All 10 countries in the African Region that were reviewed had > 50% coverage with vector control activities allergy treatment and breastfeeding buy generic allegra 180mg on-line. Some evidence of changes in the malaria burden in other countries with high coverage rates has been published allergy medicine infants generic allegra 120 mg otc, but the studies in Equatorial Guinea (8) allergy testing johannesburg buy generic allegra 120 mg line, the Gambia (9) and Kenya (10) were confined to limited geographical areas allergy symptoms gums buy discount allegra 120mg on-line, and the generalizability of the results is uncertain allergy symptoms cough dry buy allegra 120mg without prescription. More studies are needed to measure the impact of high coverage in the countries identified in Chapter 3 allergy testing number scale cheap allegra 120 mg mastercard, particularly high-transmission areas in western and central Africa allergy testing long island order allegra 120 mg with visa. The main reason for the lack of additional evidence for a change in the malaria burden has been weak disease surveillance systems allergy testing gold coast order allegra 120mg mastercard. Although many governments and partners have scaled-up malaria control interventions massively, their impact is not being measured consistently and continuously. The ability of malaria-endemic countries to monitor changes in the numbers of confirmed malaria cases, admissions for severe malaria and malaria-associated deaths must be strengthened. Inadequate monitoring can lead to poor adjustment of strategies, inefficient use of funds and inadequate "learning" for malaria programmes. Once malaria transmission has been reduced, national programmes must be able to detect malaria resurgence quickly and respond with appropriate resources. As experience suggests that malaria transmission decreases heterogeneously, robust surveillance systems are essential to identify residual transmission foci and target additional resources to those areas. Strengthening of surveillance systems will require investment in diagnostic services, reporting systems and capacity-building to manage systems and undertake appropriate data analysis and dissemination. In countries where malaria control has been scaled-up, not only have the rates of malaria cases, hospitalizations and deaths dropped dramatically, but overall child mortality rates are also in steep decline. National disease surveillance data from Eritrea, Sao Tome and Principe, Rwanda, Zambia and Zanzibar, United Republic of Tanzania, showed a > 50% reduction in malaria cases and deaths in health facilities after the introduction of accelerated malaria control. In Sao Tome and Principe and Zanzibar, these gains were mirrored by a > 50% decrease in inpatient cases and deaths from all causes among children < 5 years of age. In Zambia, child mortality rates from all causes fell by 35%, as measured both by the number of deaths recorded in health facilities and by < 5 mortality rates derived from the Demographic and Health Survey of 2007. The magnitude of these decreases is similar to that found in a recent study on Bioko Island, Equatorial Guinea, in which population-based mortality among children < 5 had decreased by 66% in the fourth year after the start of intensive malaria control (8). The European Region has been the most successful, as almost all countries have reduced their case loads. Most small countries in the South-East Asia Region also reported substantial progress in reducing their malaria burden, while in other regions, large decreases in the number of malaria cases were observed in countries with strong political and financial support and well-developed health systems at central and peripheral levels. Of the 34 countries that showed a decrease of > 25% in the number of cases, there was evidence of extensive control activities in 27 (in comparison with 4 of 22 for which there was limited evidence of a decrease). The magnitude and consistency of the changes observed in these countries are unlikely to be due to variations in case reporting, and, while factors such as climate variation, the environment or improved living conditions may have had some influence on the number of cases, they are unlikely to be entirely responsible for the change. It was not possible to link the scale and timing of interventions precisely with the changes in disease incidence in the analyses undertaken here; that would require disaggregation of the information on numbers of cases and control activities by month and subnationally. Until more detailed analyses can be undertaken, the association between implementation of control activities and changes in disease incidence is suggestive but not conclusive. The size of the decrease observed in health facility data may not be seen in the wider community; however, with changes as large as those observed and with typically 40% of affected persons attending public health facilities, some impact can be expected in the wider community. The analytical approach used might result in an underestimate of the impact of control efforts in countries in which the effect is not noticeable at national level or in which the impact is more recent and cannot yet be distinguished from changes due to year-toyear climate variations or possible changes in reporting practices. The countries that saw > 50% decreases in the numbers of cases comprised only 4% of the total estimated cases outside Africa in 2006 (850 000 cases out of 34 million estimated). The countries with the highest malaria burdens in each region (such as Bangladesh, Brazil, Cambodia, Colombia, Indonesia, Myanmar, Pakistan, Papua New Guinea and Sudan) were less successful in reducing the numbers of cases of malaria nationally. The scale of interventions in relation to populations at risk appears to be particularly small in the SouthEast Asia Region, presumably because of the additional challenges 4. Nevertheless, some of these countries have reported successful control in some parts of their territory, due either to targeted efforts in some communities or to phasing implementation over a wide scale. Further work is needed to determine if current levels of investment and programme implementation are likely to yield more positive results in the near future. It is possible that additional evidence of decreases in cases or widespread coverage of programmes is available at country level. Countries in bold show evidence of wide scale implementation of malaria control activities to more than 50% of the population at high risk. Therefore observed decreases of more than 50% in cases and deaths need further investigation. Effectiveness of malaria control during changing climate conditions in Eritrea, 19982003. Malaria in Sгo Tomй and Principe: on the brink of elimination after three years of effective antimalarial measures. Impact of artemisinin-based combination therapy and insecticide-treated nets on malaria burden in Zanzibar. The Tashkent Declaration: the move from malaria control to elimination in the European Region. Steep increase in child survival after four years of integrated malaria control in Bioko Island, Equatorial Guinea. Changes in malaria indices between 1999 and 2007 in the Gambia: a retrospective analysis. Effect of a fall in malaria transmission on morbidity and mortality in Kilifi, Kenya. Elimination of malaria this chapter describes the state of malaria elimination in the world, to illustrate progress towards the elimination targets. Supported by the advocacy efforts of the Malaria Elimination Group (2), there is now renewed interest in pushing the boundaries of malaria-free areas of the world even further. The elimination of malaria from selected countries is stated explicitly in the targets of the Global Malaria Action Plan (3), as follows: will have achieved zero incidence of locally transmitted infection. Current elimination efforts are driven by the ministries of health of malaria-endemic countries. Considerable progress has been made in malaria elimination during the past few years. Consistent with the goals of the Global nation phase, Armenia, Egypt and Turkmenistan, have reported no locally acquired cases for more than 3 years, and have moved to the phase of prevention of reintroduction. The types of malaria programmes currently implemented worldwide are shown in Figure 5. From a country perspective, interruption of local mosquito-borne malaria transmission or elimination of malaria is the ultimate goal of malaria control. Malaria elimination has been achieved progressively in parts of the world since the recorded history of the disease. By the mid-19th century, malaria had been eliminated from several countries in temperate zones in which it had been endemic. In the context of the Global Malaria Eradication Programme (19551968) and up to 1987, 24 countries were certified as malaria-free. Since then, an additional 9 countries have reported (periods of) zero locally acquired cases, leading to a further contraction of the world map of malaria endemicity (1). Using the momentum created by the global efforts against malaria of the past decade, some countries in the subtropical and even the tropical belt have reduced their malaria incidence to the extent that they are considering moving towards malaria elimination. Countries that have no arrows associated with their name are those which were in the same category in 2008 as in 2009. The three backwards arrows for Argentina, El Salvador and Paraguay are to correct for a previous error in classification and do not reflect a deterioration of the programme status of these countries. Azerbaijan Georgia Kyrgyzstan Tajikistan Turkey Uzbekistan Argentina El Salvador Paraguay Iran (Islamic Rep. Failure to sustain malaria control and the resulting resurgence of malaria, as has happened in the past, must be avoided at all costs. Therefore, public and government interest in intensified malaria control and elimination must be sustained, even when the malaria burden has been greatly reduced. Countries in areas of low, unstable transmission should be encouraged to proceed to malaria elimination. Before making this decision, however, they should assess its feasibility and take into account the malaria situation in neighbouring countries. Malaria elimination might require cross-border initiatives and regional support and will require strong political commitment. In areas of high, stable transmission, where a marked reduction in malaria transmission has been achieved, a "consolidation period" should be introduced, in which: i) control achievements are sustained, even in the face of limited disease; ii) health services adapt to the new clinical and epidemiological situation with a lower case load and reduced levels of immunity; and iii) surveillance systems are strengthened to allow rapid response to new cases. This transformation phase precedes a decision to reorient programmes towards elimination. Complete interruption of malaria transmission is likely to require additional, novel tools, especially in high-transmission situations. Because malaria control today relies heavily on a limited number of tools, in particular artemisinin derivatives and pyrethroids, which could be lost to resistance at any time, the development of new tools for vector control and other preventive measures, diagnosis, treatment and surveillance must be a priority. Malaria control: reducing the malaria disease burden to a level at which it is no longer a public health problem. Malaria elimination: the interruption of local mosquito-borne malaria transmission; reduction to zero of the incidence of infection caused by human malaria parasites in a defined geographical area as a result of deliberate efforts; continued measures to prevent reestablishment of transmission are required. Malaria eradication: permanent reduction to zero of the worldwide incidence of infection caused by a specific agent; applies to a particular malaria parasite species. With rapid scale-up and sustained efforts, major reductions in malaria morbidity and mortality can be made in all epidemiological situations within a relatively short time. Malaria transmission can be interrupted in low-transmission settings and greatly reduced in many areas of high transmission. The steps for eliminating malaria from a country or area that has reduced its malaria transmission intensity to low levels are shown in Figure 5. Not all countries will be able to interrupt malaria transmission with the currently available tools. These milestones should be adjusted for each country and situation, keeping in mind the resource requirements for notification, investigation and follow-up of every malaria case once the elimination programme is set in motion. The actual programme transitions will thus depend on the workload that programme staff can realistically handle, given local circumstances and infrastructure, the available resources and competing demands on the health services. Countries that are currently implementing elimination programmes made the decision to pursue elimination when they had a low remaining case load, usually < 1000 cases per year nationwide. In elimination programmes, the main indicator is the total number of locally acquired infections. The type of intervention and the required quality of operations evolve as country programmes are redirected towards an elimination approach, as shown in Table 5. The numbers of reported malaria cases in these countries over the past 10 years are shown in Figure 5. In practice, the transitions will depend on the malaria burden that a programme can realistically handle, given the local circumstances and available resources and keeping in mind the need to assure notification, investigation and due follow up of all malaria cases. The interventions mentioned in this column are introduced during this programme reorientation, to be fully operational at the start of the elimination programme. This is despite having areas with abundant malaria vectors and suitable climate conditions, which make them receptive to the resumption of transmission, and continued importation of parasites from abroad. During the period 19982008, the annual number of reported local cases was reduced 100-fold or more in nearly all the elimina- tion countries. The exception was the Republic of Korea, which showed a more sustained transmission pattern. Together, the 10 elimination countries reported just 1672 locally acquired malaria infections in 2008, and 1730 imported cases. Over 60% of the local cases were reported by the Republic of Korea, followed by Tajikistan (19%) and Turkey (10%). None of the elimination countries has reported deaths due to local malaria transmission since 1998, but imported cases continue to result in occasional deaths;. All the malaria-affected countries of the Region have moved forward one programme phase. As of 2009, these countries had been that the elimination approach is not yet fully being implemented countrywide in all affected areas. The eight pre-elimination countries reported a total of 29 245 confirmed malaria cases in the last year for which data are available, 5. With the exception of Sri Lanka, none of the pre-elimination countries has reported deaths from malaria during the past decade. In Sri Lanka, local malaria deaths decreased from 115 in 1998 to 2 in 2004; no deaths from malaria have been reported since then. Typically, relatively large parts of the territories of these countries are still affected by malaria. Eventual malaria elimination in these countries will be "ambitious and challenging" (12). Cape Verde presents a different scenario: the country took part in the malaria eradication campaign of the 1950s and 1960s, when it greatly reduced its original level of endemicity. Rebound epidemics occurred after favourable rains in the late 1970s and 1980s but were successfully controlled. At present, only one of the nine inhabited islands (Sгo Tiago) is considered to have malaria transmission, with seasonal transmission linked to rainfall, resulting over the 12-year were locally acquired. The programme incorporates many aspects of the elimination approach and is reorienting its national strategy towards elimination. The term "malaria-free" is in this context not well-defined: while some countries are trying to eliminate the last locally acquired malaria infections in well-defined areas, for instance to encourage tourism (Socotra, Yemen), others in this group are trying to reduce mortality and morbidity due to malaria to a certain level. Certification requires proving beyond reasonable doubt that the chain of local human malaria transmission by Anopheles mosquitoes has been fully interrupted in the entire country. This implies that all the available evidence has been evaluated and has been found to be consistent with the assertion that malaria elimination has been achieved and that good-quality surveillance systems are in place that would be capable of detecting local transmission if it were occurring. Details of the aspects to be covered by the evaluation teams are provided elsewhere (14). Certification of malaria elimination is based on an assessment of the current situation and the likelihood that elimination can be maintained. Of the certified countries and areas Jamaica, Mauritius and northern Venezuela (Bolivarian Republic of) were unable to maintain the absence of local transmission. Malaria elimination in Mauritius was certified in 1973, but transmission was reintroduced in 1978 and lasted 20 years. Mauritius now has comprehensive surveillance mechanisms, however, and has not reported a local case since 1998; it is once again considered free from local malaria transmission. The United Arab Emirates reported its last locally acquired malaria case in 1997, and elimination was certified in January 2007 (17). A further six countries have reported (periods of) zero cases in recent years: Armenia, Egypt, Morocco, Oman, Syrian Arab Republic and Turkmenistan. Procedures for certification are under way with Morocco and have been initiated with Turkmenistan. Financing malaria control the three major sources of funds for malaria control programmes are national government spending, external assistance from donors and household or private "out-of-pocket" expenditure. In the Global Malaria Action Plan (1), it is estimated of total spending on malaria globally in 2007. This Report does not address household expenditures but focuses on external funding for malaria and national government spending. It considers the following issues: i) trends in international and domestic financing for malaria and their relation to estimated resource requirements; ii) how funds disbursed from external agencies have been allocated to different geographical regions, countries and programmes; and iii) the relation between external financing, programme implementation and disease trends. Commitments represent a firm agreement by a funding agency to provide funds according to a prescribed plan. This may be a budget approved by a national government or a grant agreement between a funding agency and a programme implementer. Commitments provide an indication of the funding priority given to malaria, to particular countries or programmes. Information on commitments can often be obtained for the most recent financial year but do not always translate into programme expenditures, as there may be delays in disbursement of funds or problems in programme implementation which lead to reprogramming of resources. Hence, in analysing what funds have been used for malaria control, it is usually preferable to examine disbursements or actual expenditures, which give a more accurate picture of the extent to which recipients have benefited. The most comprehensive dataset on disbursements is that maintained by the Institute for Health Metrics and Evaluation, which provides information on the disbursements of 27 agencies that provide funding for malaria; this was supplemented with additional information on disbursements supplied by individual donor agencies. It is sometimes difficult to distinguish between disbursements and expenditures;. Also, some funds disbursed may not be spent during the year the disbursement was made. In such cases, actual spending may be much less than the disbursements reported by donors. Information on disbursements is, however, generally more complete than that available for expenditures, and was hence central to most of the analyses presented here. They do not include government funding or external assistance for the support of health systems, because it is difficult to assign specific amounts to malaria, even though malaria programmes clearly benefit from such support. In addition, much external assistance is provided through multilateral channels as technical support or through nongovernmental organizations, and is not always captured by the sources of information examined. Hence, it is possible that the funds available for malaria are greater than those recorded here. Nevertheless, the analysis presented gives an indication of the overall levels of funding for malaria in relation to resource requirements and how these have changed over time. This illustrates that information on commitments to malaria may not provide an accurate picture of funds immediately available for malaria control. An important issue, however, is whether government financing for malaria remains stable in the presence of large quantities of external financing, or whether it is reduced or increases. The analysis was restricted to 31 countries that provided information on government financing for malaria for at least 5 of the past 9 years and included data for 2007 or 2008. When possible, government expenditure was used; if this information was not available, government budgets for malaria were used3. Although the trends among these counties might not be generalizable, they represent the only information currently available. The evidence that external financing for malaria displaces government financing is mixed: domestic financing for malaria increased in a range of countries in all regions, but a potential downwards trend between 2007 and 2008 was seen in two regions, and there was a steady decrease between 2005 and 2008 in the South-East Asia Region.
Herrman H allergy treatment in dogs discount allegra 180 mg without a prescription, Aebi U: Intermediate filaments: molecular structure allergy medicine isn't working discount 120mg allegra free shipping, assembly mechanism lidocaine allergy testing allegra 120 mg free shipping, and integration into functionally distinct intracellular scaffolds allergy headache or migraine discount allegra 180 mg overnight delivery. The basic properties of a number of plasma proteins allergy welts order 180mg allegra overnight delivery, including the immunoglobulins (antibodies) allergy medicine 711 discount allegra 180mg visa, are described in this chapter allergy vacuum cleaner proven allegra 120mg. Changes in the amounts of various plasma proteins and immunoglobulins occur in many diseases and can be monitored by electrophoresis or other suitable procedures allergy symptoms 6 dpo allegra 120 mg generic. As indicated in an earlier chapter, alterations of the activities of certain enzymes found in plasma are of diagnostic use in a number of pathologic conditions. The relative dimensions and molecular masses of some of the most important plasma proteins are shown in Figure 501. The separation of individual proteins from a complex mixture is frequently accomplished by the use of solvents or electrolytes (or both) to remove different protein fractions in accordance with their solubility characteristics. This is the basis of the so-called salting-out methods, which find some usage in the determination of protein fractions in the clinical laboratory. Thus, one can separate the proteins of the plasma into three major groups-fibrinogen, albumin, and globulins-by the use of varying concentrations of sodium or ammonium sulfate. There are many types of electrophoresis, each using a different supporting medium. In clinical laboratories, cellulose acetate is widely used as a supporting medium. Its use permits resolution, after staining, of plasma proteins into five bands, designated albumin, 1, 2, and fractions, respectively (Figure 502). The stained strip of cellulose acetate (or other supporting medium) is called an electrophoretogram. The amounts of these five bands can be conveniently quantified by use of densitometric scanning machines. Characteristic changes in the amounts of one or more of these five bands are found in many diseases. Plasma consists of water, electrolytes, metabolites, nutrients, proteins, and hormones. The water and electrolyte composition of plasma is practically the same as that of all extracellular fluids. The proteins of the plasma are actually a complex mixture that includes not only simple proteins but also conjugated proteins such as glycoproteins and various types of lipoproteins. Use of proteomic techniques is allowing the isolation and characterization of previously unknown plasma proteins, some present in very small amounts (eg, detected in hemodialysis fluid and in the plasma of patients with cancer), thus expanding the plasma proteome. Thousands of antibod566 the Concentration of Protein in Plasma Is Important in Determining the Distribution of Fluid Between Blood & Tissues In arterioles, the hydrostatic pressure is about 37 mm Hg, with an interstitial (tissue) pressure of 1 mm Hg opposing it. The osmotic pressure (oncotic pressure) exerted by the plasma proteins is approximately 25 mm Hg. Thus, a net outward force of about 11 mm Hg drives fluid out into the interstitial spaces. In venules, the hydrostatic pressure is about 17 mm Hg, with the oncotic and interstitial pressures as described above; thus, a net force of about 9 mm Hg attracts water back into the circulation. Excretion-transport of metabolic waste to the kidneys, lungs, skin, and intestines for removal 4. Regulation of water balance through the effects of blood on the exchange of water between the circulating fluid and the tissue fluid 6. Considerable information is available about the biosynthesis, turnover, structure, and functions of the major plasma proteins. Alterations of their amounts and of their metabolism in many disease states have also been investigated. In recent years, many of the genes for plasma proteins have been cloned and their structures determined. The preparation of antibodies specific for the individual plasma proteins has greatly facilitated their study, allowing the precipitation and isolation of pure proteins from the complex mixture present in tissues or plasma. In addition, the use of isotopes has made possible the determination of their pathways of biosynthesis and of their turnover rates in plasma. However, the -globulins are synthesized in plasma cells and certain plasma proteins are synthesized in other sites, such as endothelial cells. Thus, most plasma proteins are synthesized as preproteins and initially contain amino terminal signal peptides (Chapter 46). They are usually subjected to various posttranslational modifications (proteolysis, glycosylation, phosphorylation, etc) as they travel through the cell. Transit times through the hepatocyte from the site of synthesis to the plasma vary from 30 min to several hours or more for individual proteins. Accordingly, they generally contain either N- or O-linked oligosaccharide chains, or both (Chapter 47). Removal of terminal sialic acid residues from certain plasma proteins (eg, ceruloplasmin) by exposure to neuraminidase can markedly shorten their half-lives in plasma (Chapter 47). Many Plasma Proteins Exhibit Polymorphism A polymorphism is a mendelian or monogenic trait that exists in the population in at least two phenotypes, neither of which is rare (ie, neither of which occurs with frequency of less than 12%). The polymorphic forms of these proteins can be distinguished by different procedures (eg, various types of electrophoresis or isoelectric focusing), in which each form may show a characteristic migration. Analyses of these human polymorphisms have proved to be of genetic, anthropologic, and clinical interest. Their levels are also usually elevated during chronic inflammatory states and in patients with cancer. For example, C-reactive protein can stimulate the classic complement pathway, and 1-antitrypsin can neutralize certain proteases released during the acute inflammatory state. This important factor is also involved in the expression of many cytokines, chemokines, growth factors, and cell adhesion molecules implicated in immunologic phenomena. Normally it exists in an inactive form in the cytosol but is activated and translocated to the nucleus via the action of a number of molecules (eg, interleukin-1) Each Plasma Protein Has a Characteristic Half-Life in the Circulation the half-life of a plasma protein can be determined by labeling the isolated pure protein with 131I or Cr51 under mild, nondenaturing conditions. The labeled protein is freed of unbound free isotope and its specific activity (disintegrations per minute per milligram of protein) determined. A known amount of the radioactive protein is then injected into a normal adult subject, and samples of blood are taken at various time intervals for determinations of radioactivity. The values for radioactivity are plotted against time, and the half-life of the protein (the time for the radioactivity to decline from its peak value to one-half of its peak value) can be calculated from the resulting graph, discounting the times for the injected protein to equilibrate (mix) in the blood and in the extravascular spaces. The halflives obtained for albumin and haptoglobin in normal healthy adults are approximately 20 and 5 days, respectively. For instance, in some gastrointestinal diseases such as regional ileitis (Crohn disease), considerable amounts of plasma proteins, including albumin, may be lost into the bowel through the inflamed intestinal mucosa. Patients with this condition have a protein-losing gastroenteropathy, and the half-life of injected iodinated albumin in these subjects may be reduced to as little as 1 day. The remainder of the material in this chapter presents basic information regarding selected plasma proteins: albumin, haptoglobin, transferrin, ceruloplasmin, 1antitrypsin, 2-macroglobulin, the immunoglobulins, and the complement system. New information is constantly forthcoming on plasma proteins and their variants (including those discussed here), as the techniques of proteomics, particularly sensitive new methods of determining proteins sequences by mass spectrometry (see Chapter 4), are applied to their study. A number of laboratories are participating in efforts to determine the complete human plasma protein proteome. It is believed that this will shed further light on genetic variations in humans and also provide many new biomarkers to aid in the diagnosis of many diseases. About 40% of albumin is present in the plasma, and the other 60% is present in the extracellular space. The liver produces about 12 g of albumin per day, representing about 25% of total hepatic protein synthesis and half its secreted protein. Its signal peptide is removed as it passes into the cisternae of the rough endoplasmic reticulum, and a hexapeptide at the resulting amino terminal is subsequently cleaved off farther along the secretory pathway (see Figure 4611). The synthesis of albumin is depressed in a variety of diseases, particularly those of the liver. The plasma of patients with liver disease often shows a decrease in the ratio of albumin to globulins (decreased albumin-globulin ratio). The synthesis of albumin decreases relatively early in conditions of protein malnutrition, such as kwashiorkor. Mature human albumin consists of one polypeptide chain of 585 amino acids and contains 17 disulfide bonds. By the use of proteases, albumin can be subdivided into three domains, which have different functions. Albumin has an ellipsoidal shape, which means that it does not increase the viscosity of the plasma as much as an elongated molecule such as fibrinogen does. Because of its relatively low molecular mass (about 69 kDa) and high concentration, albumin is thought to be responsible for 7580% of the osmotic pressure of human plasma. Electrophoretic studies have shown that the plasma of certain humans lacks albumin. Subjects with analbuminemia show only moderate edema, despite the fact that albumin is the major determinant of plasma osmotic pressure. It is thought that the amounts of the other plasma proteins increase and compensate for the lack of albumin. In addition, albumin appears to play an important role in transport of copper in the human body (see below). A variety of drugs, including sulfonamides, penicillin G, dicumarol, and aspirin, are bound to albumin; this finding has important pharmacologic implications. Preparations of human albumin have been widely used in the treatment of hemorrhagic shock and of burns. Similarly, ferritin is also found in plasma in small amounts, but it too is not usually characterized as a plasma protein. The amount of haptoglobin in human plasma ranges from 40 mg to 180 mg of hemoglobin-binding capacity per deciliter. Approximately 10% of the hemoglobin that is degraded each day is released into the circulation and is thus extracorpuscular. The other 90% is present in old, damaged red blood cells, which are degraded by cells of the histiocytic system. The molecular mass of hemoglobin is approximately 65 kDa, whereas the molecular mass of the simplest polymorphic form of haptoglobin (Hp 1-1) found in humans is approximately 90 kDa. Free hemoglobin passes through the glomerulus of the kidney, enters the tubules, and tends to precipitate therein (as can happen after a massive incompatible blood transfusion, when the capacity of haptoglobin to bind hemoglobin is grossly exceeded) (Figure 503). The function of Hp thus appears to be to prevent loss of free hemoglobin into the kidney. This conserves the valuable iron present in hemoglobin, which would otherwise be lost to the body. Human haptoglobin exists in three polymorphic forms, known as Hp 1-1, Hp 2-1, and Hp 2-2. Hp 1-1 migrates in starch gel electrophoresis as a single band, whereas Hp 2-1 and Hp 2-2 exhibit much more complex band patterns. It has been suggested that the haptoglobin polymorphism may be associated with the prevalence of many inflammatory diseases. This is explained by the fact that whereas the half-life of haptoglobin is approximately 5 days, the half-life of the Hb-Hp complex is about 90 min, the complex being rapidly removed from plasma by hepatocytes. Thus, when haptoglobin is bound to hemoglobin, it is cleared from the plasma about 80 times faster than normally. Accordingly, the level of haptoglobin falls rapidly in situations where hemoglobin is constantly being released from red blood cells, such as occurs in hemolytic anemias. Haptoglobin is an acute phase protein, and its plasma level is elevated in a variety of inflammatory states. It bears a high degree of homology to haptoglobin and it appears to bind hemoglobin. Its level is elevated in some patients with cancers, although the significance of this is not understood. Albumin will bind some metheme (ferric heme) to form methemalbumin, which then transfers the metheme to hemopexin. Absorption of Iron from the Small Intestine Is Tightly Regulated Transferrin (Tf) is a plasma protein that plays a central role in transporting iron around the body to sites where it is needed. Before we discuss it further, certain aspects of iron metabolism will be reviewed. Iron is important in the human body because of its occurrence in many hemoproteins such as hemoglobin, myoglobin, and the cytochromes. It is ingested in the diet either as heme or nonheme iron (Figure 504); as shown, these different forms involve separate pathways. Absorption of iron in the proximal duodenum is tightly regulated, as there is no physiologic pathway for its excretion from the body. Absorption is excessive in hereditary hemochromatosis (see case no 10, Chapter 54). Hemoglobin in red blood cells In myoglobin and various enzymes In stores (ferritin and hemosiderin) Absorption Losses 1 Transferrin Shuttles Iron to Sites Where It Is Needed Transferrin (Tf) is a 1-globulin with a molecular mass of approximately 76 kDa. Approximately 200 billion red blood cells (about 20 mL) are catabolized per day, releasing about 25 mg of iron into the body-most of which will be transported by transferrin. There are receptors (TfR1 and TfR2) on the surfaces of many cells for transferrin. Instead, it remains associated with its receptor, returns to the plasma membrane, dissociates from its receptor, reenters the plasma, picks up more iron, and again delivers the iron to needy cells. Abnormalities of the glycosylation of transferrin occur in the congenital disorders of glycosylation (Chapter 47) and in chronic alcohol abuse. Their detection by, for example, isoelectric focusing is used to help diagnose these conditions. In an adult female of similar weight, the amount in stores would generally be less (100400 mg) and the losses would be greater (1. Adult females are more prone to states of iron deficiency because some may lose excessive blood during menstruation. Incoming iron in the Fe3+ state is reduced to Fe2+ by a ferrireductase present on the surface of enterocytes (Figure 504). This protein is not specific for iron, as it can transport a wide variety of divalent cations. A recently discovered peptide (25 amino acids, synthesized by liver cells) named hepcidin appears to play an important role in iron metabolism. It down-regulates the intestinal absorption and placental transfer of iron and also the release of iron from macrophages, possibly by interaction with ferroportin. When plasma levels of iron are high, synthesis of hepcidin increases; the opposite occurs when plasma levels of iron are low. Another recently discovered protein named hemojuvelin may act by modulating the expression of hepcidin. Once inside an enterocyte, iron can either be stored as ferritin or transferred across the basolateral membrane into the plasma, where it is carried by transferrin (see below). Passage across the basolateral membrane appears to be carried out by another protein, ferroportin. This protein may interact with the copper-containing protein hephaestin, a protein similar to ceruloplasmin (see below). Hephaestin is thought to have a ferroxidase activity, which is important in the release of iron from cells. Thus, Fe2+ is converted back to Fe3+, the form in which it is transported in the plasma by transferrin. The overall regulation of iron absorption is complex and not well understood; it appears that hepcidin plays a key role. Regulation occurs at the level of the enterocyte, where further absorption of iron is blocked (likely by hepcidin) if a sufficient amount has been taken up (so-called dietary regulation exerted by "mucosal block"). It also appears to be responsive to Iron Deficiency Anemia Is Extremely Prevalent Attention to iron metabolism is particularly important in women for the reason mentioned above. Older people with poor dietary habits ("tea and toasters") may develop iron deficiency. Iron deficiency anemia due to inadequate intake, inadequate utilization, or excessive loss of iron is one of the most prevalent conditions seen in medical practice. This amount of transferrin can bind 300 g of iron per deciliter, so that this represents the total ironbinding capacity of plasma. In iron deficiency anemia, the protein is even less saturated with iron, whereas in conditions of storage of excess iron in the body (eg, hemochromatosis) the saturation with iron is much greater than one-third. Ferritin Stores Iron in Cells Ferritin is another protein that is important in the metabolism of iron. In conditions of excess iron (eg, hemochromatosis), body stores of iron are greatly increased and much more ferritin is present in the tissues, such as the liver and spleen. Ferritin contains approximately 23% iron, and apoferritin (the protein moiety free of iron) has a molecular mass of approximately 440 kDa. However, in patients with excess iron, the amount of ferritin in plasma is markedly elevated. The amount of ferritin in plasma can be conveniently measured by a sensitive and specific radioimmunoassay and serves as an index of body iron stores. Synthesis of the transferrin receptor (TfR) and that of ferritin are reciprocally linked to cellular iron content. When iron levels are high, ferritin is synthesized to store iron and no further uptake of iron is required, so the TfR is not synthesized. Conversely, when iron levels are low, ferritin is not synthesized and the TfR is synthesized in order to promote uptake of iron from transferrin. This is an important example of control of expression of proteins at the translational level. Hemosiderin is a somewhat ill-defined molecule; it appears to be a partly degraded form of ferritin but still containing iron. It can be detected by histologic stains (eg, Prussian blue) for iron, and its presence is determined histologically when excessive storage of iron occurs. Various Laboratory Tests Are Used to Assess and Many Proteins Are Involved in the Metabolism of Iron Table 504 summarizes laboratory tests useful in the assessment of patients with abnormalities of iron metabolism and Table 505 lists many of the proteins involved in iron metabolism.
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Society for Maternal-Fetal Medicine Publications Committee allergy medicine prednisone buy allegra 120 mg with amex, with assistance of Vincenzo Berghella allergy shots eustachian tube dysfunction order allegra 180 mg on line. Loop electrosurgical excision procedure and risk of preterm birth: a systematic review and metaanalysis allergy testing usa 180mg allegra for sale. Spontaneous preterm birth and small for gestational age infants in women who stop smoking early in pregnancy: prospective cohort study allergy symptoms penicillin order 180mg allegra. Primary milk allergy symptoms joint pain order allegra 120 mg visa, secondary allergy symptoms rash on face generic allegra 120mg free shipping, and tertiary interventions to reduce the morbidity and mortality of preterm birth allergy symptoms vomiting diarrhea order allegra 120mg with visa. Committee on Practice Bulletins-Obstetrics allergy testing everett wa allegra 180 mg low price, the American College of Obstetricians and Gynecologists. Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth. Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial. Increased recurrence of preterm delivery with early cessation of 17-alpha-hydroxyprogesterone caproate. Cerclage for short cervix on ultrasonography in women with singleton gestations and previous preterm birth: a meta-analysis. Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened midtrimester cervical length. Cervical pessaries for prevention of spontaneous preterm birth: past, present and future. Asymptomatic bacterial vaginosis and intermediate flora as risk factors for adverse pregnancy outcome. Intravaginal clindamycin to reduce preterm birth in women with abnormal genital tract flora. Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flora and bacterial vaginosis: a randomised controlled trial. Prospective randomised controlled trial of an infection screening programme to reduce the rate of preterm delivery. Infection and antibiotics in the aetiology, prediction and prevention of preterm birth. The influence of gestational age and smoking habits on the risk of subsequent preterm deliveries. Frequency of uterine contractions in asymptomatic pregnant women with or without a short cervix on transvaginal ultrasound scan. Ultrasonographic examination of the uterine cervix is better than cervical digital examination as a predictor of the likelihood of premature delivery in patients with preterm labor and intact membranes. Accuracy of cervicovaginal fetal fibronectin test in predicting risk of spontaneous preterm birth: systematic review. Cervicovaginal fibronectin improves the prediction of preterm delivery based on sonographic cervical length in patients with preterm uterine contractions and intact membranes. American College of Obstetricians and Gynecologists; Committee on Practice Bulletins-Obstetrics. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes. Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Different magnesium sulphate regimens for neuroprotection of the fetus for women at risk of preterm birth. Assessing the neonatal safety of indomethacin tocolysis: a systematic review with meta-analysis. Antenatal exposure to indomethacin increases the risk of severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular leukomalacia: a systematic review with metaanalysis. Effectiveness of intrapartum antibiotic prophylaxis for prevention of early-onset group B streptococcal disease. American College of Obstetricians and Gynecologists Committee on Obstetric Practice. Preterm premature rupture of membranes: diagnosis, evaluation and management strategies. Factors affecting the duration of the latency period in preterm premature rupture of membranes. The impact of digital cervical examination on expectantly managed preterm rupture of membranes. Induction versus expectant management in premature rupture of the membranes with mature amniotic fluid at 32 to 36 weeks: a randomized trial. Preterm delivery from 34 to 37 weeks of gestation: is respiratory distress syndrome a problem? Lecithin/sphingomyelin ratio and lamellar body count for fetal lung maturity: a meta-analysis. Fetal assessment methods for improving neonatal and maternal outcomes in preterm prelabour rupture of membranes. A retrospective comparison of antibiotic regimens for preterm premature rupture of membranes. Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes. Effect of magnesium sulfate administration for neuroprotection on latency in women with preterm premature rupture of membranes. Induction of labor compared with expectant management for prelabor rupture of the membranes at term. Maternal colonization with group B Streptococcus and prelabor rupture of membranes at term: the role of induction of labor. Planned early birth versus expectant management (waiting) for prelabour rupture of membranes at term (37 weeks or more). The effect of birth hospital type on the outcome of very low birth weight infants. Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes. Committee on Obstetric Practice, American College of Obstetricians and Gynecologists. Born too soon: accelerating actions for prevention and care of 15 million newborns born too soon. Extreme caution is needed before scale-up of antenatal corticosteroids to reduce preterm deaths in low-income settings. Adverse pregnancy outcomes among women with prior spontaneous or induced abortions. Presence of depressive symptoms during early pregnancy and the risk of preterm delivery: a prospective cohort study. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. Predictive Value of cervical Length Measurement and Fibronectin Testing in Threatened Preterm Labor. Both techniques have advan- tages and disadvantages, and providers should be aware of these. External monitors require frequent readjusting to obtain an adequate tracing and signal quality, and they may be difficult to use in patients who are obese, ambulating, active in bed, or pushing in varied birth positions. Morbidity, although uncommon, includes maternal and fetal soft tissue injuries and intrauterine infections. The electrode may be placed on the buttocks in breech presentations; however, care must be taken to avoid placement on the fetal genitalia. In some cases, women will remain on the fetal monitor longer if the tracing is suspicious. Selection of monitoring technique depends on risk factors present, patient and medical/nursing care provider preferences, available resources, and departmental policies. After assessing the risk factors, a decision can be made regarding optimal fetal surveillance. In-service training can be offered to familiarize nurses with the auscultative monitoring technique or enhance their skills and comfort level. Informed Consent of the Patient A discussion of labor monitoring should occur before labor onset so options can be explored and questions answered. This is a short-term benefit because at the end of 1 year, these infants did not have permanent sequelae. Cerebral palsy is attributed to events that occur before labor in approximately 70% of cases. Only 4% of cases caused by hypoxic ischemic encephalopathy can be directly linked to intrapartum events. Institutional policy should be developed to address the technique and frequency of assessment. In addition, the nurse actually has a 1:2 ratio in that he/she is caring for both the woman and the fetus(s). Culture embracing normalcy of childbirth and minimization of unnecessary interventions. These findings indicate a fetus that is well-oxygenated and non-acidotic, which can be followed in a routine manner. Place the Doppler over the area of maximum intensity of fetal heart tones, generally over the fetal back. Consideration must be given to medications, prior antepartum testing, maternal status, and fetal medical conditions, such as anomalies, growth restriction, and 4 Chapter E - Intrapartum Fetal Surveillance arrhythmias. For example, a tracing with late decelerations might be interpreted and managed differently in a woman with preeclampsia and long labor compared with that of a woman with normal pregnancy and a normal previous tracing who just received epidural analgesia and is hypotensive. Causes of a change in baseline rate may include change in fetal status, chorioamnionitis, drugs, maternal fever, position, and prematurity. Fetal causes include prolonged cord occlusion, prolapsed cord, rapid descent, or fetal decompensation. Uterine contraction frequency can be quantified as the number present over a 10-minute period, averaged over 30 minutes. Tachysystole applies to both spontaneous and stimulated labor, but management may differ if the uterine activity is induced rather than spontaneous. Persistent tachycardia greater than 180 bpm, especially if maternal fever is present, suggests chorioamnionitis. Segments that should be excluded are those that have marked variability (more than 25 bpm), are greater than or equal to 25 bpm above or below the baseline, or contain accelerations or decelerations. There must be at least a 2-minute identifiable segment within any 10-minute period. The presence of variability represents an intact nervous pathway through the cerebral cortex, the midbrain, the vagus nerve, and the normal cardiac conduction system. When the fetus is well oxygenated, the central nervous - Chapter E 5 Chapter E system responds with moderate variability. The presence of minimal, absent, or marked variability should be further evaluated within the context in which it occurs. Definitions to characterize variability are specifically classified as absent, minimal, moderate, or marked (Table 3). Sleep cycles of 20 to 40 minutes or longer may cause a normal decrease in variability. In addition, steroid administration to induce fetal lung maturation may reduce variability. If the acceleration lasts 2 minutes or more but less than 10 minutes, it is defined as a prolonged acceleration. The absence of accelerations does not necessarily indicate fetal acidemia, but may warrant the need for further evaluation. The presence of spontaneous or stimulated accelerations is highly predictive of a non-acidotic fetus. This occurs when the vein is compressed in the umbilical cord but the thicker-walled arteries remain patent. These accelerations are actually part of the variable deceleration and should not be used to assess fetal acid-base status. Therefore, if accelerations disappear, providers should look for other indicators of compromise such as decelerations worsening in depth, duration, or frequency, decreased baseline variability or baseline tachycardia, or bradycardia. In addition, providers can attempt to elicit accelerations using scalp or Table 3. Variable decelerations may be accompanied by other characteristics, the clinical significance of which requires further investigation. The presence of moderate variability or accelerations suggests the absence of acidemia. Administering oxygen and reducing or discontinuing uterine stimulants may also be helpful. If decelerations occur with 50% or greater of contractions during 20-minutes, they are considered to be recurrent decelerations. If they occur with less than 50% of contractions during 20 minutes, they are called intermittent decelerations. The onset to nadir is 30 seconds or more and the nadir occurs at the same time as the peak of the contraction. The onset, nadir, and recovery of the deceleration generally occur after the beginning, peak, and ending of the contraction, respectively. This causes sudden fetal hypertension, increased parasympathetic outflow, and slowing of the fetal pacemaker. However, interpretation is complicated because variable decelerations also can result from decreased arterial oxygen concentration secondary to uteroplacental insufficiency from other causes. If the fetus was not previously compromised, recovery will typically occur with discontinuation of the inciting event or agent, position change, increased intravenous fluids, maternal oxygen supplementation, or a combination of these measures. When accompanied by change in variability or baseline, decelerations are more likely to be associated with fetal acidbase abnormalities. These tracings require prompt evaluation and implementation of interventions to address the tracing. The sine waves undulate slowly and regularly, generally with a cycle frequency of 3 to 5 cycles (waves)/minute. The tracing must continue for at least 20 minutes,19 but providers may need to intervene sooner in emergencies (eg, bleeding from a ruptured vasa previa). In the past, this term was used to denote a tracing that frequently occurred following narcotic administration or sometimes during ultrasound, and was associated with rhythmic fetal movements such as rapid breathing, sucking movements of the mouth, hiccoughing, and thumb sucking. The presence of moderate variability and/or accelerations is highly predictive of normal fetal acid base status. The terms fetal distress and birth asphyxia are inappropriate and have no place in the assessment. Typically, Category I tracings are considered normal and can be followed routinely. These require prompt evaluation and expedient 8 Chapter E - Intrapartum Fetal Surveillance interventions to address the pattern. Some institutions now use tools for risk management and patient safety including communication strategies. Any written information on the tracing (ie, emergent situations during labor) should coincide with these automated processes to avoid confusion and minimize litigation risk. Uterine activity characteristics obtained by palpation or pressure transducer (ie, frequency, duration, intensity, presence or absence of tachysystole) 3. Moderate variability, even in the presence of decelerations, is strongly associated with an absence of acidemia (pH greater than 7. Minimal or absent (undetectable) variability in the presence of late or variable decelerations is associated with acidemia (pH less than 7. Parer and colleagues concluded that the presence of moderate variability had a 98% negative predictive value for fetal acidosis or an Apgar score less than 7. The depth of decelerations has a stronger association with fetal acidosis for late decelerations than for variable decelerations. In the fetus with decreased variability and decelerations, acidosis was shown to develop slowly over time, except in the setting of sudden bradycardia as may occur with placental abruption or cord prolapse. If the tracing reverts to Category I after appropriate intervention, then previous monitoring may be resumed. Recommendations are to correct fetal acidemia to reduce outcomes of neonatal encephalopathy, cerebral palsy, and neonatal acidosis. Preparation for delivery, development of a time frame for delivery, and performance of intrauterine resuscitative measures are essential. If tracings do not improve with appropriate corrective maneuvers, prompt delivery of the fetus is indicated. Use of this algorithm requires application of specific definitions for significant decelerations and takes into account labor phase and labor progress (Table 5). From there, the assessment includes the presence or absence of significant decelerations, the stage of labor, and whether labor is progressing normally. If delivery is indicated by the algorithm, ideally it should be initiated within 30 minutes of the decision. The algorithm can be discontinued at any time the provider feels more rapid intervention is required. While this algorithm is somewhat complex, a web-based app has simplified its use for clinical practice (available at cat2. A grid categorizes all possible heart rate patterns based on baseline rate (ie, normal, tachycardia, bradycardia), type of decelerations (ie, early, late, variable, prolonged), and quantity of variability (ie, undetectable, minimal, moderate, marked).
Recognition of the At-Risk Pregnancy Abloodsamplefromeverypregnantwomanshouldbe sentatthefirstprenatalvisitfordeterminationofthe bloodgroupandRhDtypeandforantibodyscreening allergy shots where to inject purchase allegra 120 mg amex. If the father is RhD-positive allergy forecast pleasanton ca buy allegra 180 mg visa, his Rh genotype should be determined using quantitative polymerase chain reaction allergy symptoms eye pressure purchase 120mg allegra otc. If he is homozygous for the D antigen allergy forecast iowa city buy cheap allegra 180 mg line, the fetus will be RhD-positiveandpotentiallyaffected allergy luxe pillow generic 180mg allegra overnight delivery. If the father is heterozygous allergy symptoms like flu generic allegra 180mg on line, the fetus has a 50%chanceofbeingRhD-positive allergy symptoms ears popping discount allegra 180mg fast delivery,indicatingtheneed forfetalRhDgenotyping allergy medicine while pregnant cheap allegra 180 mg online. If it is not possible to test the D antigen status and zygosity of the father, it must be assumed that he is D antigenpositive. If this testing is inconclusive, amniocentesis can be performed in the second trimesterandfetalRhDgenotypingcanbedoneusing amniocytes. In patients with a positive titer less than 1:16, repeat titers should be obtained every 2 to 4 weeks. Titersarenotgenerallyuseful for following a patient with a history of a previous fetusorneonatewithhemolyticdisease. Inthissetting, even if the titers are below the critical threshold, the patientshouldbefollowedandevaluatedasifhertiters werehigh. Theultrasonicexaminationshouldincludeadetailed fetal assessment for anatomy, growth, estimated fetal weight,and(ifviable)biophysicalprofile,plusadetermination of placental size and thickness and hepatic size. Fetal hydrops is easily diagnosed on ultrasound by the characteristic appearance of two or more of the following: ascites, pleural effusion, pericardial effusion, skin edema, or polyhydramnios. Appearanceofanyofthesefactorsduringanultrasonic examination necessitates therapeutic intervention, depending on the fetal gestationalage. The great drawback of using amniotic fluid spectrophotometry to determine the severity of fetal hemolytic disease is that amniocentesis, especially if transplacental, can increase the severity of fetomaternal transfusion and worsen the severity of the disease. Advances in fetal interventional techniques and high-resolution ultrasonography have made direct fetal blood sampling the most accurate method for the diagnosis of fetalhemolyticdisease. If the fetal hematocrit is less than 30, or morethantwostandarddeviationsbelowthemeanfor gestationalage,intrauterinetransfusionisindicated. Usingthismethod,hewas abletoestablishtheLileygraphorcurvewithpredic- C H A P T E R 15 Rhesus Alloimmunization 199 Thetechniqueforfetalbloodsamplingissimilarto that described for fetal intravenous transfusion. The major risk is fetal exsanguination from tears in placental vessels,soin most cases blood will have been ordered before the procedureandwillbeonhandincaseanintrauterine transfusion is needed (see below). If the procedure is performed by an experienced practitioner, the risk of this complication and fetal death is no more than 1-2%. Percutaneousumbilicalbloodsampling should not be a first-line method of assessing fetal statusunlessclearlyindicated. Because of this, intravascular transfusion is the method of choiceforcorrectingfetalanemia,andintraperitoneal transfusionisreservedforcasesinwhichintravascular transfusionisnotpossible,suchasgestationalageless than20weeks. Fetal survival is better with this technique than after intraperitoneal transfusions, especially if thereisascitesorotherevidenceofhydrops. Inaddition,transfusionintotheperitonealcavitycanresultin fetalbradycardiaorapseudosinusoidalfetalheartrate pattern following the procedure because of compressionatthesiteofinsertionoftheumbilicalcord. Under ultrasonic guidance, and using sterile technique, a 22-gauge spinal needle is inserted into the umbilical vein near the placental insertion. The volume of blood to be transfused is based on the estimated fetal body weight, as determinedbyultrasonography,theinitialfetalhematocrit, the target fetal hematocrit, and the hematocrit of the packedredcellstobetransfused. Transfusions are done under ultrasonicguidanceusingsteriletechnique,eitherinornear theoperatingroomifthefetusispotentiallyviableso thatdeliverycanbeaccomplishedexpeditiouslyshould thefetalstatusdeteriorateirreversibly. The overall survival rate following intrauterine transfusion is about 90%, but it is significantly lower for fetuses with hydrops before the transfusion. Phenobarbital has been used to induce fetal hepatic enzyme maturation, thereby increasing uptake and excretionofbilirubinbytheliver. Although the goal is a term delivery, the risks of intrauterine demise, including that caused by procedure-related losses, must be balanced against the risks of prematurity. There is no absolute gestational age cutoff for intrauterinetransfusions,butafter35weekstheriskof an intrauterine loss may be greater than the risk of a neonatal death. It may be prudent in this setting to deliver the fetus and transfuse the neonate, if necessary. Fetal Intraperitoneal Transfusion Redbloodcellsareabsorbedviathesubdiaphragmatic lymphatics and proceed via the right lymphatic duct intothefetalintravascularcompartment. Aftertransfusion, the absorption of blood may be monitored with serialtransverseultrasonicscansofthefetalabdomen. Rh immune globulindiminishestheavailabilityoftheRhDantigen to the maternal immune system, although the exact mechanism by which it prevents RhD alloimmunizationisnotwellunderstood. Since the advent of its use in 1967, Rh immune globulin has dramatically reduced the incidence of Rh isoimmunization. Three hundred micrograms (or 1U) of Rh immune globulin can neutralize 30mL of fetal RhDpositive blood in the maternal circulation. Because the greatest risk for fetomaternal hemorrhage occurs during labor and delivery, Rh immune globulin was initially administered only during the immediate postpartum period. The indications for the use of Rh immune globulin have therefore been broadened to include any antepartum event (such as amniocentesis) that may increase the risk of transplacental hemorrhage. It is the responsibility of every health care practitioner who is involved in the care of pregnant women to prevent RhD alloimmunization by the appropriate administration of Rh immune globulin. Rh immune globulin (300µg) should be given routinely within 72 hours of delivery to all Rh-negative, anti-Dnegative women who deliver an Rh-positivechild. For this reason, any positive antibody screen in pregnancy, even in an RhD-positive woman, should be followed up with an antibody identification and titer. If the antibody screen is positive for one or more antibodies associated with hemolytic disease of the newborn, the pregnancy should be followed in a fashionsimilartothatadvisedfortheRhD-sensitized pregnancy. Antibody titers are not as reliable for the detection of fetal anemia in this situation, probably because the anemia is due more to suppression of hematopoiesis than to hemolysis. Diabetes may precede pregnancy or may occur becauseofpregnancy,withareturntotheprepregnancy stateafterdelivery. Preexisting cardiovascular disease and conditions such as asthma and cystic fibrosis are encountered more commonly because of modern medical management that has allowed more women thaninthepasttoconsiderpregnancy. Asageneralrule, mostpregnanciescomplicatedbythesemedicalconditions are considered "high risk" for maternal and fetal morbidity and mortality. Good outcomes often require frequent maternal and fetal assessment and the ability torespondinatimelyfashiontochangesintheclinical statusofeitherthemotherorherfetus. Elective delivery for medical and surgical conditions is indicated when deteriorating maternal or fetal status occurs in the presence of a term fetus or when there is evidenceoffetallungmaturity. Obstetricians and other providers should focus on the mitigationoftheeffectsandpreventionofmedicalconditions that may complicate pregnancy. The increased prevalenceofobesityinpregnantwomenintheUnited Statesandelsewherehasresultedinmetabolicdysregulation (metabolic syndrome) that increases inflammation and insulin resistance. The risk of some medical disorders, such as diabetes, hypertension, and heart disease,isincreasedduetoexcessivebodyweightduring pregnancy. Physical activity and a healthy diet are very importantbefore,during,andafterpregnancy. Surgical conditions that may complicate pregnancy include appendicitis, cholecystitis and cholelithiasis, acutepancreatitis,bowelobstruction,abdominaltrauma, or torsion of an adnexal structure such as an ovarian tumor. When trauma is evaluated during pregnancy, the possibility of intimate partner abuse must be ruled out, as in women who are not pregnant. Laparoscopyisbecomingmore common during pregnancy, and guidelines have been published that should increase the safety for both the pregnantwomanandherfetus. Mostoftheconditionsdiscussedinthischapterarenot unique to pregnancy and understanding the causes, diagnosis, and management of them is based on the sameprinciplesthatwouldapplyinthenonpregnant woman. Important issues for the management of medical and surgical problems during pregnancy include how the physiologic changes of pregnancy may affect the diagnosis and clinical course of the disease,aswellashow the disease may affect the pregnancy,withparticularattentiontothefetus. The most common medical and surgical disorders that may complicate pregnancy are covered in this chapter. Thissyndromeconsistsofagroupof risk factors for diabetes, coronary heart disease, and stroke that occur together (central obesity, insulin resistance,andhyperlipidemia). Glucose crosses the placenta easily by facilitated diffusion, causing fetal hyperglycemia that stimulates pancreatic -cells, and results in fetal hyperinsulinism. There is a direct correlation between birth defects in diabetic pregnancies and increasing glycosylated hemoglobin A1C (HbA1C) levels in the first trimester. Fetal hyperglycemia and hyperinsulinemia later in pregnancy, especially in the third trimester, cause fetal overgrowth and macrosomia that predispose to birth trauma, including shoulder dystocia and Erb palsy. Fetal demise is most likely due to acidosis, hypotension from osmotic diuresis, or hypoxia from increased metabolism, coupled with inadequate placental oxygen transfer. Pregestationaldiabetesisgenerallyassociatedwith a higher rate of maternal and fetal complications due to the greater difficulty in achieving glycemic control, the higher rate of congenital malformations, andthehigherlikelihoodofvasculardisease. Maternal complications include worsening nephropathy and retinopathy,agreaterincidenceofpretermpreeclampsia, and a higher likelihood of diabetic ketoacidosis. Hypoglycemia is also much more common because of the need for insulin therapy and stricter glycemic control attempted during pregnancy. Fetal complications include an increased rate of abortions, anatomic birth defects, fetal growth restriction, and prematurity. In the United States, rates appear to range from 6-12%, depending on the population studied and the diagnostic criteria used. Overall, 80-90% of diabetes in pregnant women is gestational, and about 10% is pregestational. Rising levels of human placental lactogen, progesterone, prolactin, and cortisol in pregnancy are some of the primary factors associated with progressive insulin resistance during pregnancy. Pregestational diabetes mellitus refers to diabetes present before pregnancy and may be either type 1 or type 2 diabetes. This classification is helpful for assessing disease severity and the likelihood of complications (Table16-1). This timing recognizes the progressive nature of insulin resistance in pregnancy due to rising levels of hormones such as human placental lactogen, and thetestwillidentifymostwomenwithgestationaldiabetes while allowing for several weeks of therapy to reduce potentially adverse consequences. If a first-trimester screen is done and is found to be negative, it should be repeated at 24 to 28 weeks. Caloric intake is divided into 20% at breakfast, 30% at lunch, 30%atdinner,and20%atabedtimesnack. Patientswithdiabetesshouldbeencouraged to engage in mild to moderate aerobic exercise. Managementofgestationalandpre- gestationaldiabetesrequiresateamapproachinvolvingpatienteducationandcounseling,medical-nursing assessments and interventions, strategies to achieve maternaleuglycemia,andavoidanceoffetal-neonatal compromise. Ideally, this team should include the patient,obstetrician,maternal-fetalmedicinespecialist,clinicalnursespecialist,nutritionist,socialworker, andneonatologist. Caloricrequirementsarecalculatedonthebasis usually managed with diet and exercise alone, but if euglycemiacannotbeachieved,anoralhypoglycemic agent (glyburide) or insulin should be added. Glyburide does not appear to enter the fetal circulation in appreciable quantities, and it has been used successfully to treat gestational diabetes after the first trimester. Insulinisthemedicationofchoicetomaintaineuglycemia in pregnancy and is the recommended therapy in women with pregestational diabetes. Antepartum Obstetric Management Aside from achieving euglycemia, adequate surveillanceshouldbemaintainedduringpregnancytodetect and possibly mitigate maternal and fetal complications. Inadditiontoroutineprenatalscreeningtestsfor of ideal body weight: 30kcal/kg for those patients 80-120%ofidealbodyweight,35to40kcal/kgforthose C H A P T E R 16 Common Medical and Surgical Conditions Complicating Pregnancy 205 womenwithpregestationaldiabetes,a detailed obstetric ultrasonic study, fetal echocardiogram, and maternal serum -fetoprotein should be obtained in the second trimester to check for congenital malformations. Thisisespecially important if the first trimester HbA1C is significantly elevated (>8. Abnormalities of fetal growth are most likely to be presentinthethirdtrimesterandcanbeconfirmedby ultrasound. The timing of delivery depends on fetal and maternal status and the degree of glucose control. If the mother is breastfeeding, 500 calories/dayshouldbeaddedtotheprepregnancydiet. Contraception counseling should involve advising the patient that estrogen-containing oral contraceptivesarenotrecommendedforwomenwithadvancedstagediabeteswithvasculardisease. Normal Thyroid Physiology during Pregnancy With the increase in glomerular filtration rate that occursduringpregnancy,therenalexcretionofiodine increasesandplasmainorganiciodinelevelsarenearly halved. Goiters caused by iodine deficiency are not likelyifplasmainorganiciodinelevelsaregreaterthan 0. The estrogen-mediated increaseinthyroid-bindingglobulinduringpregnancy results in a pronounced rise in serum total thyroxine (T4)andtotaltriiodothyronine(T3)levels. Plasmaglucoselevelsaremeasuredfrequently, and, if elevated, a continuous infusion of regularinsulinisgiven. Insulin dosage is adjusted as needed to maintain a plasma glucose level between 80 and 120 mg/dL. Continuous electronic fetal heart rate monitoring is recommended for all patients with diabetes. Postpartum Period After delivery of the fetus and placenta, insulin requirements drop sharply because the placenta, which is the source of many insulin antagonists, has been removed. Manypatientswithinsulin-dependent diabetesmaynotrequireexogenousinsulinforthefirst 48 to 72 hours after delivery. Plasma glucose levels should be monitored and lispro or regular insulin given when plasma glucose levels are elevated. Women withpregestationaldiabetes canbe restarted ontwothirdsoftheprepregnancyinsulindosage,withadjustments made as necessary. Although iodine deficiency is rare during pregnancy, it can occur in areas where preconception and prenatal care are inadequate. Patients with Graves disease tend to have a remission during the third trimester of pregnancy and an exacerbation duringthepostpartumperiod. Theincreasedimmunologictoleranceduringpregnancymayleadtoadecrease in thyroid antibodies, which may account for the remission. The clinical diagnosis of hyperthyroidism in pregnancy is difficult,becausemanyof thesignsandsymptomsofthehyperdynamiccirculationassociatedwithhyperthyroidismarepresentina normal euthyroid pregnant woman. A resting pulse rate greater than 100 beats per minute, a wide pulse pressure, tremor, eye changes (exophthalmos), failure togainweightdespitenormalorincreasedfoodintake, and heat intolerance, when present, are all helpful in makingtheclinicaldiagnosis. Serum free thyroxine (free T4) and free triiodothyronine (free T3) levels usually remain in the normal range. Bythe end of the first trimester (11 to 12 weeks), the fetal thyroidisabletoproduceiodothyroninesandT4,and by12to14weeks,itisabletoconcentrateiodine. Levels ofthesehormonesremainlowevenatterm,butthey increase rapidly in the neonate within 48 hours of birth. Because radioactive iodine treatment is contraindicated during pregnancy, medical treatment is generally given. When there is significant maternal tachycardia, -blockers such as atenolol or propranolol may be used for short-term treatment, withlonger-termtreatmentincreasingtheriskoffetal growth restriction. These drugs readily cross the placenta, and a concern during maternal treatment is the development of fetal goiter and hypothyroidism. Limited transfer ofT4 occurs across the placenta and appears tobeimportantforfetalneuraldevelopmentinthefirst trimesterbeforefetalthyroidfunctionbegins. Thyroid-releasinghormonecan cross the placental barrier, but there is no significant placental transfer because of circulating low levels. Maternal Hyperthyroidism the incidence of maternal thyrotoxicosis is about 1 per 500 pregnancies. Managementalso involves intensive maternal and fetal monitoring and correction of precipitating factors. Importantly,antithyroiddrugsshould be reduced to the lowest dose that results in free T4 levelswithintheupperrangeofnormal. Surgical management of a pregnant patient with hyperthyroidism during the second trimester is recommended only when medical treatment fails. Itistransientandlastslessthan2to3months, but if clinically significant and untreated, it is associatedwithneonatalmorbidityandmortality. Afetal goiter can often be identified by ultrasonography in suchcases,andfetalgrowthrestrictionmaybepresent. Hypothyroidism Hypothyroidism (overt or subclinical) complicates up to 3% of pregnancies. However, pregnant women with symptoms consistent with low thyroid hormonelevels(fatigue,intolerancetocold,excessive weight gain) or with risk factors. Pregnant women on appropriatethyroidreplacementtherapycanexpecta normal pregnancy outcome, but untreated maternal hypothyroidism has been associated with an increased risk of spontaneous abortion, preeclampsia, abruption, low-birth-weight or stillborn infants, and lower cognitive function in offspring. Thyroid hormone defi- Thyroid Storm the major risk for a pregnant patient with thyrotoxicosis is the development of a thyroid storm. Precipitating factors include infection, labor, cesarean delivery, or noncompliance with the medication regimen. It is not uncommon to mistakenly attribute thesignsandsymptomsofseverehyperthyroidismto preeclampsia. Intheformer,significantproteinuriais usually absent, but both may be present in the same patient. Thyroid storm in a pregnant woman is a lifethreatening medical emergency and should be treated in an intensive care setting. The signs and symptoms associated with a thyroid storm include hyperthermia, marked maternal tachycardia, perspiration, and high-output renal failure or severe dehydration. Theetiologicfactorsincludethyroiddysgenesis,inborn errors of thyroid function, and iodine deficiency. Newborn screening programs can identify many cases of congenital hypothyroidism, and with early administration of thyroid hormone replacement, the impairment can be minimized. If the anatomic defect has been corrected during childhood with no residualdamage,thepatientisexpectedtogothrough pregnancywithoutcomplications. Patientswithpersistentatrialorventricularseptaldefectsandthosewith tetralogy of Fallot with complete surgical correction generally tolerate pregnancy well. However, patients with primary pulmonary hypertension or cyanotic heart disease with residual pulmonary hypertension are in danger of experiencing decompensation during pregnancy. Pulmonaryhypertensionfromanycauseis associatedwithanincreasedriskofmaternalmortality during pregnancy or in the immediate postpartum period.
