All patients with HELLP syndrome may have an underlying coagulopathy that is usually undetectable. Between 38 and 93 percent of patients with HELLP syndrome receive some form of blood product.15 Patients with a platelet count greater than 40,000 per mm3 (40 109 per L) are unlikely to bleed. Anemia is the consequence of either less-than-optimal production of red blood cells or hemoglobin, or increased destruction or shortened life span of red blood cells. Moreover, if multiple deficiencies contribute to the severity of anemia, supplementation with iron alone may not achieve adequate hemoglobin response. This deficit, or excess, of iron prejudices the mother-child wellbeing. Evaluation of Patients with Leukocytosis | AAFP The use of inappropriate evaluative hemoglobin criteria during pregnancy can result in misinterpretation of the relation between anemia and resulting health outcomes. The differential diagnosis of HELLP syndrome includes acute fatty liver of pregnancy, thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. The acronym HELLP was coined in 1982 to describe a syndrome consisting of h emolysis, e levated l iver enzyme levels and l ow p latelet count. Many investigators consider the syndrome to be a variant of preeclampsia, but it may be a separate entity. Blood pressure control in pregnancy is challenging because of the uncertain risks of mild hypertension and potential uteroplacental insufficiency with overtreatment. The goal is to maintain diastolic blood pressure between 90 and 100 mm Hg. Clinical manifestation of erythrocyte disorders. Acute hypertensive episodes in pregnancy can be dangerous to mother and infant. I sat on the committee that wrote the 1993 Institute of Medicine report. Throughout normal pregnancy, blood volume expands by an average of 50% compared with the nonpregnant state (33). Those who become pregnant and are taking medications to treat chronic hypertension should have blood pressure goals set at 120 to 159 mm Hg systolic and 80 to 109 mm Hg diastolic. PMID: 7332361 DOI: 10.1007/BF02110019 Abstract We measured erythrocyte aggregation and hematocrit in 155 uncomplicated pregnancies and in 55 pregnant women with pre-eclampsia. Patients who develop DIC generally do so in the setting of well-developed HELLP syndrome. Several epidemiologic studies showed that both low and high hemoglobin concentrations are associated with increased adverse birth outcomes, including fetal death, intrauterine growth retardation, preterm delivery, and low birth weight (69). A hypertensive crisis may be treated with a continuous infusion of nitroglycerin or sodium nitroprusside (Nipride). Therefore, supplementation with iron (and folate) alone may not be effective in correcting nutritional anemia and may address only part of the problem concerning nutritional deficiencies. Dr Rush: I agree with Dr Yip's comment. Because these known mechanisms can explain the observed association, attributing the increased perinatal complications to the increased hemoglobin concentration in women with pregnancy-induced hypertensive disorders would be difficult. Mandani G, Branson HE. In reality, there is the risk that all severe anemia in developing countries will be assumed to be due to iron deficiency regardless of whether it actually is, subjecting patients to unneeded iron treatment. Often, the deficient state is a clearly defined disease or nutritional disorder with specific signs and symptoms, eg, beriberi for severe thiamin deficiency. All Rights Reserved. Preeclampsia refers to the new onset of hypertension and proteinuria or the new onset of hypertension plus significant end-organ dysfunction with or without proteinuria in a previously normotensive patient, typically after 20 weeks of gestation or postpartum ( table 1) [ 2,6-8 ]. hemoconcentration: [ hemo-konsen-trashun ] increase in the proportion of formed elements in the blood, as a result of a decrease in its fluid content. Up to 1.5% of pregnant women have chronic hypertension, which can result in harm to the mother and infant. In these patients, plasmapheresis has resulted in an increase in the platelet count and a decrease in the lactate dehydrogenase level.2325. Ross and Thomas (17) estimated that 20% of maternal mortality can be attributed to severe anemia. Neonatal polycythemia. Medical treatment of chronic hypertension in pregnancy, that is, hypertension present before 20 weeks' gestation, is recommended at 160 mm Hg systolic or 110 mm Hg diastolic with labetalol or extended-release nifedipine, treating to 120 to 159 mm Hg systolic and 80 to 109 mm Hg diastolic. Therefore, HELLP syndrome should be suspected in any patient who shows a significant drop in the platelet count during the antenatal period.10 A positive D-dimer test in the setting of preeclampsia has recently been reported to be predictive of patients who will develop HELLP syndrome.11 The D-dimer is a more sensitive indicator of subclinical coagulopathy and may be positive before coagulation studies are abnormal. Red blood cells become fragmented as they pass through small blood vessels with endothelial damage and fibrin deposits. The process to prove such evidence often involves controlled trials with proper randomization. Nevertheless, in many developing countries, limiting nutritional factors besides iron have to be considered if a meaningful reduction in anemia is to be achieved. Some studies hinted at a relation but none has clearly established an association. Coverage of guidelines from other organizations does not imply endorsement by AFP or the AAFP. The most plausible explanation for the observed association between a high hemoglobin concentration and perinatal morbidity and mortality is that both conditions are often the result of hypertensive disorders of pregnancy or preeclampsia. Use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, renin inhibitors, and mineralocorticoid receptor antagonists should be avoided in pregnancy. In addition, several iron supplementation studies of children and women showed that the resulting mean hemoglobin concentration, or the hemoglobin distribution, never exceeded that of the reference populations who were iron replete (43, 44). Prophylactic transfusion of platelets at delivery does not reduce the incidence of postpartum hemorrhage or hasten normalization of the platelet count.15 Patients with DIC should be given fresh frozen plasma and packed red blood cells. Nevertheless, it has not been established that there is any benefit to iron supplementation during pregnancy to prevent iron deficiency anemia and thus reduce adverse pregnancy outcomes. Very high hemoglobin concentrations cause high blood viscosity, which results in both compromised oxygen delivery to tissues and cerebrovascular complications. Existing evidence does not support the hypothesis that high hemoglobin concentrations during pregnancy, within a range not classified as high, result in poor pregnancy outcomes. Lower serum insulin-like growth factor-1 levels are independently associated with anemia in patients undergoing maintenance hemodialysis. This dose is followed by a maintenance infusion of 2 g per hour. Lu ZM, Goldenburg RL, Cliver SP, Cutter G, Blankson ML. Unless DIC is present, the prothrombin time, partial thromboplastin time and fibrinogen level are normal in patients with HELLP syndrome. Adapting iron dose supplementation in pregnancy for greater January 2019;133(1):215219, Available at:https://journals.lww.com/greenjournal/fulltext/2019/01000/ACOG_Practice_Bulletin_No__203_Summary__Chronic.43.aspx. This is often manifested as peripheral cyanosis and impaired mental function resulting from compromised cerebral blood circulation (21). Pain relief with intravenous narcotics and local anesthesia is acceptable but certainly not optimal for pain control. Early diagnosis is critical because the morbidity and mortality rates associated with the syndrome have been reported to be as high as 25 percent. Because iron deficiency is often a major cause of anemia in many parts of the world, anemia screening is commonly used as a substitute for screening for iron deficiency. Hemoconcentration. A placebo-controlled trial is unlikely. Under conditions of poor diet quality, micronutrients other than iron are affected, including vitamin A, zinc, calcium, riboflavin, and vitamin B-12, and some of these micronutrient deficiencies also contribute to the severity of anemia (27, 51, 52). An appropriate trial has not yet been conducted to test the benefit of iron supplementation in reducing adverse reproductive outcomes. From the perspective of reproductive health outcomes, only very severe anemia has clearly been shown to result in maternal mortality. Hypertension, hypovolemia, and poor placenta perfusion are all part of the physiologic disturbances of preeclampsia (39). The hematocrit may be decreased or normal and is typically the last of the three abnormalities to appear. A more recent study, however, did not show that the risk of malaria justifies the withholding of iron (50). The other is whether we continue with routine supplementation for all women. I do not think that making a blanket statement that iron unmasks malaria is possible. Plasma volume increases more than does red blood cell mass, which produces a declining hemoglobin concentration during the first half of pregnancy. Pregnant women with chronic hypertension should start antihypertensive medication when their blood pressure reaches 160 mm Hg systolic or 110 mm Hg diastolic, although it may be initiated earlier if the patient has concerning comorbidities or impaired renal function. HELLP, a syndrome characterized by hemolysis, elevated liver enzyme levels and a low platelet count, is an obstetric complication that is frequently misdiagnosed at initial presentation. In other words, there is evidence of a benefit or efficacy associated with iron supplementation. Consequently, where multiple nutrient deficiencies are common, a more appropriate micronutrient supplement formulation beyond iron and folate should be considered. The effect of first trimester hemoglobin levels on pregnancy outcomes Patients who have had HELLP syndrome may subsequently use oral contraceptive pills safely.29 Patients who develop atypical early-onset preeclampsia or HELLP syndrome should be screened for the presence of antiphospholipid antibodies.30, Much controversy surrounds the use of acetylsalicylic acid (aspirin) or calcium to prevent preeclampsia. The decision of whether to treat chronic hypertension at lower blood pressure levels should be based on a discussion with the patient as well as the presence of comorbid conditions that might warrant lower blood pressure. Iron supplementation during pregnancy: is it effective? There was a further significant fall when the chief medical officer of health at the Ministry of Health in the beginning of the postwar period introduced a rule to the flying squads sent out for cases of hemorrhages. In developing countries, especially where severe maternal anemia is more common, other nutritional factors and infections, including malaria, can often coexist with iron deficiency, contributing to anemia (23). In maternal anemia and iron deficiency, the anemia itself is often regarded as an adverse outcome. Because iron deficiency is a common cause of maternal anemia, iron supplementation is a common practice to reduce the incidence of maternal anemia. Lancet 1997;350:8449; Hemminki E, Uski A, Koponen P, et al. Point-of-care ultrasound: The new district focus. In such known clinical cases, iron supplementation can be avoided, but only if a sophisticated laboratory is available to diagnose the type of anemia. The physical examination may be normal in patients with HELLP syndrome. Mild anemia is routinely defined as a hemoglobin value within 10 g/L of the anemia cutoff value. Evidence does not suggest that this association is causal; it could be better attributed to hypertensive disorders of pregnancy and to preeclampsia. Interdependence of vitamin A and iron: an important association for programs of anemia control, Weekly compared to daily iron supplementation, 2000 American Society for Clinical Nutrition, Whole-grain food intake among US adults, based on different definitions of whole-grain foods, NHANES 20032018, A unified definition of whole-grain foods is needed, Is it caffeine? Author disclosure: No relevant financial affiliations. Women with superimposed preeclampsia without severe features can be expectantly managed until 37 weeks' gestation, if close monitoring can be provided. The thrombocytopenia has been attributed to increased consumption and/or destruction of platelets. One issue is that the association between mild-to-moderate anemia and other adverse reproductive outcomes is weak (evidence of risk only). These conditions of increased red blood cell production share the one basic feature of increased red cell mass with normal or increased total blood volume. The most notable consequence is increased blood viscosity. Labetalol and nifedipine are the preferred medications and hydrochlorothiazide and methyldopa are considered secondary options. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. Severe anemia has multiple causes much more often than does moderate or mild anemia. Women remote from term should be considered for conservative management, whereas those at term should be delivered. Maternal Hemoglobin Concentration and its Association with Birth Weight Heilman L, Siekmann U, Schmid-Schonbein H, Ludwig H. Hallberg L, Hulthen L, Bengston C, Lapidus L, Lindstedt G. Presented at the meeting Iron and Maternal Mortality in the Developing World, held in Washington, DC, July 67, 1998. Signs helpful in its diagnosis include presentation during late gestation in a nullipara with edema and proteinuria, and one or more of the following: hemoconcentration, hypoalbuminemia, liver function and/or coagulation abnormalities, and increased urate levels. There are 2 aspects to this problem: one is related to the nature of the supplementation and the other is related to the operation of the program. The clinical significance of low or high hemoglobin concentrations that are less extreme has more to do with underlying conditions that cause abnormally high or low hemoglobin concentrations. There is a supported opinion about the increased adverse pregnancy outcomes both with low and high hemoglobin levels. Could you comment on that possible interaction and, also, whether there is a larger literature outside women and pregnancy just relating anemia to the risk of blood loss from X, Y, and Z in men and women? The risk factors for HELLP syndrome differ from those associated with preeclampsia (Table 1). There was a remarkable linear association between hemoglobin concentration and risk of surgical mortality and morbidity 30 d after surgery. Labetolol (Normodyne) and nifedipine (Procardia) have also been used with success. Mr Alnwick: I thought that there was a consensus, at least for young children, that antimalarial treatment with iron was good and that there was no complication with oral iron. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. Although the association between high hemoglobin concentration and adverse pregnancy outcome is probably best explained by inadequate plasma volume expansion, this has not been directly demonstrated. This is related to each person having a set optimal hemoglobin concentration, and the only driving force that can increase this above the set point is the need to maintain the blood's oxygen carrying capacity (42). In summary, sufficient evidence shows that moderate to very severe anemia can produce undesirable health consequences. These issues are separate and, given sufficient resources, we could pursue both programs. It is to be expected that pregnant women as a group, in most populations, including those in developed countries, have some degree of iron deficiency; iron supplementation can cause a significant rise in hemoglobin concentrations in those who are iron deficient. The syndrome seems to be the final manifestation of some insult that leads to microvascular endothelial damage and intravascular platelet activation. Laboratory test results may appear similar when values would differ if adjusted for hemodilution and hemoconcentration. The principal mechanism for perinatal morbidity and mortality due to preeclampsia is poor placental and fetal perfusion. (These studies were completed in 1958-1978 when such tests were not contraindicated in gravid women). This obstruction leads to periportal necrosis and, in severe cases, intrahepatic hemorrhage, subcapsular hematoma formation or hepatic rupture. A woman who has a normal hemoglobin concentration when she is perfectly healthy but because of some condition (eg, pulmonary emphysema) has her hemoglobin shift from 120 to 140 g/L is at risk. An example of such misinterpretation is the disregard of normal hemoglobin concentration variations related to plasma volume changes during pregnancy, which can result in a striking association between preterm births and anemia (13, 14). The pathogenesis of HELLP syndrome remains unclear. The antenatal administration of dexamethasone (Decadron) in a high dosage of 10 mg intravenously every 12 hours has been shown to markedly improve the laboratory abnormalities associated with HELLP syndrome.21 Patients treated with dexamethasone exhibit longer time to delivery; this facilitates maternal transfer to a tertiary care center and postnatal maturity of fetal lungs. Acute iron poisoning is one of the most common fatal accidental childhood poisonings in some countries. Nevertheless, this did not ring true. It makes me wonder whether iron deficiency anemia is likely to be a major factor in developing countries. In examining the evidence related to high and low hemoglobin concentrations, it is important to evaluate the meaning of hemoglobin concentration. The incidence of hemorrhagic complications is higher when platelet counts are less than 40,000 per mm3 (40 109 per L).15 However, hepatic imaging and liver biopsy have shown that laboratory abnormalities do not correlate with the severity of HELLP syndrome.16,17 Therefore, patients with HELLP syndrome who complain of severe right upper quadrant pain, neck pain or shoulder pain should be considered for hepatic imaging regardless of the severity of the laboratory abnormalities, to assess for subcapsular hematoma or rupture.17, Prompt recognition of HELLP syndrome and timely initiation of therapy are vital to ensure the best outcome for mother and fetus. Specifically, he notes that a high hemoglobin value during pregnancy has been associated with adverse birth outcomes. Besides the lack of evidence supporting the causal association between high hemoglobin concentrations and adverse birth outcomes, there is a lack of evidence indicating that iron supplementation can result in abnormally high hemoglobin concentrations. An elevated hemoglobin concentration is usually the result of 2 mechanisms: increased red blood cell production as a compensatory mechanism when blood oxygen carrying capacity is compromised to meet the demand of tissue (with a net increase in red cell mass), or contracted plasma volume resulting in an appearance of greater red cell volume (without a net increase in red cell mass) (28). Combining other micronutrients with iron supplements is likely to increase the cost-effectiveness of programs because the same amount of effort will be exerted to provide not only iron, but other micronutrients as well. This level is associated with adverse outcomes for both mother and fetus. By convention, the central 95% of the reference hemoglobin distribution was considered the normal range. In this system, patients are classified as having partial HELLP syndrome (one or two abnormalities) or full HELLP syndrome (all three abnormalities). When blood transfusion became widely available to the public, which was during World War II, hemorrhage-related deaths also fell. Preventing and controlling iron deficiency anemia through primary health care. It also may be beneficial to assess for secondary hypertension, which occurs in 11% to 14% of pregnant women with chronic hypertension. First, if iron deficiency anemia was more common in the 1930s and 1920s than it is now, we should have seen a fall in deaths from hemorrhage and we did not. In some situations, women who present before 34 weeks' gestation and have superimposed preeclampsia with severe features can be expectantly managed until 34 weeks' gestation if admitted to a facility with appropriate resources to care for mother and infant. The effect of very low or very high hemoglobin concentrations on the cardiovascular system and resulting compromised delivery of oxygen to tissues can directly cause severe morbidity or mortality. A collection of Practice Guidelines published in AFP is available at https://www.aafp.org/afp/practguide. Dr Fleming: The study Mr Alnwick refers to showed an increase of mortality when the hemoglobin was <80 g/L and the blood loss was >500 mL without transfusion. In the study by Pritchard et al (34), the average hematocrit for women with preeclampsia was 0.405, compared with a mean of 0.374 for women with a normal pregnancy. Pregnant women were at 15-41 years age group and their education was at the secondary level in 45.7 percent of cases and about 60 percent of pregnant women were experiencing their first pregnancy. This lack of evidence does not negate the evidence for controlling maternal anemia. A major factor that has limited the benefit of iron supplementation programs is the lack of clear evidence of an effective reduction in maternal anemia in field settings (3, 4). Routine, universal, unmonitored supplementation with oral iron is unlikely to be of much benefit to the severely anemic woman. In South Asia and Africa, where severe maternal anemia is common, classifying very severe anemia as a major cause of maternal mortality along with eclampsia, obstructed birth, hemorrhage, and sepsis is appropriate. Therefore the aims of the . For example, malaria is well known to cause severe anemia in many tropical areas, particularly among primigravidae, and it also contributes to the low birth weight of infants. Cigarette and tobacco products in pregnancy: Impact on pregnancy and the neonate; Clinical features and detection of congenital hypothyroidism . Preeclampsia (PE) is a serious pregnancy complication and samples obtained from PE patients may be relatively hemoconcentrated when compared to those of normal pregnancy, where hemodilution is the norm. Hemoconcentration: Big word, big problem - Center for Phlebotomy Education Anemia may not be a direct cause of poor pregnancy outcomes, except in the case of maternal mortality resulting directly from severe anemia due to hypoxia and heart failure. The production of red blood cells and their principal componenthemoglobinis a complex process, one that can be adversely affected by many congenital and acquired conditions (22). Randomized placebo-controlled trial of iron supplementation and malaria chemoprophylaxis for prevention of severe anaemia and malaria in Tanzanian infants. The magnitude of hemoconcentration with eclampsia - PubMed Is hemoglobin concentration a predictor or risk factor for poor pregnancy outcomes as used in epidemiologic studies (a potential cause), or is it a physiologic variable that can be regarded as an outcome in itself (a consequence)? Serum water analysis in normal pregnancy and preeclampsia The relationship of hemoglobin and hematocrit in the first and second The only evidence of risk associated with anemia is based on epidemiologic studies that showed an association between increased risk of poor birth outcomes and anemia or iron deficiency anemia. Search for other works by this author on: Nutrition and maternal mortality in the developing world. Background Currently, there is no consensus regarding iron supplementation dose that is most beneficial for maternal and offspring health during gestation. Hydrochlorothiazide, 12.5 to 25 mg daily. Am J Clin Nutr 2000;72(suppl):247S56S]. Supplementation is justified on the basis that moderate and severe anemia is undesirable (evidence of deficiency and risk). Oxford University Press is a department of the University of Oxford. The first is based on the number of abnormalities that are present. Although one study suggested that aspirin therapy might be helpful in selected patients with early-onset severe preeclampsia,31 a large, double-blind, randomized, controlled trial failed to demonstrate benefit for this approach.32 In this recently released large study, aspirin therapy did not reduce the incidence of preeclampsia or improve perinatal outcomes in pregnant women at high risk for this complication of pregnancy.32 Likewise, several studies suggested that calcium might be useful in preventing preeclampsia in high-risk patients.33,34 Yet a recent large, multicenter study found that calcium supplementation during pregnancy did not prevent preeclampsia or adverse perinatal outcomes.35. If higher than normal hemoglobin concentrations lead to poor birth outcomes, then a related question is, Should we be concerned about iron supplementation during pregnancy, given that iron supplementation can increase the hemoglobin concentration of some women? The Hemminki trial was of selective compared with routine iron use [Murray MJ, Murray AB, Murray MB, et al. This rule was that no woman should be moved to a hospital without having had a drip put up. Accordingly, higher than normal hemoglobin concentrations should be regarded as an indicator of possible pregnancy complications, not necessarily as a sign of adequate iron nutrition, because iron supplementation does not increase hemoglobin higher than the optimal concentration needed for oxygen delivery. Two interesting issues have emerged from this change in perspective. Better efforts to ensure program functioning appear to be a prudent alternative to abandoning programs. Clearly, women with severe anemia are far more liable to many hazards during pregnancy than those with mild or moderate anemia; indeed, it remains unproven that there is any additional risk for those with mild or moderate anemia. The rates of chronic hypertension are increasing and are predicted to continue because of obesity and older maternal age. Iron supplementation during pregnancyexperiences of a randomized trial relying on health services personnel. The relationship between hemoglobin levels and pregnancy outcomes is still a challenging issue. Hookworm causes upper gastrointestinal blood loss, which contributes directly to iron deficiency anemia (25). When assessing patients diagnosed with hypertension before pregnancy or when they present for pregnancy care, a complete blood count and measurements of transaminase, creatinine, electrolyte, and blood urea nitrogen levels should be obtained as well as a spot urine protein/creatinine ratio, with a 24-hour urine test for total protein if elevated. Respiratory and cyanotic cardiac conditions, which compromise proper oxygenation of blood, are the principal pathologic reasons for elevated hemoglobin concentration (28). In areas where malaria is endemic or can be severe, any nutrition supplementation program probably should also be combined with an effective program of either chemoprophylaxis or treatment for malaria. Hercherg S, Galan P, Chauliac M, Zohoun I, Mass-Raimbault AM. Etiology of anemia in pregnancy in south Malawi. Epidemiologic studies that showed an association between maternal anemia and increased risk of poor birth outcomes did not establish a causal relation (evidence of risk only) (69). One requirement for a large-scale program is evidence of effectiveness, ie, sufficient benefit under the field conditions. Dr Rush: A comment on the ethics committee problem. Patients with severe HELLP syndrome, superimposed DIC or a gestation of less than 32 weeks should be delivered by cesarean section. The acronym HELLP was coined in 1982 to describe a syndrome consisting of hemolysis, elevated liver enzyme levels and low platelet count.1 The syndrome has been considered a variant of preeclampsia, but it can occur on its own or in association with preeclampsia. In the later group we found increased erythrocyte aggregation and a higher hematocrit than in normal patients of comparable gestational age.Erythrocyte aggregation correlated well with plasma fibrinogen levels (r = 0.74) but other high molecular weight proteins such . Platelet count appears to be the most reliable indicator of the presence of HELLP syndrome. Iron deficiency can be a major contributory factor to very severe anemia, but no evidence exists to show that a very high hemoglobin concentration is due to too much iron or to iron supplementation. For women, a hemoglobin concentration >170 g/L can perhaps be regarded as a moderately elevated value.