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Deep Learning Technology: Sebastian Arnold, Betty van Aken, Paul Grundmann, Felix A. Gers and Alexander Löser. Learning Contextualized Document Representations for Healthcare Answer Retrieval. The Web Conference 2020 (WWW'20)
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Drugs used during pregnancy can have temporary or permanent effects on the fetus. Anything (including drugs) that can cause permanent deformities in the fetus are labeled as teratogens. In the U.S., drugs were classified into categories A, B, C, D and X based on the Food and Drug Administration (FDA) rating system to provide therapeutic guidance based on potential benefits and fetal risks. Drugs, including some multivitamins, that have demonstrated no fetal risks after controlled studies in humans are classified as Category A. On the other hand, drugs like thalidomide with proven fetal risks that outweigh all benefits are classified as Category X.
The apprehension is not necessarily data driven and is a cautionary response to the lack of clinical studies in pregnant women. The indication is a trade-off between the adverse effects of the drug, the risks associated with intercurrent diseases and pregnancy complications, and the efficiency of the drug to prevent or ameliorate such risks. In some cases, the use of drugs in pregnancy carries benefits that outweigh the risks. For example, high fever is harmful for the fetus in the early months, thus the use of paracetamol (acetaminophen) is generally associated with lower risk than the fever itself. Similarly, diabetes mellitus during pregnancy may need intensive therapy with insulin to prevent complications to mother and baby. Pain management for the mother is another important area where an evaluation of the benefits and risks is needed. NSAIDs such as Ibuprofen and Naproxen are probably safe for use for a short period of time, 48–72 hours, once the mother has reached the second trimester. If taking aspirin for pain management the mother should never take a dose higher than 100 mg.
Nutrition during pregnancy is important to ensure healthy growth of the fetus. Nutrition during pregnancy is different from the non-pregnant state. There are increased energy requirements and specific micronutrient requirements. Women benefit from education to encourage a balanced energy and protein intake during pregnancy. Some women may need professional medical advice if their diet is affected by medical conditions, food allergies, or specific religious/ ethical beliefs.
Adequate periconceptional (time before and right after conception) folic acid (also called folate or Vitamin B) intake has been shown to decrease the risk of fetal neural tube defects, such as spina bifida. The neural tube develops during the first 28 days of pregnancy, a urine pregnancy test is not usually positive until 14 days post-conception, explaining the necessity to guarantee adequate folate intake before conception. Folate is abundant in green leafy vegetables, legumes, and citrus. In the United States and Canada, most wheat products (flour, noodles) are fortified with folic acid.
DHA omega-3 is a major structural fatty acid in the brain and retina, and is naturally found in breast milk. It is important for the woman to consume adequate amounts of DHA during pregnancy and while nursing to support her well-being and the health of her infant. Developing infants cannot produce DHA efficiently, and must receive this vital nutrient from the woman through the placenta during pregnancy and in breast milk after birth.
Several micronutrients are important for the health of the developing fetus, especially in areas of the world where insufficient nutrition is common. Women living in low and middle income countries are suggested to take multiple micronutrient supplements containing iron and folic acid. These supplements have been shown to improve birth outcomes in developing countries, but do not have an effect on perinatal mortality. Adequate intake of folic acid, and iron is often recommended. In developed areas, such as Western Europe and the United States, certain nutrients such as Vitamin D and calcium, required for bone development, may also require supplementation. Vitamin E supplementation has not been shown to improve birth outcomes. Zinc supplementation has been associated with a decrease in preterm birth, but it is unclear whether it is causative. Daily iron supplementation reduces the risk of maternal anemia. Studies of routine daily iron supplementation for pregnant women found improvement in blood iron levels, without a clear clinical benefit. The nutritional needs for women carrying twins or triplets. are higher than those of women carrying one baby.
Women are counseled to avoid certain foods, because of the possibility of contamination with bacteria or parasites that can cause illness. Careful washing of fruits and raw vegetables may remove these pathogens, as may thoroughly cooking leftovers, meat, or processed meat. Unpasteurized dairy and deli meats may contain "Listeria," which can cause neonatal meningitis, stillbirth and miscarriage. Pregnant women are also more prone to "Salmonella" infections, can be in eggs and poultry, which should be thoroughly cooked. Cat feces and undercooked meats may contain the parasite Toxoplasma gondii and can cause toxoplasmosis. Practicing good hygiene in the kitchen can reduce these risks.
Women are also counseled to eat seafood in moderation and to eliminate seafood known to be high in mercury because of the risk of birth defects. Pregnant women are counseled to consume caffeine in moderation, because large amounts of caffeine are associated with miscarriage. However, the relationship between caffeine, birthweight, and preterm birth is unclear.
The World Health Organization recommends that women with severe hypertension during pregnancy should receive treatment with anti-hypertensive agents. Severe hypertension is generally considered systolic BP of at least 160 or diastolic BP of at least 110. Evidence does not support the use of one anti-hypertensive over another. The choice of which agent to use should be based on the prescribing clinician's experience with a particular agent, its cost, and its availability. Diuretics are not recommended for prevention of preeclampsia and its complications. Labetolol, Hydralazine and Nifedipine are commonly used antihypertensive agents for hypertension in pregnancy. ACE inhibitors and angiotensin receptor blockers are contraindicated as they affect fetal development.
The goal of treatment of severe hypertension in pregnancy is to prevent cardiovascular, kidney, and cerebrovascular complications. The target blood pressure has been proposed to be 140–160 mmHg systolic and 90–105 mmHg diastolic, although values are variable.
The intrapartum and postpartum administration of magnesium sulfate is recommended in severe pre-eclampsia for the prevention of eclampsia. Further, magnesium sulfate is recommended for the treatment of eclampsia over other anticonvulsants. Magnesium sulfate acts by interacting with NMDA receptors.
U.S. Code of Federal Regulations requires that certain drugs and biological products must be labelled very specifically with respect to their effects on pregnant populations, including a definition of a "pregnancy category." These rules are enforced by the Food and Drug Administration (FDA). The FDA does not regulate labelling for all hazardous and non-hazardous substances and some potentially hazardous substances are not assigned a pregnancy category.
Australia’s categorisations system takes into account the birth defects, the effects around the birth or when the mother gives birth, and problems that will arise later in the child's life caused from the drug taken. The system places them into a category of their severity that the drug could cause to the infant when it crosses the placenta(Australian Government, 2014).
The goal of antiretroviral use during pregnancy is to reduce the risk of transmission of HIV from mother to child. It is important to choose medications that are safe for the mother and the fetus and which are effective at decreasing the total viral load. Some studies have shown an increase in stillbirths, preterm delivery, and delayed fetal growth in women using high doses of antiretroviral drugs during pregnancy. However, the overall benefits of ART are believed to outweigh the risks and all women are encouraged to use ART for the duration of their pregnancy.
Due to physiological changes in the body during pregnancy, it may be necessary to alter the dosing of medications so that they remain effective. Generally, the dose or the frequency of dosing are increased to account for these changes.
The recommended ART regimen for HIV-positive pregnant women consists of drugs from 4 different classes of medications listed below. In the United States, the favored regimen is a three-drug regimen where the first two drugs are NRTIs and the third is either a protease inhibitor, an integrase inhibitor, or an NNRTI.
- Nucleoside reverse transcriptase inhibitors (NRTIs) are considered the "backbone" of ART and 2 medications are generally used in combination. Due to its known safety profile and extensive use in pregnant patients, zidovudine-lamivudine (ZDV/3TC) is the preferred choice as the NRTI backbone. Zidovudine may worsen anemia, so patients with anemia are advised to use an alternative agent. For women who are coinfected with Hepatitis B, tenofovir with either emtricitabine or lamivudine is the preferred NRTI backbone. NRTI use may cause lactic acidosis in some women, so it is important to monitor patients for this complication. Deaths from lactic acidosis and liver failure have been associated with the use of two NRTIs, stavudine and didanosine (Zerit and Videx, respectively); therefore, combinations involving these drugs should be avoided in pregnancy.
- Protease inhibitors (PIs) have been studied extensively in pregnancy and are therefore the preferred third drug in the regimen. Atazanavir-ritonavir and darunavir-ritonavir are two of the most common PIs used during pregnancy. There is conflicting data regarding their association with preterm births, so women who are at a high risk for premature delivery are advised not to use PIs. Some PIs have been associated with hyperglycemia but is unclear whether they add to the risk of developing gestational diabetes. Some PIs have been noted to cause hyperbilirubinemia and nausea, so these side effects should be monitored for closely.
- Integrase inhibitors (IIs) are generally the third drug in the regimen when a PI cannot be used. They rapidly reduce the viral load and for this reason, they are often used in women who are diagnosed with HIV late in the pregnancy. Raltegravir is the most common II used.
- Non-nucleoside reverse transcriptase inhibitors (NNRTIs), the most popular being efavirenz and nevirapine, may be used during pregnancy. However, there are significant toxicities associated with their use, making them a less desirable option.
- Efavirenz (brand name Sustiva, and a component of the combination drug Atripla) is classified as a category D drug by the US Food and Drug Administration indicating there are risks associated with its use during pregnancy. In a study analyzing the use of the drug in pregnant women, 2.3% of births were associated with birth defects. However, a systematic review of the safety of efavirenz use in humans during the first trimester found no increase in birth defects among women using the drug. Given the uncertain potential for risk the U.S. DHHS recommends against using efavirenz in the first trimester of pregnancy or in women who may become pregnant. They instead recommend a protease inhibitor based regimen with lopinavir or atazanavir. However, to simplify regimens and provide a uniform recommendation for HIV-infected individuals during pregnancy, the WHO continues to recommend efavirenz as a first line agent for HIV positive women. Women using efavirenz prior to their pregnancy may continue with the drug as it is more dangerous to stop or change medications during pregnancy because this can result in improper control of the viral load.
- Nevirapine (trade name Viramune) increases the risk of very serious liver damage in women with CD4 counts greater than 250 cells/mm . It is generally avoided in pregnant women. Women taking nevirapine safely prior to pregnancy may continue with the medication because nevirapine-related liver damage has not been seen in women previously using the medication.
Protamine reverses the effect of unfractionated heparin, but only partially binds to and reverses LMWH. A dose of 1 mg protamine / 100 IU LMWH reverses 90% of its anti-IIa and 60% of anti-Xa activity, but the clinical effect of the residual anti-Xa activity is not known. Both anti-IIa and anti-Xa activity may return up to three hours after protamine reversal, possibly due to release of additional LMWH from depot tissues.
Warfarin, heparin and LMWH do not seem to pass into breast milk, so these are not contraindicated in breastfeeding.
Acute fatty liver of pregnancy is best treated in a centre with expertise in hepatology, high-risk obstetrics, maternal-fetal medicine and neonatology. The physicians who treat this condition will often consult with experts in liver transplantation in severe cases. Admission to the intensive care unit is recommended.
Initial treatment involves supportive management with intravenous fluids, intravenous glucose and blood products, including fresh frozen plasma and cryoprecipitate to correct DIC. The foetus should be monitored with cardiotocography. After the mother is stabilized, arrangements are usually made for delivery. This may occur vaginally, but, in cases of severe bleeding or compromise of the mother's status, a caesarian section may be needed. Often AFLP is not diagnosed until the mother and baby are in trouble, so it is most likely that an emergency C-section is needed.
The complications of acute fatty liver of pregnancy may require treatment after delivery, especially if pancreatitis occurs. Liver transplantation is rarely required for treatment of the condition, but may be needed for mothers with severe DIC, those with rupture of the liver, or those with severe encephalopathy.
An initial assessment to determine the status of the mother and fetus is required. Although mothers used to be treated in the hospital from the first bleeding episode until birth, it is now considered safe to treat placenta previa on an outpatient basis if the fetus is at less than 30 weeks of gestation, and neither the mother nor the fetus are in distress. Immediate delivery of the fetus may be indicated if the fetus is mature or if the fetus or mother are in distress. Blood volume replacement (to maintain blood pressure) and blood plasma replacement (to maintain fibrinogen levels) may be necessary.
Corticosteroids are indicated at 24–34 weeks gestation, given the higher risk of premature birth.
The method of delivery is determined by clinical state of the mother, fetus and ultrasound findings. In minor degrees (traditional grade I and II), vaginal delivery is possible. RCOG recommends that the placenta should be at least 2 cm away from internal os for an attempted vaginal delivery. When a vaginal delivery is attempted, consultant obstetrician and anesthetists are present in delivery suite. In cases of fetal distress and major degrees (traditional grade III and IV) a caesarean section is indicated. Caesarian section is contraindicated in cases of disseminated intravascular coagulation. An obstetrician may need to divide the anterior lying placenta. In such cases, blood loss is expected to be high and thus blood and blood products are always kept ready. In rare cases, hysterectomy may be required.
Early treatment of an ectopic pregnancy with methotrexate is a viable alternative to surgical treatment which was developed in the 1980s. If administered early in the pregnancy, methotrexate terminates the growth of the developing embryo; this may cause an abortion, or the developing embryo may then be either resorbed by the woman's body or pass with a menstrual period. Contraindications include liver, kidney, or blood disease, as well as an ectopic embryonic mass > 3.5 cm.
Also, it may lead to the inadvertent termination of an undetected intrauterine pregnancy, or severe abnormality in any surviving pregnancy. Therefore, it is recommended that methotrexate should only be administered when hCG has been serially monitored with a rise less than 35% over 48 hours, which practically excludes a viable intrauterine pregnancy.
Vitamin A plays a role in the immune system and is a low-cost intervention that has been suggested to help with preventing mother-to-child transmission of HIV. A Cochrane review summarised the evidence of five trials conducted in Malawi, South Africa, Tanzania and Zimbabwe between 1995 and 2005, where none of the participants received antiretroviral therapy. They found that giving vitamin A supplementation to pregnant women or to women after they delivered a baby probably has little or no effect on mother-to-child transmission of HIV. The intervention has been largely suspended by antiretroviral therapy.
If bleeding has already occurred, surgical intervention may be necessary. However, whether to pursue surgical intervention is an often difficult decision in a stable patient with minimal evidence of blood clot on ultrasound.
Surgeons use laparoscopy or laparotomy to gain access to the pelvis and can either incise the affected Fallopian and remove only the pregnancy (salpingostomy) or remove the affected tube with the pregnancy (salpingectomy). The first successful surgery for an ectopic pregnancy was performed by Robert Lawson Tait in 1883. It is estimated that an acceptable rate of PULs that eventually undergo surgery is between 0.5 and 11%.
Autotransfusion of a woman's own blood as drained during surgery may be useful in those who have a lot of bleeding into their abdomen.
Published reports that a re-implanted embryo survived to birth were debunked as false.
In cases of Rho(D) incompatibility, Rho(D) immunoglobulin is given to prevent sensitization. However, there is no comparable immunotherapy available for other blood group incompatibilities.
Early pregnancy
- IVIG - IVIG stands for Intravenous Immunoglobulin. It is used in cases of previous loss, high maternal titers, known aggressive antibodies, and in cases where religion prevents blood transfusion. Ivig can be more effective than IUT alone. Fetal mortality was reduced by 36% in the IVIG and IUT group than in the IUT alone group. IVIG and plasmapheresis together can reduce or eliminate the need for an IUT.
- Plasmapheresis - Plasmapheresis aims to decrease the maternal titer by direct plasma replacement. Plasmapheresis and IVIG together can even be used on women with previously hydropic fetuses and losses.
Mid to late pregnancy
- IUT - Intrauterine Transfusion (IUT) is done either by intraperitoneal transfusion (IPT) or intravenous transfusion (IVT). IVT is preferred over IPT. IUTs are only done until 35 weeks. After that, the risk of an IUT is greater than the risk from post birth transfusion.
- Steroids - Steroids are sometimes given to the mother before IUTs and early delivery to mature the fetal lungs.
- Phenobarbital - Phenobarbital is sometimes given to the mother to help mature the fetal liver and reduce hyperbilirubinemia.
- Early Delivery - Delivery can occur anytime after the age of viability. Emergency delivery due to failed IUT is possible, along with induction of labor at 35–38 weeks.
Rhesus-negative mothers who have had a pregnancy who are pregnant with a rhesus-positive infant are offered Rho(D) immune globulin (RhIG) at 28 weeks during pregnancy, at 34 weeks, and within 48 hours after delivery to prevent sensitization to the D antigen. It works by binding any fetal red blood cells with the D antigen before the mother is able to produce an immune response and form anti-D IgG. A drawback to pre-partum administration of RhIG is that it causes a positive antibody screen when the mother is tested, which can be difficult to distinguish from natural immunological responses that result in antibody production. Without Rho(D) immunoglobulin, the risk of isoimmunization is approximately 17%; with proper administration the risk is reduced to less than 0.1-0.2%.
There is no cure for FASD, but treatment is possible. Because CNS damage, symptoms, secondary disabilities, and needs vary widely by individual, there is no one treatment type that works for everyone.
After birth, treatment depends on the severity of the condition, but could include temperature stabilization and monitoring, phototherapy, transfusion with compatible packed red blood, exchange transfusion with a blood type compatible with both the infant and the mother, sodium bicarbonate for correction of acidosis and/or assisted ventilation.
- Phototherapy - Phototherapy is used for cord bilirubin of 3 or higher. Some doctors use it at lower levels while awaiting lab results.
- IVIG - IVIG has been used to successfully treat many cases of HDN. It has been used not only on anti-D, but on anti-E as well. IVIG can be used to reduce the need for exchange transfusion and to shorten the length of phototherapy. The AAP recommends "In isoimmune hemolytic disease, administration of intravenousγ-globulin (0.5-1 g/kg over 2 hours) is recommended if the TSB is rising despite intensive phototherapy or the TSB level is within 2 to 3 mg/dL (34-51 μmol/L) of the exchange level . If necessary, this dose can be repeated in 12 hours (evidence quality B: benefits exceed harms). Intravenous γ-globulin has been shown to reduce the need for exchange transfusions in Rh and ABO hemolytic disease."
- Exchange transfusion - Exchange transfusion is used when bilirubin reaches either the high or medium risk lines on the nonogram provided by the American Academy of Pediatrics (Figure 4). Cord bilirubin >4 is also indicative of the need for exchange transfusion.
Psychoactive drugs are frequently tried on those with FASD as many FASD symptoms are mistaken for or overlap with other disorders, most notably ADHD.
Developmental toxicity is the alterations of the developmental processes (organogenesis, morphogenesis) rather than functional alterations of already developed organs. The effects of the toxicants depends on the dose, threshold and duration. The effects of toxicity are:
1. Minor structural deformities - e.g. Anticonvulsant drugs, Warfarin, Retinoic Acid derivatives
2. Major structural deformities - e.g. DES (diethylstilbestrol), cigarette smoking
3. Growth Retardation - e.g. Alcohol, Polychlorinated Biphenyls
4. Functional alterations - e.g. Retinoic Acid derivatives, Polychlorinated Biphenyls, Phenobarbitol, Lead
5. Death- e.g. Rubella, ACE inhibitors
Fetal alcohol spectrum disorders (FASD) is a term that constitutes the set of conditions that can occur in a person whose mother drank alcohol during the course of pregnancy. These effects can include physical and cognitive problems. FASD patient usually has a combination of these problems. Extent of effect depends on exposure frequency, dose and rate of ethanol elimination from amniotic fluid. FAS disrupts normal development of the fetus, which may cause certain developmental stages to be delayed, skipped, or immaturely developed. Since alcohol elimination is slow in a fetus than in an adult and the fact that they do not have a developed liver to metabolize the alcohol, alcohol levels tend to remain high and stay in the fetus longer. Birth defects associated with prenatal exposure to alcohol can occur in the first three to eight weeks of pregnancy before a woman even knows that she is pregnant.
A number of antiemetics are effective and safe in pregnancy including: pyridoxine/doxylamine, antihistamines (such as diphenhydramine), metoclopramide, and phenothiazines (such as promethazine). With respect to effectiveness it is unknown if one is superior to another. In the United States and Canada, the doxylamine-pyridoxine combination (as Diclegis in US and Diclectin in Canada) is the only approved pregnancy category "A" prescription treatment for nausea and vomiting of pregnancy.
Ondansetron may be beneficial, but there are some concerns regarding an association with cleft palate, and there is little high quality data. Metoclopramide is also used and relatively well tolerated. Evidence for the use of corticosteroids is weak.
The pregnancy category of a medication is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does "not" include any risks conferred by pharmaceutical agents or their metabolites in breast milk.
Every drug has specific information listed in its product literature. The British National Formulary used to provide a table of drugs to be avoided or used with caution in pregnancy, and did so using a limited number of key phrases, but now Appendix 4 (which was the Pregnancy table) has been removed. Appendix 4 is now titled "Intravenous Additives". However, information that was previously available in the former Appendix 4 (pregnancy) and Appendix 5 (breast feeding) is now available in the individual drug monographs.
Often, this disease is treated by giving aspirin to inhibit platelet activation, and/or warfarin as an anticoagulant. The goal of the prophylactic treatment with warfarin is to maintain the patient's INR between 2.0 and 3.0. It is not usually done in patients who have had no thrombotic symptoms.
Anticoagulation appears to prevent miscarriage in pregnant women. In pregnancy, low molecular weight heparin and low-dose aspirin are used instead of warfarin because of warfarin's teratogenicity. Women with recurrent miscarriage are often advised to take aspirin and to start low molecular weight heparin treatment after missing a menstrual cycle. In refractory cases plasmapheresis may be used.
Most Rh disease can be prevented by treating the mother during pregnancy or promptly (within 72 hours) after childbirth. The mother has an intramuscular injection of anti-Rh antibodies (Rho(D) immune globulin). This is done so that the fetal rhesus D positive erythrocytes are destroyed before the immune system of the mother can discover them and become sensitized. This is passive immunity and the effect of the immunity will wear off after about 4 to 6 weeks (or longer depending on injected dose) as the anti-Rh antibodies gradually decline to zero in the maternal blood.
It is part of modern antenatal care to give all rhesus D negative pregnant women an anti-RhD IgG immunoglobulin injection at about 28 weeks gestation (with or without a booster at 34 weeks gestation). This reduces the effect of the vast majority of sensitizing events which mostly occur after 28 weeks gestation. Giving Anti-D to all Rhesus negative pregnant women can mean giving it to mothers who do not need it (because her baby is Rhesus negative or their blood did not mix). Many countries routinely give Anti-D to Rhesus D negative women in pregnancy. In other countries, stocks of Anti-D can run short or even run out. Before Anti-D is made routine in these countries, stocks should be readily available so that it is available for women who need Anti-D in an emergency situation.
A recent review found research into giving Anti-D to all Rhesus D negative pregnant women is of low quality. However the research did suggest that the risk of the mother producing antibodies to attack Rhesus D positive fetal cells was lower in mothers who had the Anti-D in pregnancy. There were also fewer mothers with a positive kleihauer test (which shows if the mother’s and unborn baby’s blood has mixed).
Anti-RhD immunoglobulin is also given to non-sensitized rhesus negative women immediately (within 72 hours—the sooner the better) after potentially sensitizing events that occur earlier in pregnancy.
The discovery of cell-free DNA in the maternal plasma has allowed for the non-invasive determination of the fetal RHD genotype. In May 2017, the Society for Obstetrics and Gynecology of Canada is now recommending that the optimal management of the D-negative pregnant woman is based on the prediction of the fetal D-blood group by cell-free DNA in maternal plasma with targeted antenatal anti-D prophylaxis. This provides the optimal care for D-negative pregnant women and has been adopted as the standard approach in a growing number of countries around the world. It is no longer considered appropriate to treat all D-negative pregnant women with human plasma derivatives when there are no benefits to her or to the fetus in a substantial percentage of cases.