<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Mesothelioma and explain in detail? [/INST] Mesothelioma is a type of cancer that develops from the thin layer of tissue that covers many of the internal organs (known as the mesothelium). The most common area affected is the lining of the lungs and chest wall. Less commonly the lining of the abdomen and rarely the sac surrounding the heart, or the sac surrounding the testis may be affected. Signs and symptoms of mesothelioma may include shortness of breath due to fluid around the lung, a swollen abdomen, chest wall pain, cough, feeling tired, and weight loss. These symptoms typically come on slowly.More than 80% of mesothelioma cases are caused by exposure to asbestos. The greater the exposure the greater the risk. As of 2013, about 125 million people worldwide have been exposed to asbestos at work. High rates of disease occur in people who mine asbestos, produce products from asbestos, work with asbestos products, live with asbestos workers, or work in buildings containing asbestos. Asbestos exposure and the onset of cancer are generally separated by about 40 years. Washing the clothing of someone who worked with asbestos also increases the risk. Other risk factors include genetics and infection with the simian virus 40. The diagnosis may be suspected based on chest X-ray and CT scan findings, and is confirmed by either examining fluid produced by the cancer or by a tissue biopsy of the cancer.Prevention focuses on reducing exposure to asbestos. Treatment often includes surgery, radiation therapy, and chemotherapy. A procedure known as pleurodesis, which involves using substances such as talc to scar together the pleura, may be used to prevent more fluid from building up around the lungs. Chemotherapy often includes the medications cisplatin and pemetrexed. The percentage of people that survive five years following diagnosis is on average 8% in the United States.In 2015, about 60,800 people had mesothelioma, and 32,000 died from the disease. Rates of mesothelioma vary in different areas of the world. Rates are higher in Australia, the United Kingdom, and lower in Japan. It occurs in about 3,000 people per year in the United States. It occurs more often in males than females. Rates of disease have increased since the 1950s. Diagnosis typically occurs after the age of 65 and most deaths occur around 70 years old. The disease was rare before the commercial use of asbestos.

Signs and symptoms
Lungs
Symptoms or signs of mesothelioma may not appear until 20 to 50 years (or more) after exposure to asbestos. Shortness of breath, cough, and pain in the chest due to an accumulation of fluid in the pleural space (pleural effusion) are often symptoms of pleural mesothelioma.Mesothelioma that affects the pleura can cause these signs and symptoms:
Chest wall pain
Pleural effusion, or fluid surrounding the lung
Shortness of breath – which could be due to a collapsed lung
Fatigue or anemia
Wheezing, hoarseness, or a cough
Blood in the sputum (fluid) coughed up (hemoptysis)In severe cases, the person may have many tumor masses. The individual may develop a pneumothorax, or collapse of the lung. The disease may metastasize, or spread to other parts of the body.

Abdomen
The most common symptoms of peritoneal mesothelioma are abdominal swelling and
pain due to ascites (a buildup of fluid in the abdominal cavity). Other features may include weight loss, fever, night sweats, poor appetite, vomiting, constipation, and umbilical hernia. If the cancer has spread beyond the mesothelium to other parts of the body, symptoms may include pain, trouble swallowing, or swelling of the neck or face. These symptoms may be caused by mesothelioma or by other, less serious conditions.Tumors that affect the abdominal cavity often do not cause symptoms until they are at a late stage. Symptoms include:
Abdominal pain
Ascites, or an abnormal buildup of fluid in the abdomen
A mass in the abdomen
Problems with bowel function
Weight loss

Heart
Pericardial mesothelioma is not well characterized, but observed cases have included cardiac symptoms, specifically constrictive pericarditis, heart failure, pulmonary embolism, and cardiac tamponade. They have also included nonspecific symptoms, including substernal chest pain, orthopnea (shortness of breath when lying flat), and cough. These symptoms are caused by the tumor encasing or infiltrating the heart.

End stage
In severe cases of the disease, the following signs and symptoms may be present:
Blood clots in the veins, which may cause thrombophlebitis
Disseminated intravascular coagulation, a disorder causing severe bleeding in many body organs
Jaundice, or yellowing of the eyes and skin
Low blood sugar
Pleural effusion
Pulmonary embolism, or blood clots in the arteries of the lungs
Severe ascitesIf a mesothelioma forms metastases, these most commonly involve the liver, adrenal gland, kidney, or other lung.

Causes
Working with asbestos is the most common risk factor for mesothelioma. However, mesothelioma has been reported in some individuals without any known exposure to asbestos. Tentative evidence also raises concern about carbon nanotubes.

Asbestos
The incidence of mesothelioma has been found to be higher in populations living near naturally occurring asbestos. People can be exposed to naturally occurring asbestos in areas where mining or road construction is occurring, or when the asbestos-containing rock is naturally weathered. Another common route of exposure is through asbestos-containing soil, which is used to whitewash, plaster, and roof houses in Greece. In central Cappadocia, Turkey, mesothelioma was causing 50% of all deaths in three small villages—Tuzköy, Karain, and Sarıhıdır. Initially, this was attributed to erionite. Environmental exposure to asbestos has caused mesothelioma in places other than Turkey, including Corsica, Greece, Cyprus, China, and California. In the northern Greek mountain town of Metsovo, this exposure had resulted in mesothelioma incidence around 300 times more than expected in asbestos-free populations, and was associated with very frequent pleural calcification known as Metsovo lung.The documented presence of asbestos fibers in water supplies and food products has fostered concerns about the possible impact of long-term and, as yet, unknown exposure of the general population to these fibers.Exposure to talc is also a risk factor for mesothelioma; exposure can affect those who live near talc mines, work in talc mines, or work in talc mills.In the United States, asbestos is considered the major cause of malignant mesothelioma and has been considered "indisputably" associated with the development of mesothelioma.  Indeed, the relationship between asbestos and mesothelioma is so strong that many consider mesothelioma a "signal" or "sentinel" tumor. A history of asbestos exposure exists in most cases.
Pericardial mesothelioma may not be associated with asbestos exposure.Asbestos was known in antiquity, but it was not mined and widely used commercially until the late 19th century. The dangers were not unknown in antiquity. Pliny the Elder, a Roman author and naturalist, observed that quarry slaves from asbestos mines tended to die young. Its use greatly increased during World War II. Since the early 1940s, millions of American workers have been exposed to asbestos dust. Initially, the risks associated with asbestos exposure were not publicly known. However, an increased risk of developing mesothelioma was later found among naval personnel (e.g., Navy, Marine Corps, and Coast Guard), shipyard workers, people who work in asbestos mines and mills, producers of asbestos products, workers in the heating and construction industries, and other tradespeople. Today, the official position of the U.S. Occupational Safety and Health Administration (OSHA) and the U.S. EPA is that protections and "permissible exposure limits" required by U.S. regulations, while adequate to prevent most asbestos-related non-malignant disease, are not adequate to prevent or protect against asbestos-related cancers such as mesothelioma. Likewise, the British Governments Health and Safety Executive (HSE) states formally that any threshold for exposure to asbestos must be at a very low level and it is widely agreed that if any such threshold does exist at all, then it cannot currently be quantified. For practical purposes, therefore, HSE assumes that no such "safe" threshold exists. Others have noted as well that there is no evidence of a threshold level below which there is no risk of mesothelioma. There appears to be a linear, dose–response relationship, with increasing dose producing increasing risk of disease. Nevertheless, mesothelioma may be related to brief, low level or indirect exposures to asbestos. The dose necessary for effect appears to be lower for asbestos-induced mesothelioma than for pulmonary asbestosis or lung cancer.  Again, there is no known safe level of exposure to asbestos as it relates to increased risk of mesothelioma.
The time from first exposure to onset of the disease, is between 25 and 70 years. It is virtually never less than fifteen years and peaks at 30–40 years. The duration of exposure to asbestos causing mesothelioma can be short. For example, cases of mesothelioma have been documented with only 1–3 months of exposure.

Occupational
Exposure to asbestos fibers has been recognized as an occupational health hazard since the early 20th century. Numerous epidemiological studies have associated occupational exposure to asbestos with the development of pleural plaques, diffuse pleural thickening, asbestosis, carcinoma of the lung and larynx, gastrointestinal tumors, and diffuse malignant mesothelioma of the pleura and peritoneum. Asbestos has been widely used in many industrial products, including cement, brake linings, gaskets, roof shingles, flooring products, textiles, and insulation.Commercial asbestos mining at Wittenoom, Western Australia, took place from 1937 to 1966. The first case of mesothelioma in the town occurred in 1960. The second case was in 1969, and new cases began to appear more frequently thereafter. The lag time between initial exposure to asbestos and the development of mesothelioma varied from 12 years 9 months up to 58 years. A cohort study of miners employed at the mine reported that 85 deaths attributable to mesothelioma had occurred by 1985. By 1994, 539 reported deaths due to mesothelioma had been reported in Western Australia.Occupational exposure to asbestos in the United States mainly occurs when people are maintaining buildings that already have asbestos. Approximately 1.3 million US workers are exposed to asbestos annually; in 2002, an estimated 44,000 miners were potentially exposed to asbestos.

Paraoccupational secondary exposure
Family members and others living with asbestos workers have an increased risk of developing mesothelioma, and possibly other asbestos-related diseases. This risk may be the result of exposure to asbestos dust brought home on the clothing and hair of asbestos workers via washing a workers clothes or coming into contact with asbestos-contaminated work clothing. To reduce the chance of exposing family members to asbestos fibres, asbestos workers are usually required to shower and change their clothing before leaving the workplace.

Asbestos in buildings
Many building materials used in both public and domestic premises prior to the banning of asbestos may contain asbestos. Those performing renovation works or DIY activities may expose themselves to asbestos dust. In the UK, use of chrysotile asbestos was banned at the end of 1999. Brown and blue asbestos were banned in the UK around 1985. Buildings built or renovated prior to these dates may contain asbestos materials.Therefore, it is a legal requirement that all who may come across asbestos in their day-to-day work have been provided with the relevant asbestos training.

Genetic disposition
In a recent research carried on white American population in 2012, it was found that people with a germline mutation in their BAP1 gene are at higher risk of developing mesothelioma and uveal melanoma.

Erionite
Erionite is a zeolite mineral with similar properties to asbestos and is known to cause mesothelioma. Detailed epidemiological investigation has shown that erionite causes mesothelioma mostly in families with a genetic predisposition. Erionite is found in deposits in the Western United States, where it is used in gravel for road surfacing, and in Turkey, where it is used to construct homes. In Turkey, the United States, and Mexico, erionite has been associated with mesothelioma and has thus been designated a "known human carcinogen" by the US National Toxicology Program.

Other
In rare cases, mesothelioma has also been associated with irradiation of the chest or abdomen, intrapleural thorium dioxide (thorotrast) as a contrast medium, and inhalation of other fibrous silicates, such as erionite or talc. Some studies suggest that simian virus 40 (SV40) may act as a cofactor in the development of mesothelioma. This has been confirmed in animal studies, but studies in humans are inconclusive.

Pathophysiology
Systemic
The mesothelium consists of a single layer of flattened to cuboidal cells forming the epithelial lining of the serous cavities of the body including the peritoneal, pericardial and pleural cavities. Deposition of asbestos fibers in the parenchyma of the lung may result in the penetration of the visceral pleura from where the fiber can then be carried to the pleural surface, thus leading to the development of malignant mesothelial plaques. The processes leading to the development of peritoneal mesothelioma remain unresolved, although it has been proposed that asbestos fibers from the lung are transported to the abdomen and associated organs via the lymphatic system. Additionally, asbestos fibers may be deposited in the gut after ingestion of sputum contaminated with asbestos fibers.Pleural contamination with asbestos or other mineral fibers has been shown to cause cancer. Long thin asbestos fibers (blue asbestos, amphibole fibers) are more potent carcinogens than "feathery fibers" (chrysotile or white asbestos fibers).  However, there is now evidence that smaller particles may be more dangerous than the larger fibers. They remain suspended in the air where they can be inhaled, and may penetrate more easily and deeper into the lungs. "We probably will find out a lot more about the health aspects of asbestos from [the World Trade Center attack], unfortunately," said Dr. Alan Fein, chief of pulmonary and critical-care medicine at North Shore-Long Island Jewish Health System.Mesothelioma development in rats has been demonstrated following intra-pleural inoculation of phosphorylated chrysotile fibers. It has been suggested that in humans, transport of fibers to the pleura is critical to the pathogenesis of mesothelioma. This is supported by the observed recruitment of significant numbers of macrophages and other cells of the immune system to localized lesions of accumulated asbestos fibers in the pleural and peritoneal cavities of rats. These lesions continued to attract and accumulate macrophages as the disease progressed, and cellular changes within the lesion culminated in a morphologically malignant tumor.Experimental evidence suggests that asbestos acts as a complete carcinogen with the development of mesothelioma occurring in sequential stages of initiation and promotion. The molecular mechanisms underlying the malignant transformation of normal mesothelial cells by asbestos fibers remain unclear despite the demonstration of its oncogenic capabilities (see next-but-one paragraph). However, complete in vitro transformation of normal human mesothelial cells to a malignant phenotype following exposure to asbestos fibers has not yet been achieved. In general, asbestos fibers are thought to act through direct physical interactions with the cells of the mesothelium in conjunction with indirect effects following interaction with inflammatory cells such as macrophages.

Intracellular
Analysis of the interactions between asbestos fibers and DNA has shown that phagocytosed fibers are able to make contact with chromosomes, often adhering to the chromatin fibers or becoming entangled within the chromosome. This contact between the asbestos fiber and the chromosomes or structural proteins of the spindle apparatus can induce complex abnormalities. The most common abnormality is monosomy of chromosome 22. Other frequent abnormalities include structural rearrangement of 1p, 3p, 9p and 6q chromosome arms.Common gene abnormalities in mesothelioma cell lines include deletion of the tumor suppressor genes:
Neurofibromatosis type 2 at 22q12
P16INK4A
P14ARFAsbestos has also been shown to mediate the entry of foreign DNA into target cells. Incorporation of this foreign DNA may lead to mutations and oncogenesis by several possible mechanisms:
Inactivation of tumor suppressor genes
Activation of oncogenes In tumor cells, these genes are often mutated, or expressed at high levels.
Activation of proto-oncogenes due to incorporation of foreign DNA containing a promoter region
Activation of DNA repair enzymes, which may be prone to error
Activation of telomerase
Prevention of apoptosisSeveral genes are commonly mutated in mesothelioma, and may be prognostic factors. These include epidermal growth factor receptor (EGFR) and C-Met, receptor tyrosine kinases which are overexpressed in many mesotheliomas. Some association has been found with EGFR and epithelioid histology but no clear association has been found between EGFR overexpression and overall survival. Expression of AXL receptor tyrosine kinase is a negative prognostic factor. Expression of PDGFRB is a positive prognostic factor. In general, mesothelioma is characterized by loss of function in tumor suppressor genes, rather than by an overexpression or gain of function in oncogenes.As an environmentally triggered malignancy, mesothelioma tumors have been found to be polyclonal in origin, by performing an X-inactivation based assay on epitheloid and biphasic tumors obtained from female patients. These results suggest that an environmental factor, most likely asbestos exposure, may damage and transform a group of cells in the tissue, resulting in a population of tumor cells that are, albeit only slightly, genetically different.

Immune system
Asbestos fibers have been shown to alter the function and secretory properties of macrophages, ultimately creating conditions which favour the development of mesothelioma. Following asbestos phagocytosis, macrophages generate increased amounts of hydroxyl radicals, which are normal by-products of cellular anaerobic metabolism. However, these free radicals are also known clastogenic (chromosome-breaking)
and membrane-active agents thought to promote asbestos carcinogenicity. These oxidants can participate in the oncogenic process by directly and indirectly interacting with DNA, modifying membrane-associated cellular events, including oncogene activation and perturbation of cellular antioxidant defences.Asbestos also may possess immunosuppressive properties. For example, chrysotile fibres have been shown to depress the in vitro proliferation of phytohemagglutinin-stimulated peripheral blood lymphocytes, suppress natural killer cell lysis and significantly reduce lymphokine-activated killer cell viability and recovery. Furthermore, genetic alterations in asbestos-activated macrophages may result in the release of potent mesothelial cell mitogens such as platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β) which in turn, may induce the chronic stimulation and proliferation of mesothelial cells after injury by asbestos fibres.

Diagnosis
Diagnosis of mesothelioma can be suspected with imaging but is confirmed with biopsy. It must be clinically and histologically differentiated from other pleural and pulmonary malignancies, including reactive pleural disease, primary lung carcinoma, pleural metastases of other cancers, and other primary pleural cancers.
Primary pericardial mesothelioma is often diagnosed after it has metastasized to lymph nodes or the lungs.

Imaging
Diagnosing mesothelioma is often difficult because the symptoms are similar to those of a number of other conditions. Diagnosis begins with a review of the patients medical history. A history of exposure to asbestos may increase clinical suspicion for mesothelioma. A physical examination is performed, followed by chest X-ray and often lung function tests. The X-ray may reveal pleural thickening commonly seen after asbestos exposure and increases suspicion of mesothelioma. A CT (or CAT) scan or an MRI is usually performed. If a large amount of fluid is present, abnormal cells may be detected by cytopathology if this fluid is aspirated with a syringe. For pleural fluid, this is done by thoracentesis or tube thoracostomy (chest tube); for ascites, with paracentesis or ascitic drain; and for pericardial effusion with pericardiocentesis. While absence of malignant cells on cytology does not completely exclude mesothelioma, it makes it much more unlikely, especially if an alternative diagnosis can be made (e.g., tuberculosis, heart failure). However, with primary pericardial mesothelioma, pericardial fluid may not contain malignant cells and a tissue biopsy is more useful in diagnosis. Using conventional cytology  diagnosis of malignant mesothelioma is difficult, but immunohistochemistry has greatly enhanced the accuracy of cytology.

Biopsy
Generally, a biopsy is needed to confirm a diagnosis of malignant mesothelioma. A doctor removes a sample of tissue for examination under a microscope by a pathologist. A biopsy may be done in different ways, depending on where the abnormal area is located. If the cancer is in the chest, the doctor may perform a thoracoscopy. In this procedure, the doctor makes a small cut through the chest wall and puts a thin, lighted tube called a thoracoscope into the chest between two ribs. Thoracoscopy allows the doctor to look inside the chest and obtain tissue samples. Alternatively, the cardiothoracic surgeon might directly open the chest (thoracotomy). If the cancer is in the abdomen, the doctor may perform a laparoscopy. To obtain tissue for examination, the doctor makes a small incision in the abdomen and inserts a special instrument into the abdominal cavity. If these procedures do not yield enough tissue, an open surgical procedure may be necessary.

Immunochemistry
Immunohistochemical studies play an important role for the pathologist in differentiating malignant mesothelioma from neoplastic mimics, such as breast or lung cancer that has metastasized to the pleura. There are numerous tests and panels available, but no single test is perfect for distinguishing mesothelioma from carcinoma or even benign versus malignant. The positive markers indicate that mesothelioma is present; if other markers are positive it may indicate another type of cancer, such as breast or lung adenocarcinoma. Calretinin is a particularly important marker in distinguishing mesothelioma from metastatic breast or lung cancer.

Subtypes
There are three main histological subtypes of malignant mesothelioma: epithelioid, sarcomatous, and biphasic. Epithelioid and biphasic mesothelioma make up approximately 75-95% of mesotheliomas and have been well characterized histologically, whereas sarcomatous mesothelioma has not been studied extensively. Most mesotheliomas express high levels of cytokeratin 5 regardless of subtype.Epithelioid mesothelioma is characterized by high levels of calretinin.Sarcomatous mesothelioma does not express high levels of calretinin.Other morphological subtypes have been described:

Desmoplastic
Clear cell
Deciduoid
Adenomatoid
Glandular
Mucohyaline
Cartilaginous and osseous metaplasia
Lymphohistiocytic

Differential diagnosis
Metastatic adenocarcinoma
Pleural sarcoma
Synovial sarcoma
Thymoma
Metastatic clear cell renal cell carcinoma
Metastatic osteosarcoma

Staging
Staging of mesothelioma is based on the recommendation by the International Mesothelioma Interest Group. TNM classification of the primary tumor, lymph node involvement, and distant metastasis is performed. Mesothelioma is staged Ia–IV (one-A to four) based on the TNM status.

Prevention
Mesothelioma can be prevented in most cases by preventing exposure to asbestos. The US National Institute for Occupational Safety and Health maintains a recommended exposure limit of 0.1 asbestos fiber per cubic centimeter.

Screening
There is no universally agreed protocol for screening people who have been exposed to asbestos. Screening tests might diagnose mesothelioma earlier than conventional methods thus improving the survival prospects for patients. The serum osteopontin level might be useful in screening asbestos-exposed people for mesothelioma. The level of soluble mesothelin-related protein is elevated in the serum of about 75% of patients at diagnosis and it has been suggested that it may be useful for screening. Doctors have begun testing the Mesomark assay, which measures levels of soluble mesothelin-related proteins (SMRPs) released by mesothelioma cells.

Treatment
Mesothelioma is generally resistant to radiation and chemotherapy treatment. Long-term survival and cures are exceedingly rare. Treatment of malignant mesothelioma at earlier stages has a better prognosis. Clinical behavior of the malignancy is affected by several factors including the continuous mesothelial surface of the pleural cavity which favors local metastasis via exfoliated cells, invasion to underlying tissue and other organs within the pleural cavity, and the extremely long latency period between asbestos exposure and development of the disease. The histological subtype and the patients age and health status also help predict prognosis. The epithelioid histology responds better to treatment and has a survival advantage over sarcomatoid histology.The effectiveness of radiotherapy compared to chemotherapy or surgery for malignant pleural mesothelioma is not known.

Surgery
Surgery, by itself, has proved disappointing. In one large series, the median survival with surgery (including extrapleural pneumonectomy) was only 11.7 months. However, research indicates varied success when used in combination with radiation and chemotherapy (Duke, 2008), or with one of the latter. A pleurectomy/decortication is the most common surgery, in which the lining of the chest is removed. Less common is an extrapleural pneumonectomy (EPP), in which the lung, lining of the inside of the chest, the hemi-diaphragm and the pericardium are removed. In localized pericardial mesothelioma, pericardectomy can be curative; when the tumor has metastasized, pericardectomy is a palliative care option. It is often not possible to remove the entire tumor.

Radiation
For patients with localized disease, and who can tolerate a radical surgery, radiation can be given post-operatively as a consolidative treatment. The entire hemithorax is treated with radiation therapy, often given simultaneously with chemotherapy.  Delivering radiation and chemotherapy after a radical surgery has led to extended life expectancy in selected patient populations. It can also induce severe side-effects, including fatal pneumonitis. As part of a curative approach to mesothelioma, radiotherapy is commonly applied to the sites of chest drain insertion, in order to prevent growth of the tumor along the track in the chest wall.Although mesothelioma is generally resistant to curative treatment with radiotherapy alone, palliative treatment regimens are sometimes used to relieve symptoms arising from tumor growth, such as obstruction of a major blood vessel. Radiation therapy, when given alone with curative intent, has never been shown to improve survival from mesothelioma. The necessary radiation dose to treat mesothelioma that has not been surgically removed would be beyond human tolerance. Radiotherapy is of some use in pericardial mesothelioma.

Chemotherapy
Chemotherapy is the only treatment for mesothelioma that has been proven to improve survival in randomised and controlled trials. The landmark study published in 2003 by Vogelzang and colleagues compared cisplatin chemotherapy alone with a combination of cisplatin and pemetrexed (brand name Alimta) chemotherapy in patients who had not received chemotherapy for malignant pleural mesothelioma previously and were not candidates for more aggressive "curative" surgery. This trial was the first to report a survival advantage from chemotherapy in malignant pleural mesothelioma, showing a statistically significant improvement in median survival from 10 months in the patients treated with cisplatin alone to 13.3 months in the group of patients treated with cisplatin in the combination with pemetrexed and who also received supplementation with folate and vitamin B12. Vitamin supplementation was given to most patients in the trial and pemetrexed related side effects were significantly less in patients receiving pemetrexed when they also received daily oral folate 500mcg and intramuscular vitamin B12 1000mcg every 9 weeks compared with patients receiving pemetrexed without vitamin supplementation. The objective response rate increased from 20% in the cisplatin group to 46% in the combination pemetrexed group. Some side effects such as nausea and vomiting, stomatitis, and diarrhoea were more common in the combination pemetrexed group but only affected a minority of patients and overall the combination of pemetrexed and cisplatin was well tolerated when patients received vitamin supplementation; both quality of life and lung function tests improved in the combination pemetrexed group. In February 2004, the United States Food and Drug Administration (FDA) approved pemetrexed for treatment of malignant pleural mesothelioma. However, there are still unanswered questions about the optimal use of chemotherapy, including when to start treatment, and the optimal number of cycles to give. Cisplatin and pemetrexed together give patients a median survival of 12.1 months.Cisplatin in combination with raltitrexed has shown an improvement in survival similar to that reported for pemetrexed in combination with cisplatin, but raltitrexed is no longer commercially available for this indication. For patients unable to tolerate pemetrexed, cisplatin in combination with gemcitabine or vinorelbine is an alternative, or vinorelbine on its own, although a survival benefit has not been shown for these drugs. For patients in whom cisplatin cannot be used, carboplatin can be substituted but non-randomised data have shown lower response rates and high rates of haematological toxicity for carboplatin-based combinations, albeit with similar survival figures to patients receiving cisplatin. Cisplatin in combination with premetrexed disodium, folic acid, and vitamin B12 may also improve survival for people who are responding to chemotherapy.In January 2009, the United States FDA approved using conventional therapies such as surgery in combination with radiation and or chemotherapy on stage I or II Mesothelioma after research conducted by a nationwide study by Duke University concluded an almost 50 point increase in remission rates.In pericardial mesothelioma, chemotherapy – typically adriamycin or cisplatin – is primarily used to shrink the tumor and is not curative.

Immunotherapy
Treatment regimens involving immunotherapy have yielded variable results. For example, intrapleural inoculation of Bacillus Calmette-Guérin (BCG) in an attempt to boost the immune response, was found to be of no benefit to the patient (while it may benefit patients with bladder cancer). Mesothelioma cells proved susceptible to in vitro lysis by LAK cells following activation by interleukin-2 (IL-2), but patients undergoing this particular therapy experienced major side effects. Indeed, this trial was suspended in view of the unacceptably high levels of IL-2 toxicity and the severity of side effects such as fever and cachexia. Nonetheless, other trials involving interferon alpha have proved more encouraging with 20% of patients experiencing a greater than 50% reduction in tumor mass combined with minimal side effects.In October 2020, the FDA approved the combination of nivolumab (Opdivo) with ipilimumab (Yervoy) for the first-line treatment of adults with malignant pleural mesothelioma (MPM) that cannot be removed by surgery. Nivolumab and ipilimumab are both monoclonal antibodies that, when combined, decrease tumor growth by enhancing T-cell function. The combination therapy was evaluated through a randomized, open-label trial in which participants who received nivolumab in combination with ipilimumab survived a median of 18.1 months while participants who underwent chemotherapy survived a median of 14.1 months.

Hyperthermic intrathoracic chemotherapy
Hyperthermic intrathoracic chemotherapy is used in conjunction with surgery, including in patients with malignant pleural mesothelioma.  The surgeon removes as much of the tumor as possible followed by the direct administration of a chemotherapy agent, heated to between 40 and 48 °C, in the abdomen. The fluid is perfused for 60 to 120 minutes and then drained. High concentrations of selected drugs are then administered into the pleural cavity. Heating the chemotherapy treatment increases the penetration of the drugs into tissues. Also, heating itself damages the malignant cells more than the normal cells.

Multimodality therapy
Multimodal therapy, which includes a combined approach of surgery, radiation or photodynamic therapy, and chemotherapy, is not suggested for routine practice for treating malignant pleural mesothelioma. The effectiveness and safety of multimodal therapy is not clear (not enough research has been performed) and one clinical trial has suggested a possible increased risk of adverse effects.Large series of examining multimodality treatment have only demonstrated modest improvement in survival (median survival 14.5 months and only 29.6% surviving 2 years). Reducing the bulk of the tumor with cytoreductive surgery is key to extending survival. Two surgeries have been developed: extrapleural pneumonectomy and pleurectomy/decortication. The indications for performing these operations are unique. The choice of operation namely depends on the size of the patients tumor. This is an important consideration because tumor volume has been identified as a prognostic factor in mesothelioma. Pleurectomy/decortication spares the underlying lung and is performed in patients with early stage disease when the intention is to remove all gross visible tumor (macroscopic complete resection), not simply palliation.  Extrapleural pneumonectomy is a more extensive operation that involves resection of the parietal and visceral pleurae, underlying lung, ipsilateral (same side) diaphragm, and ipsilateral pericardium. This operation is  indicated for a subset of patients with more advanced tumors, who can tolerate a pneumonectomy.

Prognosis
Mesothelioma usually has a poor prognosis. Typical survival despite surgery is between 12 and 21 months depending on the stage of disease at diagnosis with about 7.5% of people surviving for 5 years.Women, young people, people with low-stage cancers, and people with epithelioid cancers have better prognoses. Negative prognostic factors include sarcomatoid or biphasic histology, high platelet counts (above 400,000), age over 50 years, white blood cell counts above 15.5, low glucose levels in the pleural fluid, low albumin levels, and high fibrinogen levels. Several markers are under investigation as prognostic factors, including nuclear grade, and serum c-reactive protein. Long-term survival is rare.Pericardial mesothelioma has a 10-month median survival time.In peritoneal mesothelioma, high expression of WT-1 protein indicates a worse prognosis.

Epidemiology
Although reported incidence rates have increased in the past 20 years, mesothelioma is still a relatively rare cancer. The incidence rate varies from one country to another, from a low rate of less than 1 per 1,000,000 in Tunisia and Morocco, to the highest rate in Britain, Australia and Belgium: 30 per 1,000,000 per year. For comparison, populations with high levels of smoking can have a lung cancer incidence of over 1,000 per 1,000,000. Incidence of malignant mesothelioma currently ranges from about 7 to 40 per 1,000,000 in industrialized Western nations, depending on the amount of asbestos exposure of the populations during the past several decades. Worldwide incidence is estimated at 1-6 per 1,000,000. Incidence of mesothelioma lags behind that of asbestosis due to the longer time it takes to develop; due to the cessation of asbestos use in developed countries, mesothelioma incidence is expected to decrease. Incidence is expected to continue increasing in developing countries due to continuing use of asbestos. Mesothelioma occurs more often in men than in women and risk increases with age, but this disease can appear in either men or women at any age. Approximately one fifth to one third of all mesotheliomas are peritoneal. Less than 5% of mesotheliomas are pericardial. The prevalence of pericardial mesothelioma is less than 0.002%; it is more common in men than women. It typically occurs in a persons 50s-70s.Between 1940 and 1979, approximately 27.5 million people were occupationally exposed to asbestos in the United States. Between 1973 and 1984, the incidence of pleural mesothelioma among Caucasian males increased 300%. From 1980 to the late 1990s, the death rate from mesothelioma in the USA increased from 2,000 per year to 3,000, with men four times more likely to acquire it than women. More than 80% of mesotheliomas are caused by asbestos exposure.The incidence of peritoneal mesothelioma is 0.5–3.0 per million per year in men, and 0.2–2.0 per million per year in women.

UK
Mesothelioma accounts for less than 1% of all cancers diagnosed in the UK, (around 2,600 people were diagnosed with the disease in 2011), and it is the seventeenth most common cause of cancer death (around 2,400 people died in 2012).

History
The connection between asbestos exposure and mesothelioma was discovered in the 1970s. In the United States, asbestos manufacture stopped in 2002. Asbestos exposure thus shifted from workers in asbestos textile mills, friction product manufacturing, cement pipe fabrication, and insulation manufacture and installation to maintenance workers in asbestos-containing buildings.

Society and culture
Notable cases
Mesothelioma, though rare, has had a number of notable patients:

Malcolm McLaren, musician and manager of the punk rock band the Sex Pistols, was diagnosed with peritoneal mesothelioma in October 2009 and died on 8 April 2010 in Switzerland.
Steve McQueen, American actor, was diagnosed with peritoneal mesothelioma on December 22, 1979.  He was not offered surgery or chemotherapy because doctors felt the cancer was too advanced.  McQueen subsequently sought alternative treatments at clinics in Mexico.  He died of a heart attack on November 7, 1980, in Juárez, Mexico, following cancer surgery.  He may have been exposed to asbestos while serving with the U.S. Marines as a young adult—asbestos was then commonly used to insulate ships piping—or from its use as an insulating material in automobile racing suits (McQueen was an avid racing driver and fan).
Mickie Most, record producer, died of peritoneal mesothelioma in May 2003; however, it has been questioned whether this was due to asbestos exposure.
Warren Zevon, American musician, was diagnosed with pleural mesothelioma in 2002, and died on September 7, 2003. It is believed that this was caused through childhood exposure to asbestos insulation in the attic of his fathers shop.
David Martin, Australian sailor and politician, died on 10 August 1990 of pleural mesothelioma. It is believed that this was caused by his exposure to asbestos on military ships during his career in the Royal Australian Navy.
Paul Kraus, diagnosed in 1997, is considered the longest currently living (as of 2017) mesothelioma survivor in the world.
F. W. De Klerk, South African retired politician, was diagnosed with mesothelioma on March 19, 2021, and died in November 2021.
Paul Gleason, American actor, died on May 27, 2006, just a few months after diagnosis.Although life expectancy with this disease is typically limited, there are notable survivors. In July 1982, Stephen Jay Gould, a well-regarded paleontologist, was diagnosed with peritoneal mesothelioma. After his diagnosis, Gould wrote "The Median Isnt the Message", in which he argued that statistics such as median survival are useful abstractions, not destiny. Gould lived for another 20 years, eventually succumbing to cancer not linked to his mesothelioma.

Legal issues
Some people who were exposed to asbestos have collected damages for an asbestos-related disease, including mesothelioma. Compensation via asbestos funds or class action lawsuits is an important issue in law practices regarding mesothelioma.The first lawsuits against asbestos manufacturers were in 1929. Since then, many lawsuits have been filed against asbestos manufacturers and employers, for neglecting to implement safety measures after the links between asbestos, asbestosis, and mesothelioma became known (some reports seem to place this as early as 1898). The liability resulting from the sheer number of lawsuits and people affected has reached billions of dollars.  The amounts and method of allocating compensation have been the source of many court cases, reaching up to the United States Supreme Court, and government attempts at resolution of existing and future cases. However, to date, the US Congress has not stepped in and there are no federal laws governing asbestos compensation.
In 2013, the "Furthering Asbestos Claim Transparency (FACT) Act of 2013" passed the US House of representatives and was sent to the US Senate, where it was referred to the Senate Judiciary Committee.  As the Senate did not vote on it before the end of the 113th Congress, it died in committee.  It was revived in the 114th Congress, where it has not yet been brought before the House for a vote.

History
The first lawsuit against asbestos manufacturers was brought in 1929. The parties settled that lawsuit, and as part of the agreement, the attorneys agreed not to pursue further cases. In 1960, an article published by Wagner et al. was seminal in establishing mesothelioma as a disease arising from exposure to asbestos. The article referred to over 30 case studies of people who had had mesothelioma in South Africa. Some exposures were transient and some were mine workers </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Methanol toxicity and explain in detail? [/INST] Methanol toxicity (also methanol poisoning) is poisoning from methanol, characteristically via ingestion. Symptoms may include a decreased level of consciousness, poor or no coordination, hypothermia, vomiting, abdominal pain, and a specific smell on the breath. Decreased vision may start as early as twelve hours after exposure. Long-term outcomes may include blindness and kidney failure. Toxicity and death may occur after drinking in large quantities.Methanol poisoning most commonly occurs following the drinking of windshield washer fluid. This may be accidental or as part of an attempted suicide. Toxicity may also rarely occur through extensive skin exposure or breathing in fumes. When methanol is broken down by the body it results in formaldehyde, formic acid, and formate which cause much of the toxicity. The diagnosis may be suspected when there is acidosis or an increased osmol gap and confirmed by directly measuring blood levels. Other conditions that can produce similar symptoms include infections, exposure to other toxic alcohols, serotonin syndrome, and diabetic ketoacidosis.Early treatment increases the chance of a good outcome. Treatment consists of stabilizing the person, followed by the use of an antidote. The preferred antidote is fomepizole, with ethanol used if this is not available. Hemodialysis may also be used in those where there is organ damage or a high degree of acidosis. Other treatments may include sodium bicarbonate, folate, and thiamine.Outbreaks of methanol ingestion have occurred due to contamination of drinking alcohol. This is more common in the developing world. In 2013 more than 1700 cases occurred in the United States. Those affected are usually adult and male. Toxicity to methanol has been described as early as 1856.

Signs and symptoms
The initial symptoms of methanol intoxication include central nervous system depression, headache, dizziness, nausea, lack of coordination, and confusion. Sufficiently large doses cause unconsciousness and death. The initial symptoms of methanol exposure are usually less severe than the symptoms from the ingestion of a similar quantity of ethanol. Once the initial symptoms have passed, a second set of symptoms arises, from 10 to as many as 30 hours after the initial exposure, that may include blurring or complete loss of vision, acidosis, and putaminal hemorrhages, an uncommon but serious complication. These symptoms result from the accumulation of toxic levels of formate in the blood, and may progress to death by respiratory failure. Physical examination may show tachypnea, and eye examination may show dilated pupils with hyperemia of the optic disc and retinal edema.

Cause
Methanol has a moderate to high toxicity in humans. As little as 10 mL of pure methanol when drunk is metabolized into formic acid, which can cause permanent blindness by destruction of the optic nerve. 15 mL is potentially fatal, although the median lethal dose is typically 100 mL (3.4 fl oz) (i.e. 1–2 mL/kg body weight of pure methanol). Reference dose for methanol is 0.5 mg/kg/day.Ethanol is sometimes denatured (adulterated), and made poisonous, by the addition of methanol. The result is known as methylated spirit, "meths" (British use) or "metho" (Australian slang). This is not to be confused with "meth", a common abbreviation for methamphetamine and for methadone in Britain and the United States.

Mechanism
Methanol is toxic by two mechanisms. First, methanol (whether it enters the body by ingestion, inhalation, or absorption through the skin) can be fatal due to its CNS depressant properties in the same manner as ethanol poisoning. Second, in a process of toxication, it is metabolized to formic acid (which is present as the formate ion) via formaldehyde in a process initiated by the enzyme alcohol dehydrogenase in the liver. Methanol is converted to formaldehyde via alcohol dehydrogenase and formaldehyde is converted to formic acid (formate) via aldehyde dehydrogenase </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Mevalonate kinase deficiency and explain in detail? [/INST] Mevalonate kinase deficiency (MKD) is an autosomal recessive metabolic disorder that disrupts the biosynthesis of cholesterol and isoprenoids. It is a very rare genetic disease.
It is characterized by an elevated level of immunoglobulin D in the blood.
Mevalonate kinase (MVK) is an enzyme involved in biosynthesis of cholesterols and isoprenoids and is necessary for the conversion of mevalonate to mevalonate-5-phosphate in the presence of Mg2+. MKD is due to a mutation in the gene that encodes mevalonate kinase which results in a reduced or deficient activity of this enzyme. Because of this deficiency, mevalonic acid can build up in the body, with high levels found in the urine.
The severity of MKD depends on the level of this deficiency with hyperimmunoglobulinemia D syndrome (first described as HIDS in 1984) being less severe, but more common, and mevalonic aciduria (MVA); a more severe, but rarer form.

Genetics
Mevalonate kinase deficiency is inherited in an autosomal recessive manner, meaning that a child must inherit a defective copy of the gene from both parents to be affected. It is an example of a loss-of-function mutation. The gene which codes for mevalonate kinase consists of 10 exons at locus 12q14. About 63 pathological sequence variations in the gene have been characterized. The most common of these are V377I, I268T, H20P/N and P167L, present in 70% of affected individuals.

Immunoglobulin D
Immunoglobulin D (IgD) is a protein produced by a certain type of white blood cells. There are five classes of Immunoglobulin: IgG, IgA, IgM, IgE and IgD. They each play an important role in the immune system. The function of IgD is still unclear, although one of its many effects is to active the immune system.

Biochemistry
There is an increased secretion of the fever promoting cytokine interleukin 1 beta (IL-1β) in MKD, most likely mediated by defective protein prenylation. Prenylation refers to addition of hydrophobic isoprenoids to proteins, such as farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP). When isoprenoids such as these are coupled to a target protein, this affects the proteins cellular location and function. In a human monocytic MKD model it was found that the deficiency of GGPP leads to overproduction of IL-1β and defective prenylation of RhoA. This causes an increased level of Rac1 and PKB which in turn affects GTPases and B7-glycoproteins. It was earlier found that Rac1/PI3K/PKB pathway had been linked to the pathogenesis of MKD. The inactivation of RhoA acts an inducer of IL-1β mRNA transcription independent of NLRP3- or caspase-1 activity. Due to defective RhoA there is a formation of defective mitochondria (elongated and instable) in the cell. Normally, defective mitochondria are cleared in the cell by the mechanism of autophagy. But, in MKD the clearance of defective mitochondria from the cytosol is disrupted. As a result, mitochondrial DNA starts accumulating in the cytosol, binding and activating NLRP3, which is responsible for the production of IL-1β. The activation can be direct or indirect. It can also be activated by reactive oxygen species (ROS).
It is known that monocytes and macrophages in affected individuals also produce higher levels of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) other than IL-Iβ During febrile (fever) attacks, C-reactive protein (CRP) also increases. CRP is released by liver which causes inflammation.

Hyper-IgD syndrome
Hyperimmunoglobulinemia D with recurrent fever is a periodic fever syndrome originally described in 1984 by the internist Jos van der Meer, then at Leiden University Medical Centre. No more than 300 cases have been described worldwide. It is now recognised as an allelic variant of MKD.

Signs and symptoms
HIDS is one of a number of periodic fever syndromes. It is characterised by attacks of fever, arthralgia, skin lesions including cyclical mouth ulcers, and diarrhea. Laboratory features include an acute phase response (elevated CRP and ESR) and markedly elevated IgD (and often IgA), although cases with normal IgD have been described.It has mainly been described in the Netherlands and France, although the international registry includes a number of cases from other countries.The differential diagnosis includes fever of unknown origin, familial Mediterranean fever (FMF) and familial Hibernian fever (or TNFα reception associated periodic syndrome/TRAPS).

Cause
Virtually all people with the syndrome have mutations in the gene for mevalonate kinase, which is part of the HMG-CoA reductase pathway, an important cellular metabolic pathway. Indeed, similar fever attacks (but normal IgD) have been described in patients with mevalonic aciduria – an inborn error of metabolism now seen as a severe form of HIDS.

Pathophysiology
It is not known how mevalonate kinase mutations cause the febrile episodes, although it is presumed that other products of the cholesterol biosynthesis pathway, the prenylation chains (geranylgeraniol and farnesol) might play a role.

Diagnosis
Mevalonate kinase deficiency causes an accumulation of mevalonic acid in the urine, resulting from insufficient activity of the enzyme mevalonate kinase (ATP:mevalonate 5-phosphotransferase; EC 2.7.1.36).

The disorder was first described in 1985.Classified as an inborn error of metabolism, mevalonate kinase deficiency usually results in developmental delay, hypotonia, anemia, hepatosplenomegaly, various dysmorphic features, mental retardation, an overall failure to thrive and several other features.

Treatment
There is no treatment for MKD. But, the inflammation and the other effects can be reduced to a certain extent.

IL-1 targeting drugs can be used to reduce the effects of the disorder. Anakinra is antagonist to IL-1 receptors. Anakinra binds the IL-1 receptor, preventing the actions of both IL-1α and IL-1β, and it has been proved to reduce the clinical and biochemical inflammation in MKD. It can effectively decreases the frequency as well as the severity of inflammatory attacks when used on a daily basis. Disadvantages with the usage of this drug are occurrence of painful injection site reaction and as the drug is discontinued in the near future the febrile attacks start. (Examined in a 12-year-old patient).
Canakinumab is a long acting monoclonal antibody which is directed against IL-1β has shown to be effective in reducing both frequency and severity in patients with mild and severe MKD in case reports and observational case series. It reduces the physiological effects but the biochemical parameter still remain elevated (Galeotti et al. demonstrated that it is more effective than anakinra –considered 6 patients with MKD).
Anti-TNF therapy might be effective in MKD, but the effect is mostly partial and therapy failure and clinical deterioration have been described frequently in patients on infliximab or etanercept. A beneficial effect of human monoclonal anti-TNFα antibody adalimumab was seen in a small number of MKD patients.
Most MKD patients are benefited by anti-IL-1 therapy. However, anti-IL-1-resistant disease may also occur. Example. tocilizumab (a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor) </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Microscopic polyangiitis and explain in detail? [/INST] Microscopic polyangiitis is an ill-defined autoimmune disease characterized by a systemic, pauci-immune, necrotizing, small-vessel vasculitis without clinical or pathological evidence of necrotizing granulomatous inflammation.

Signs and symptoms
Clinical features may include constitutional symptoms like fever, loss of appetite, weight loss, fatigue, and kidney failure. A majority of patients may have blood in the urine and protein in the urine. Rapidly progressive glomerulonephritis may occur </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Microsporidiosis and explain in detail? [/INST] Microsporidiosis is an opportunistic intestinal infection that causes diarrhea and wasting in immunocompromised individuals (HIV, for example). It results from different species of microsporidia, a group of microbial (unicellular) fungi.In HIV infected individuals, microsporidiosis generally occurs when CD4+ T cell counts fall below 150.
Microsporidia have emerged with significant mortality risk in immunocompromised individuals. These are small, single-celled, obligately intracellular parasites linked to water sources as well as wild, and domestic animals. They were once considered protozoans or protists, but are now known to be fungi, or a sister group to fungi.  The most common causes of microsporidiosis is Enterocytozoon bieneusi and Encephalitozoon intestinalis.

Cause
At least 15 microsporidian species have been recognized as human pathogens, spread across nine genera:

Anncaliia
A. algerae, A. connori, A. vesicularum
Encephalitozoon
E. cuniculi, E. hellem, E. intestinalis
Enterocytozoon
E. bieneusi
Microsporidium
M. ceylonensis, M. africanum
Nosema
N. ocularum
Pleistophora  sp.
Trachipleistophora
T. hominis, T </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Miscarriage and explain in detail? [/INST] Miscarriage, also known in medical terms as a spontaneous abortion and pregnancy loss, is the death of an embryo or fetus before it is able to survive independently. Some use the cutoff of 20 weeks of gestation, after which fetal death is known as a stillbirth. The most common symptom of a miscarriage is vaginal bleeding with or without pain. Sadness, anxiety, and guilt may occur afterwards. Tissue and clot-like material may leave the uterus and pass through and out of the vagina. Recurrent miscarriage may also be considered a form of infertility.Risk factors for miscarriage include being an older parent, previous miscarriage, exposure to tobacco smoke, obesity, diabetes, thyroid problems, and drug or alcohol use. About 80% of miscarriages occur in the first 12 weeks of pregnancy (the first trimester). The underlying cause in about half of cases involves chromosomal abnormalities. Diagnosis of a miscarriage may involve checking to see if the cervix is open or closed, testing blood levels of human chorionic gonadotropin (hCG), and an ultrasound. Other conditions that can produce similar symptoms include an ectopic pregnancy and implantation bleeding.Prevention is occasionally possible with good prenatal care. Avoiding drugs, alcohol, infectious diseases, and radiation may decrease the risk of miscarriage. No specific treatment is usually needed during the first 7 to 14 days. Most miscarriages will complete without additional interventions. Occasionally the medication misoprostol or a procedure such as vacuum aspiration is used to remove the remaining tissue. Women who have a blood type of rhesus negative (Rh negative) may require Rho(D) immune globulin. Pain medication may be beneficial. Emotional support may help with processing the loss.Miscarriage is the most common complication of early pregnancy. Among women who know they are pregnant, the miscarriage rate is roughly 10% to 20%, while rates among all fertilisation is around 30% to 50%. In those under the age of 35 the risk is about 10% while it is about 45% in those over the age of 40. Risk begins to increase around the age of 30. About 5% of women have two miscarriages in a row. Some recommend not using the term "abortion" in discussions with those experiencing a miscarriage in an effort to decrease distress. In Britain, the term "miscarriage" has replaced any use of the term "spontaneous abortion" in relation to pregnancy loss and in response to complaints of insensitivity towards women who had suffered such loss. An additional benefit of this change is reducing confusion among medical laymen, who may not realize that the term "spontaneous abortion" refers to a naturally-occurring medical phenomenon, and not the intentional termination of pregnancy.

Signs and symptoms
Signs of a miscarriage include vaginal spotting, abdominal pain, cramping, and fluid, blood clots, and tissue passing from the vagina. Bleeding can be a symptom of miscarriage, but many women also have bleeding in early pregnancy and do not miscarry. Bleeding during the first half of pregnancy may be referred to as a threatened miscarriage. Of those who seek treatment for bleeding during pregnancy, about half will miscarry. Miscarriage may be detected during an ultrasound exam, or through serial human chorionic gonadotropin (HCG) testing.

Risk factors
Miscarriage may occur for many reasons, not all of which can be identified. Risk factors are those things that increase the likelihood of having a miscarriage but do not necessarily cause a miscarriage. Up to 70 conditions, infections, medical procedures, lifestyle factors, occupational exposures, chemical exposure, and shift work are associated with increased risk for miscarriage. Some of these risks include endocrine, genetic, uterine, or hormonal abnormalities, reproductive tract infections, and tissue rejection caused by an autoimmune disorder.

Trimesters
First trimester
Most clinically apparent miscarriages (two-thirds to three-quarters in various studies) occur during the first trimester. About 30% to 40% of all fertilized eggs miscarry, often before the pregnancy is known. The embryo typically dies before the pregnancy is expelled; bleeding into the decidua basalis and tissue necrosis causes uterine contractions to expel the pregnancy. Early miscarriages can be due to a developmental abnormality of the placenta or other embryonic tissues. In some instances an embryo does not form but other tissues do. This has been called a "blighted ovum".Successful implantation of the zygote into the uterus is most likely eight to ten days after fertilization. If the zygote has not implanted by day ten, implantation becomes increasingly unlikely in subsequent days.A chemical pregnancy is a pregnancy that was detected by testing but ends in miscarriage before or around the time of the next expected period.Chromosomal abnormalities are found in more than half of embryos miscarried in the first 13 weeks. Half of embryonic miscarriages (25% of all miscarriages) have an aneuploidy (abnormal number of chromosomes). Common chromosome abnormalities found in miscarriages include an autosomal trisomy (22–32%), monosomy X (5–20%), triploidy (6–8%), tetraploidy (2–4%), or other structural chromosomal abnormalities (2%). Genetic problems are more likely to occur with older parents; this may account for the higher rates observed in older women.Luteal phase progesterone deficiency may or may not be a contributing factor to miscarriage.

Second and third trimesters
Second trimester losses may be due to maternal factors such as uterine malformation, growths in the uterus (fibroids), or cervical problems. These conditions also may contribute to premature birth. Unlike first-trimester miscarriages, second-trimester miscarriages are less likely to be caused by a genetic abnormality; chromosomal aberrations are found in a third of cases. Infection during the third trimester can cause a miscarriage.

Age
The age of the pregnant woman is a significant risk factor. Miscarriage rates increase steadily with age, with more substantial increases after age 35. In those under the age of 35 the risk is about 10% while it is about 45% in those over the age of 40. Risk begins to increase around the age of 30. Paternal age is associated with increased risk.

Obesity, eating disorders and caffeine
Not only is obesity associated with miscarriage; it can result in sub-fertility and other adverse pregnancy outcomes. Recurrent miscarriage is also related to obesity. Women with bulimia nervosa and anorexia nervosa may have a greater risk for miscarriage. Nutrient deficiencies have not been found to impact miscarriage rates but hyperemesis gravidarum sometimes precedes a miscarriage.Caffeine consumption also has been correlated to miscarriage rates, at least at higher levels of intake. However, such higher rates are statistically significant only in certain circumstances.
Vitamin supplementation has generally not shown to be effective in preventing miscarriage. Chinese traditional medicine has not been found to prevent miscarriage.

Endocrine disorders
Disorders of the thyroid may affect pregnancy outcomes. Related to this, iodine deficiency is strongly associated with an increased risk of miscarriage. The risk of miscarriage is increased in those with poorly controlled insulin-dependent diabetes mellitus. Women with well-controlled diabetes have the same risk of miscarriage as those without diabetes.

Food poisoning
Ingesting food that has been contaminated with listeriosis, toxoplasmosis, and salmonella is associated with an increased risk of miscarriage.

Amniocentesis and chorionic villus sampling
Amniocentesis and chorionic villus sampling (CVS) are procedures conducted to assess the fetus. A sample of amniotic fluid is obtained by the insertion of a needle through the abdomen and into the uterus. Chorionic villus sampling is a similar procedure with a sample of tissue removed rather than fluid. These procedures are not associated with pregnancy loss during the second trimester but they are associated with miscarriages and birth defects in the first trimester. Miscarriage caused by invasive prenatal diagnosis (chorionic villus sampling (CVS) and amniocentesis) is rare (about 1%).

Surgery
The effects of surgery on pregnancy are not well-known including the effects of bariatric surgery. Abdominal and pelvic surgery are not risk factors for miscarriage. Ovarian tumours and cysts that are removed have not been found to increase the risk of miscarriage. The exception to this is the removal of the corpus luteum from the ovary. This can cause fluctuations in the hormones necessary to maintain the pregnancy.

Medications
There is no significant association between antidepressant medication exposure and spontaneous abortion. The risk of miscarriage is not likely decreased by discontinuing SSRIs prior to pregnancy. Some available data suggest that there is a small increased risk of miscarriage for women taking any antidepressant, though this risk becomes less statistically significant when excluding studies of poor quality.Medicines that increase the risk of miscarriage include:

retinoids
nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen
misoprostol
methotrexate
statins

Immunizations
Immunizations have not been found to cause miscarriage. Live vaccinations, like the MMR vaccine, can theoretically cause damage to the fetus as the live virus can cross the placenta and potentially increase the risk for miscarriage. Therefore, the Center for Disease Control (CDC) recommends against pregnant women receiving live vaccinations. However, there is no clear evidence that has shown live vaccinations to increase the risk for miscarriage or fetal abnormalities.Some live vaccinations include: MMR, varicella, certain types of the influenza vaccine, and rotavirus.

Treatments for cancer
Ionizing radiation levels given to a woman during cancer treatment cause miscarriage. Exposure can also impact fertility. The use of chemotherapeutic drugs used to treat childhood cancer increases the risk of future miscarriage.

Pre-existing diseases
Several pre-existing diseases in pregnancy can potentially increase the risk of miscarriage, including diabetes, polycystic ovary syndrome (PCOS), hypothyroidism, certain infectious diseases, and autoimmune diseases. PCOS may increase the risk of miscarriage. Two studies suggested treatment with the drug metformin significantly lowers the rate of miscarriage in women with PCOS, but the quality of these studies has been questioned. Metformin treatment in pregnancy has not been shown to be safe. In 2007 the Royal College of Obstetricians and Gynaecologists also recommended against use of the drug to prevent miscarriage. Thrombophilias or defects in coagulation and bleeding were once thought to be a risk in miscarriage but have been subsequently questioned. Severe cases of hypothyroidism increase the risk of miscarriage. The effect of milder cases of hypothyroidism on miscarriage rates has not been established. A condition called luteal phase defect (LPD) is a failure of the uterine lining to be fully prepared for pregnancy. This can keep a fertilized egg from implanting or result in miscarriage.Mycoplasma genitalium infection is associated with increased risk of preterm birth and miscarriage.Infections can increase the risk of a miscarriage: rubella (German measles), cytomegalovirus, bacterial vaginosis, HIV, chlamydia, gonorrhoea, syphilis, and malaria.

Immune status
Autoimmunity is a possible cause of recurrent or late-term miscarriages. In the case of an autoimmune-induced miscarriage, the womans body attacks the growing fetus or prevents normal pregnancy progression. Autoimmune disease may cause abnormalities in embryos, which in turn may lead to miscarriage. As an example, Celiac disease increases the risk of miscarriage by an odds ratio of approximately 1.4. A disruption in normal immune function can lead to the formation of antiphospholipid antibody syndrome. This will affect the ability to continue the pregnancy, and if a woman has repeated miscarriages, she can be tested for it. Approximately 15% of recurrent miscarriages are related to immunologic factors. The presence of anti-thyroid autoantibodies is associated with an increased risk with an odds ratio of 3.73 and 95% confidence interval 1.8–7.6. Having lupus also increases the risk for miscarriage. Immunohistochemical studies on decidual basalis and chorionic villi found that the imbalance of the immunological environment could be associated with recurrent pregnancy loss.

Anatomical defects and trauma
Fifteen per cent of women who have experienced three or more recurring miscarriages have some anatomical defect that prevents the pregnancy from being carried for the entire term. The structure of the uterus affects the ability to carry a child to term. Anatomical differences are common and can be congenital.
In some women, cervical incompetence or cervical insufficiency occurs with the inability of the cervix to stay closed during the entire pregnancy. It does not cause first trimester miscarriages. In the second trimester, it is associated with an increased risk of miscarriage. It is identified after a premature birth has occurred at about 16–18 weeks into the pregnancy. During the second trimester, major trauma can result in a miscarriage.

Smoking
Tobacco (cigarette) smokers have an increased risk of miscarriage. There is an increased risk regardless of which parent smokes, though the risk is higher when the gestational mother smokes.

Morning sickness
Nausea and vomiting of pregnancy (NVP, or morning sickness) is associated with a decreased risk. Several possible causes have been suggested for morning sickness but there is still no agreement. NVP may represent a defense mechanism which discourages the mothers ingestion of foods that are harmful to the fetus; according to this model, a lower frequency of miscarriage would be an expected consequence of the different food choices made by women experiencing NVP.

Chemicals and occupational exposure
Chemical and occupational exposures may have some effect in pregnancy outcomes. A cause and effect relationship almost can never be established. Those chemicals that are implicated in increasing the risk for miscarriage are DDT, lead, formaldehyde, arsenic, benzene and ethylene oxide. Video display terminals and ultrasound have not been found to have an effect on the rates of miscarriage. In dental offices where nitrous oxide is used with the absence of anesthetic gas scavenging equipment, there is a greater risk of miscarriage. For women who work with cytotoxic antineoplastic chemotherapeutic agents there is a small increased risk of miscarriage. No increased risk for cosmetologists has been found.

Other
Alcohol increases the risk of miscarriage. Cocaine use increases the rate of miscarriage. Some infections have been associated with miscarriage. These include Ureaplasma urealyticum, Mycoplasma hominis, group B streptococci, HIV-1, and syphilis. Infections of Chlamydia trachomatis, Camphylobacter fetus, and Toxoplasma gondii have not been found to be linked to miscarriage. Subclinical infections of the lining of the womb, commonly known as chronic endometritis are also associated with poor pregnancy outcomes, compared to women with treated chronic endometritis or no chronic endometritis.

Diagnosis
In the case of blood loss, pain, or both, transvaginal ultrasound is performed. If a viable intrauterine pregnancy is not found with ultrasound, blood tests (serial βHCG tests) can be performed to rule out ectopic pregnancy, which is a life-threatening situation.If hypotension, tachycardia, and anemia are discovered, exclusion of an ectopic pregnancy is important.A miscarriage may be confirmed by an obstetric ultrasound and by the examination of the passed tissue. When looking for microscopic pathologic symptoms, one looks for the products of conception. Microscopically, these include villi, trophoblast, fetal parts, and background gestational changes in the endometrium. When chromosomal abnormalities are found in more than one miscarriage, genetic testing of both parents may be done.

Ultrasound criteria
A review article in The New England Journal of Medicine based on a consensus meeting of the Society of Radiologists in Ultrasound in America (SRU) has suggested that miscarriage should be diagnosed only if any of the following criteria are met upon ultrasonography visualization:

Classification
A threatened miscarriage is any bleeding during the first half of pregnancy. At investigation it may be found that the fetus remains viable and the pregnancy continues without further problems.An anembryonic pregnancy (also called an "empty sac" or "blighted ovum") is a condition where the gestational sac develops normally, while the embryonic part of the pregnancy is either absent or stops growing very early. This accounts for approximately half of miscarriages. All other miscarriages are classified as embryonic miscarriages, meaning that there is an embryo present in the gestational sac. Half of embryonic miscarriages have aneuploidy (an abnormal number of chromosomes).An inevitable miscarriage occurs when the cervix has already dilated, but the fetus has yet to be expelled. This usually will progress to a complete miscarriage. The fetus may or may not have cardiac activity.

 A complete miscarriage is when all products of conception have been expelled; these may include the trophoblast, chorionic villi, gestational sac, yolk sac, and fetal pole (embryo); or later in pregnancy the fetus, umbilical cord, placenta, amniotic fluid, and amniotic membrane. The presence of a pregnancy test that is still positive, as well as an empty uterus upon transvaginal ultrasonography, does, however, fulfil the definition of pregnancy of unknown location. Therefore, there may be a need for follow-up pregnancy tests to ensure that there is no remaining pregnancy, including ectopic pregnancy.
An incomplete miscarriage occurs when some products of conception have been passed, but some remains inside the uterus. However, an increased distance between the uterine walls on transvaginal ultrasonography may also simply be an increased endometrial thickness and/or a polyp. The use of a Doppler ultrasound may be better in confirming the presence of significant retained products of conception in the uterine cavity. In cases of uncertainty, ectopic pregnancy must be excluded using techniques like serial beta-hCG measurements.
A missed miscarriage is when the embryo or fetus has died, but a miscarriage has not yet occurred. It is also referred to as delayed miscarriage, silent miscarriage, or missed abortion.A septic miscarriage occurs when the tissue from a missed or incomplete miscarriage becomes infected, which carries the risk of spreading infection (septicaemia) and can be fatal.Recurrent miscarriage ("recurrent pregnancy loss" (RPL) or "habitual abortion") is the occurrence of multiple consecutive miscarriages; the exact number used to diagnose recurrent miscarriage varies. If the proportion of pregnancies ending in miscarriage is 15% and assuming that miscarriages are independent events, then the probability of two consecutive miscarriages is 2.25% and the probability of three consecutive miscarriages is 0.34%. The occurrence of recurrent pregnancy loss is 1%. A large majority (85%) of those who have had two miscarriages will conceive and carry normally afterward.The physical symptoms of a miscarriage vary according to the length of pregnancy, though most miscarriages cause pain or cramping. The size of blood clots and pregnancy tissue that are passed become larger with longer gestations. After 13 weeks gestation, there is a higher risk of placenta retention.

Prevention
Prevention of a miscarriage can sometimes be accomplished by decreasing risk factors. This may include good prenatal care, avoiding drugs and alcohol, preventing infectious diseases, and avoiding x-rays. Identifying the cause of the miscarriage may help prevent future pregnancy loss, especially in cases of recurrent miscarriage. Often there is little a person can do to prevent a miscarriage. Vitamin supplementation before or during pregnancy has not been found to affect the risk of miscarriage. Progesterone has been shown to prevent miscarriage in women with 1) vaginal bleeding early in their current pregnancy and 2) a previous history of miscarriage.

Non-modifiable risk factors
Preventing a miscarriage in subsequent pregnancies may be enhanced with assessments of:

Modifiable risk factors
Maintaining a healthy weight and good prenatal care can reduce the risk of miscarriage. Some risk factors can be minimized by avoiding the following:

Smoking
Cocaine use
Alcohol
Poor nutrition
Occupational exposure to agents that can cause miscarriage
Medications associated with miscarriage
Drug abuse

Management
Women who miscarry early in their pregnancy usually do not require any subsequent medical treatment but they can benefit from support and counseling. Most early miscarriages will complete on their own; in other cases, medication treatment or aspiration of the products of conception can be used to remove remaining tissue. While bed rest has been advocated to prevent miscarriage, this has not been found to be of benefit. Those who are experiencing or who have experienced a miscarriage benefit from the use of careful medical language. Significant distress can often be managed by the ability of the clinician to clearly explain terms without suggesting that the woman or couple are somehow to blame.Evidence to support Rho(D) immune globulin after a spontaneous miscarriage is unclear. In the UK, Rho(D) immune globulin is recommended in Rh-negative women after 12 weeks gestational age and before 12 weeks gestational age in those who need surgery or medication to complete the miscarriage.

Methods
No treatment is necessary for a diagnosis of complete miscarriage (so long as ectopic pregnancy is ruled out). In cases of an incomplete miscarriage, empty sac, or missed abortion there are three treatment options: watchful waiting, medical management, and surgical treatment. With no treatment (watchful waiting), most miscarriages (65–80%) will pass naturally within two to six weeks. This treatment avoids the possible side effects and complications of medications and surgery, but increases the risk of mild bleeding, need for unplanned surgical treatment, and incomplete miscarriage. Medical treatment usually consists of using misoprostol (a prostaglandin) alone or in combination with mifepristone pre-treatment. These medications help the uterus to contract and expel the remaining tissue out of the body. This works within a few days in 95% of cases. Vacuum aspiration or sharp curettage can be used, with vacuum aspiration being lower-risk and more common.

Delayed and incomplete miscarriage
In delayed or incomplete miscarriage, treatment depends on the amount of tissue remaining in the uterus. Treatment can include surgical removal of the tissue with vacuum aspiration or misoprostol. Studies looking at the methods of anaesthesia for surgical management of incomplete miscarriage have not shown that any adaptation from normal practice is beneficial.

Induced miscarriage
An induced abortion may be performed by a qualified healthcare provider for women who cannot continue the pregnancy. Self-induced abortion performed by a woman or non-medical personnel can be dangerous and is still a cause of maternal mortality in some countries. In some locales it is illegal or carries heavy social stigma. However, in the United States, many choose to self-induce or self-manage their abortion and have done so safely.

Sex
Some organizations recommend delaying sex after a miscarriage until the bleeding has stopped to decrease the risk of infection. However, there is not sufficient evidence for the routine use of antibiotic to try to avoid infection in incomplete abortion. Others recommend delaying attempts at pregnancy until one period has occurred to make it easier to determine the dates of a subsequent pregnancy. There is no evidence that getting pregnant in that first cycle affects outcomes and an early subsequent pregnancy may actually improve outcomes.

Support
Organizations exist that provide information and counselling to help those who have had a miscarriage. Family and friends often conduct a memorial or burial service. Hospitals also can provide support and help memorialize the event. Depending on locale others desire to have a private ceremony. Providing appropriate support with frequent discussions and sympathetic counselling are part of evaluation and treatment. Those who experience unexplained miscarriage can be treated with emotional support.

Miscarriage leave
Miscarriage leave is leave of absence in relation to miscarriage. The following countries offer paid or unpaid leave to women who have had a miscarriage.

The Philippines – 60 days fully paid leave for miscarriages (before 20 weeks of gestation) or emergency termination of the pregnancy (on the 20th week or after) The husband of the mother gets seven days fully paid leave up to the 4th pregnancy.
India – six weeks leave
New Zealand – three days bereavement leave for both parents
Mauritius – two weeks leave
Indonesia – six weeks leave
Taiwan – five days, one week or four weeks, depending on how advanced the pregnancy was

Outcomes
Psychological and emotional effects
Every womans personal experience of miscarriage is different, and women who have more than one miscarriage may react differently to each event.In Western cultures since the 1980s, medical providers assume that experiencing a miscarriage "is a major loss for all pregnant women". A miscarriage can result in anxiety, depression or stress for those involved. It can have an effect on the whole family. Many of those experiencing a miscarriage go through a grieving process. "Prenatal attachment" often exists that can be seen as parental sensitivity, love and preoccupation directed toward the unborn child. Serious emotional impact is usually experienced immediately after the miscarriage. Some may go through the same loss when an ectopic pregnancy is terminated. In some, the realization of the loss can take weeks. Providing family support to those experiencing the loss can be challenging because some find comfort in talking about the miscarriage while others may find the event painful to discuss. The father can have the same sense of loss. Expressing feelings of grief and loss can sometimes be harder for men. Some women are able to begin planning their next pregnancy after a few weeks of having the miscarriage. For others, planning another pregnancy can be difficult. Some facilities acknowledge the loss. Parents can name and hold their infant. They may be given mementos such as photos and footprints. Some conduct a funeral or memorial service. They may express the loss by planting a tree.Some health organizations recommend that sexual activity be delayed after the miscarriage. The menstrual cycle should resume after about three to four months. Women report that they were dissatisfied with the care they received from physicians and nurses.

Subsequent pregnancies
Some parents want to try to have a baby very soon after the miscarriage. The decision of trying to become pregnant again can be difficult. Reasons exist that may prompt parents to consider another pregnancy. For older mothers, there may be some sense of urgency. Other parents are optimistic that future pregnancies are likely to be successful. Many are hesitant and want to know about the risk of having another or more miscarriages. Some clinicians recommend that the women have one menstrual cycle before attempting another pregnancy. This is because the date of conception may be hard to determine. Also, the first menstrual cycle after a miscarriage can be much longer or shorter than expected. Parents may be advised to wait even longer if they have experienced late miscarriage or molar pregnancy, or are undergoing tests. Some parents wait for six months based upon recommendations from their health care provider.The risks of having another miscarriage vary according to the cause. The risk of having another miscarriage after a molar pregnancy is very low. The risk of another miscarriage is highest after the third miscarriage. Pre-conception care is available in some locales.

Later cardiovascular disease
There is a significant association between miscarriage and later development of coronary artery disease, but not of cerebrovascular disease.

Epidemiology
Among women who know they are pregnant, the miscarriage rate is roughly 10% to 20%, while rates among all fertilized zygotes are around 30% to 50%. A 2012 review found the risk of miscarriage between 5 and 20 weeks from 11% to 22%. Up to the 13th week of pregnancy, the risk of miscarriage each week was around 2%, dropping to 1% in week 14 and reducing slowly between 14 and 20 weeks.The precise rate is not known because a large number of miscarriages occur before pregnancies become established and before the woman is aware she is pregnant. Additionally, those with bleeding in early pregnancy may seek medical care more often than those not experiencing bleeding. Although some studies attempt to account for this by recruiting women who are planning pregnancies and testing for very early pregnancy, they still are not representative of the wider population.The prevalence of miscarriage increases with the age of both parents. In a Danish register-based study where the prevalence of miscarriage was 11%, the prevalence rose from 9% at 22 years of age to 84% by 48 years of age. Another, later study in 2013 found that when either parent was over the age of 40, the rate of known miscarriages doubled.In 2010, 50,000 inpatient admissions for miscarriage occurred in the UK.

Terminology
Most affected women and family members refer to miscarriage as the loss of a baby, rather than an embryo or fetus, and healthcare providers are expected to respect and use the language that the person chooses. Clinical terms can suggest blame, increase distress, and even cause anger. Terms that are known to cause distress in those experiencing miscarriage include:

abortion (including spontaneous abortion) rather than miscarriage,
habitual aborter rather than a woman experiencing recurrent pregnancy loss,
products of conception rather than baby,
blighted ovum rather than early pregnancy loss or delayed miscarriage,
cervical incompetence rather than cervical weakness, and
evacuation of retained products of conception (ERPC) rather than surgical management of miscarriage.Pregnancy loss is a broad term that is used for miscarriage, ectopic and molar pregnancies. The term fetal death applies variably in different countries and contexts, sometimes incorporating weight, and gestational age from 16 weeks in Norway, 20 weeks in the US and Australia, 24 weeks in the UK to 26 weeks in Italy and Spain. A fetus that died before birth after this gestational age may be referred to as a stillbirth. Under UK law, all stillbirths should be registered, although this does not apply to miscarriages.

History
The medical terminology applied to experiences during early pregnancy has changed over time. Before the 1980s, health professionals used the phrase spontaneous abortion for a miscarriage and induced abortion for a termination of the pregnancy. In the late 1980s and 1990s, doctors became more conscious of their language in relation to early pregnancy loss. Some medical authors advocated change to use of miscarriage instead of spontaneous abortion because they argued this would be more respectful and help ease a distressing experience. The change was being recommended by some in the profession in Britain in the late 1990s. In 2005 the European Society for Human Reproduction and Embryology (ESHRE) published a paper aiming to facilitate a revision of nomenclature used to describe early pregnancy events.

Society and culture
Societys reactions to miscarriage have changed over time. In the early 20th century, the focus was on the mothers physical health and the difficulties and disabilities that miscarriage could produce. Other reactions, such as the expense of medical treatments and relief at ending an unwanted pregnancy, were also heard. In the 1940s and 1950s, people were more likely to express relief, not because the miscarriage ended an unwanted or mistimed pregnancy, but because people believed that miscarriages were primarily caused by birth defects, and miscarrying meant that the family would not raise a child with disabilities. The dominant attitude in the mid-century was that a miscarriage, although temporarily distressing, was a blessing in disguise for the family, and that another pregnancy and a healthier baby would soon follow, especially if women trusted physicians and reduced their anxieties. Media articles were illustrated with pictures of babies, and magazine articles about miscarriage ended by introducing the healthy baby—usually a boy—that had shortly followed it.Beginning in the 1980s, miscarriage in the US was primarily framed in terms of the individual womans personal emotional reaction, and especially her grief over a tragic outcome. The subject was portrayed in the media with images of an empty crib or an isolated, grieving woman, and stories about miscarriage were published in general-interest media outlets, not just womens magazines or health magazines. Family members were encouraged to grieve, to memorialize their losses through funerals and other rituals, and to think of themselves as being parents. This shift to recognizing these emotional responses was partly due to medical and political successes, which created an expectation that pregnancies are typically planned and safe, and to womens demands that their emotional reactions no longer be dismissed by the medical establishments. It also reinforces the anti-abortion movement’s belief that human life begins at conception or early in pregnancy, and that motherhood is a desirable life goal. The modern one-size-fits-all model of grief does not fit every womans experience, and an expectation to perform grief creates unnecessary burdens for some women. The reframing of miscarriage as a private emotional experience brought less awareness of miscarriage and a sense of silence around the subject, especially compared to the public discussion of miscarriage during campaigns for access to birth control during the early 20th century, or the public campaigns to prevent miscarriages, stillbirths, and infant deaths by reducing industrial pollution during the 1970s.In places where induced abortion is illegal or carries social stigma, suspicion may surround miscarriage, complicating an already sensitive issue.
In the 1960s, the use of the word miscarriage in Britain (instead of spontaneous abortion) occurred after changes in legislation.
Developments in ultrasound technology (in the early 1980s) allowed them to identify earlier miscarriages.According to French statutes, an infant born before the age of viability, determined to be 28 weeks, is not registered as a child. If birth occurs after this, the infant is granted a certificate that allows women who have given birth to a stillborn child, to have a symbolic record of that child. This certificate can include a registered and given name to allow a funeral and acknowledgement of the event.

Other animals
Miscarriage occurs in all animals that experience pregnancy, though in such contexts it is more commonly referred to as a spontaneous abortion (the two terms are synonymous) </s>