs the benefits in decreasing the incidence of pre-eclampsia. It is recommended that smoking be stopped prior to, during and after pregnancy.

Immune modulation

Some studies have suggested the importance of a woman's gestational immunological tolerance to her baby's father, as the baby and father share genetics. There is tentative evidence that ongoing exposure either by vaginal or oral sex to the same semen that resulted in the pregnancy decreases the risk of pre-eclampsia. As one early study described, "although pre-eclampsia is a disease of first pregnancies, the protective effect of multiparity is lost with change of partner". The study also concluded that although women with changing partners are strongly advised to use condoms to prevent sexually transmitted diseases, "a certain period of sperm exposure within a stable relation, when pregnancy is aimed for, is associated with protection against pre-eclampsia".

Several other studies have since investigated the decreased incidence of pre-eclampsia in women who had received blood transfusions from their partner, those with long preceding histories of sex without barrier contraceptives, and in women who had been regularly performing oral sex.

Having already noted the importance of a woman's immunological tolerance to her baby's paternal genes, several Dutch reproductive biologists decided to take their research a step further. Consistent with the fact that human immune systems tolerate things better when they enter the body via the mouth, the Dutch researchers conducted a series of studies that confirmed a surprisingly strong correlation between a diminished incidence of pre-eclampsia and a woman's practice of oral sex, and noted that the protective effects were strongest if she swallowed her partner's semen. A team from the University of Adelaide has also investigated to see if men who have fathered pregnancies which have ended in miscarriage or pre-eclampsia had low seminal levels of critical immune modulating factors such as TGF-beta. The team has found that certain men, dubbed "dangerous males", are several times more likely to father pregnancies that would end in either pre-eclampsia or miscarriage. Among other things, most of the "dangerous males" seemed to lack sufficient levels of the seminal immune factors necessary to induce immunological tolerance in their partners.

As the theory of immune intolerance as a cause of pre-eclampsia has become accepted, women with repeated pre-eclampsia, miscarriages, or in vitro fertilization failures could potentially be administered key immune factors such as TGF-beta along with the father's foreign proteins, possibly either orally, as a sublingual spray, or as a vaginal gel to be applied onto the vaginal wall before intercourse.

Treatment

The definitive treatment for pre-eclampsia is the delivery of the baby and placenta, but danger to the mother persists after delivery, and full recovery can take days or weeks. The timing of delivery should balance the desire for optimal outcomes for the baby while reducing risks for the mother. The severity of disease and the maturity of the baby are primary considerations. These considerations are situation-specific and management will vary with situation, location, and institution. Treatment can range from expectant management to expedited delivery by induction of labor or Caesarean section, in addition to medications. Important in management is the assessment of the mother's organ systems, management of severe hypertension, and prevention and treatment of eclamptic seizures. Separate interventions directed at the baby may also be necessary. Bed rest has not been found to be useful and is thus not routinely recommended.

Blood pressure

The World Health Organization recommends that women with severe hypertension during pregnancy should receive treatment with anti-hypertensive agents. Severe hypertension is generally considered systolic BP of at least 160 or diastolic BP of at least 110. Evidence does not support the use of one anti-hypertensive over another. The choice of which agent to use should be based on the prescribing clinician's experience with a particular agent, its cost, and its availability. Diuretics are not recommended for prevention of pre-eclampsia and its complications. Labetalol, hydralazine and nifedipine are commonly used antihypertensive agents for hypertension in pregnancy. ACE inhibitors and angiotensin receptor blockers are contraindicated as they affect fetal development.

The goal of treatment of severe hypertension in pregnancy is to prevent cardiovascular, kidney, and cerebrovascular complications. The target blood pressure has been proposed to be 140–160 mmHg systolic and 90–105 mmHg diastolic, although values are variable.

Prevention of eclampsia

The intrapartum and postpartum administration of magnesium sulfate is recommended in severe pre-eclampsia for the prevention of eclampsia. Further, magnesium sulfate is recommended for the treatment of eclampsia over other anticonvulsants. Magnesium sulfate acts by interacting with NMDA receptors.

Epidemiology

Pre-eclampsia affects approximately 2–8% of all pregnancies worldwide. The incidence of pre-eclampsia has risen in the U.S. since the 1990s, possibly as a result of increased prevalence of predisposing disorders, such as chronic hypertension, diabetes, and obesity.

Pre-eclampsia is one of the leading causes of maternal and perinatal morbidity and mortality worldwide. Nearly one-tenth of all maternal deaths in Africa and Asia and one-quarter in Latin America are associated with hypertensive diseases in pregnancy, a category that encompasses pre-eclampsia.

Pre-eclampsia is much more common in women who are pregnant for the first time. Women who have previously been diagnosed with pre-eclampsia are also more likely to experience pre-eclampsia in subsequent pregnancies. Pre-eclampsia is also more common in women who have pre-existing hypertension, obesity, diabetes, autoimmune diseases such as lupus, various inherited thrombophilias such as Factor V Leiden, renal disease, multiple gestation (twins or multiple birth), and advanced maternal age. Women who live at high altitude are also more likely to experience pre-eclampsia. Pre-eclampsia is also more common in some ethnic groups (e.g. African-Americans, Sub-Saharan Africans, Latin Americans, African Caribbeans, and Filipinos). Change of paternity in a subsequent pregnancy has been implicated as affecting risk, except in those with a family history of hypertensive pregnancy.

Eclampsia is a major complication of pre-eclampsia. Eclampsia affects 0.56 per 1,000 pregnant women in developed countries and almost 10 to 30 times as many women in low-income countries as in developed countries.

Complications

Complications of pre-eclampsia can affect both the mother and the fetus. Acutely, pre-eclampsia can be complicated by eclampsia, the development of HELLP syndrome, hemorrhagic or ischemic stroke, liver damage and dysfunction, acute kidney injury, and acute respiratory distress syndrome (ARDS).

Pre-eclampsia is also associated with increased frequency of Caesarean section, preterm delivery, and placental abruption. Furthermore, an elevation in blood pressure can occur in some individuals in the first week postpartum attributable to volume expansion and fluid mobilization. Fetal complications include fetal growth restriction and potential fetal or perinatal death.

Long-term, an individual with pre-eclampsia is at increased risk for recurrence of pre-eclampsia in subsequent pregnancies.

Eclampsia

Eclampsia is the development of new convulsions in a pre-eclamptic patient that may not be attributed to other causes. It is a sign that the underlying pre-eclamptic condition is severe and is associated with high rates of perinatal and maternal morbidity and mortality. Warning symptoms for eclampsia in an individual with current pre-eclampsia may include headaches, visual disturbances, and right upper quadrant or epigastric abdominal pain, with a headache being the most consistent symptom. During pregnancy brisk or hyperactive reflexes are common, however ankle clonus is a sign of neuromuscular irritability that usually reflects severe pre-eclampsia and also can precede eclampsia. Magnesium sulfate is used to prevent convulsions in cases of severe pre-eclampsia.

HELLP Syndrome

HELLP syndrome is defined as hemolysis (microangiopathic), elevated liver enzymes (liver dysfunction), and low platelets (thrombocytopenia). This condition may occur in 10–20% of patients with severe pre-eclampsia and eclampsia and is associated with increased maternal and fetal morbidity and mortality. In 50% of instances, HELLP syndrome develops preterm, while 20% of cases develop in late gestation and 30% during the post-partum period.

Long term

Preeclampsia predisposes for future cardiovascular disease and a history of preeclampsia/eclampsia doubles the risk for cardiovascular mortality later in life.

 Other risks include stroke, chronic hypertension, kidney disease and venous thromboembolism. Preeclampsia and cardiovascular disease share many risk factors such as age, elevated BMI, family history and certain chronic diseases.

It seems that pre-eclampsia does not increase the risk of cancer.

Lowered blood supply to the fetus in pre-eclampsia causes lowered nutrient supply, which could result in intrauterine growth restriction (IUGR) and low birth weight. The fetal origins hypothesis states that fetal undernutrition is linked with coronary heart disease later in adult life due to disproportionate growth.

Because pre-eclampsia leads to a mismatch between the maternal energy supply and fetal energy demands, pre-eclampsia can lead to IUGR in the developing fetus. Infants with IUGR are prone to have poor neuronal development and in increased risk for adult disease according to the Barker hypothesis. Associated adult diseases of the fetus due to IUGR include, but are not limited to, coronary artery disease (CAD), type 2 diabetes mellitus (T2DM), cancer, osteoporosis, and various psychiatric illnesses.

The risk of pre-eclampsia and development of placental dysfunction has also been shown to be recurrent cross-generationally on the maternal side and most likely on the paternal side. Fetuses born to mothers who were born small for gestational age (SGA) were 50% more likely to develop pre-eclampsia while fetuses born to both SGA parents were three-fold more likely to develop pre-eclampsia in future pregnancies.

History

The word "eclampsia" is from the Greek term for lightning. 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.