In vivo metabolism of complement. I. Metabolism of the third component (C'3) in acquired hemolytic anemia.

The in vivo metabolism of purified third component of complement labeled with (125)-iodine (C'3-(125)I) was studied in normal subjects and in patients with acquired hemolytic anemias. 27 such studies were performed; in addition, three studies were performed using C'3i, the biologically inactive reaction product of C'3. In normal subjects the mean fractional catabolic rate of C'3 was 2.12%/hr and the normal range (defined throughout as the mean +/- 2 SD) was from 1.56 to 2.68. The mean percentage of C'3 that was intravascular was 66.6% and the normal range was from 51 to 83. The C'3 synthesis rate averaged 1.16 mg/kg per hr with a normal range of from 0.90 to 1.42. The mean serum concentration of C'3 was 1.43 mg/ml with a normal range of from 1.00 to 1.87. The fractional catabolic rate and synthesis rate of C'3 were at the upper limit of normal or were increased above normal in patients who had warm antibody autoimmune hemolytic anemia with complement on their erythrocytes and in patients with paroxysmal nocturnal hemoglobinuria studied during periods of active hemolysis. An increased C'3 synthesis rate was also found in one patient who was hematologically normal but had an active peptic ulcer and elevated serum concentration of C'3.A normal fractional catabolic rate and C'3 synthesis rate were found in patients with autoimmune hemolytic anemia associated with alpha-methyldopa administration, atypical cold antibody autoimmune hemolytic anemia, and in paroxysmal nocturnal hemoglobinuria during an asymptomatic interval. The three studies with C'3i-(125)I revealed a very rapid removal of the labeled protein from the plasma with less than 10% remaining after 2 hr and with a corresponding increase in urinary excretion rate of the label. The fractional catabolic rate of C'3i averaged 37%/hr. The findings are consistent with the previously elucidated in vitro reaction mechanism of C'3 and strengthen the concept that serum complement participates in immune reactions in vivo.

Etiology of anemia in pregnancy in south Malawi.

BACKGROUND: Anemia in pregnancy is a major public health problem in developing countries. In sub-Saharan Africa, such anemia is generally accepted as resulting from nutritional deficiencies, particularly iron deficiency. OBJECTIVE: We comprehensively assessed the full spectrum of nutritional and nonnutritional factors associated with pregnancy anemia. DESIGN: Iron, folate, vitamin B-12, and vitamin A were measured in serum in a cross-sectional study of 150 pregnant women in Blantyre, Malawi. Bone marrow aspirates were evaluated, peripheral blood films were examined for malaria parasites, stool and urine samples were examined for helminthic infection, and tests were done for genetic disorders and for HIV infection. C-reactive protein (CRP) concentrations and erythrocyte sedimentation rates were measured as markers of inflammation. RESULTS: Of the 150 anemic women, 23% were iron deficient with no evidence of folate, vitamin B-12, or vitamin A deficiencies; 32% were deficient in iron and one or more of the other micronutrients; 26% were not iron deficient but had evidence of one of the other micronutrient deficiencies, most often vitamin A; and 19% were not deficient in any of the micronutrients studied. CRP concentrations were notably high in 54% of the anemic women with no nutritional deficiencies and in 73.5% of the anemic women who were iron replete by bone marrow assessment. CONCLUSION: The role of chronic inflammation as a possible contributing factor to anemia in pregnancy has important implications for the clinical evaluation and treatment of women.

Hemolysis following correction of double-outlet right ventricle.

A 41/2-year-old child developed a severe degree of intravascular hemolysis within 24 hours after intraventricular correction of double-outlet right ventricle with a Dacron patch. The child developed jaundice, with a serum bilirubin of 4.3 mg. per cent. The hematocrit value fell from 47 to 25 per cent and the reticulocyte count rose to 22 per cent. The hemolysis diminished after 3 weeks and completely disappeared after 6 weeks. We presume that the hemolysis was due to turbulence caused by a long, curved patch and that its disappearance coincided with the endothelialization of the patch. The child is well 3 years after the operation.

Serum ferritin in children with thalassaemia regularly transfused.

A controlled trial of continuous chelation therapy in regularly transfused children with homozygous beta-thalassaemia has been in progress at the Hospital for Sick Children since April 1966. In the sixth and seventh years of the trial the effect of this treatment on iron overload has been assessed by estimating serum ferritin levels and liver iron concentrations in both chelator-treated and control groups. When compared with non-chelated controls, results of both these estimations were invariably lower in the chelated group. However, all the results in both groups were very high, and fell within the ranges observed in untreated idiopathic haemochromatosis. A close correlation was found between serum ferritin levels and liver iron concentrations in these children, indicating that serum ferritin is a valuable alternative to liver iron concentration in the assessment of visceral iron overload, even when massive tissue siderosis is present.

Fetal macrocytosis in association with chromosomal abnormalities.

Mean red cell volume (MCV) was determined in 264 fetuses between 15-41 weeks. After exclusion of anemic, hypoxic, and chromosomally abnormal fetuses, the MCV in 208 umbilical venous samples was shown to decrease with gestation (r = 0.64; P less than .001), and a normal range was constructed by linear regression analysis. An elevated MCV was found in both fetuses with triploidy, in four of five with monosomy X, and in four of ten with trisomies 18 or 21. The MCV was similarly raised in four of five fetuses with gross anomalies in whom cytogenetic cultures had failed. Significant correlations were found in chromosomally abnormal fetuses between the elevation in MCV and both the nucleated red cell (r = 0.69; P less than .01) and reticulocyte counts (r = 0.57; P less than .05). There was a similar correlation with nucleated red cells in 16 severely anemic fetuses with Rh disease, 12 of whom had a raised MCV. Elevation in MCV was unrelated to hypoxia. Macrocytosis had a sensitivity of 71% and a specificity of 95% in the second trimester for predicting an abnormal karyotype in nonanemic fetuses (kappa index 0.60). Fetal MCV may provide clinically useful information while one awaits culture results. We suggest that karyotyping be considered in fetuses undergoing blood sampling for other indications in whom the MCV is raised.

Needle modifications for invasive fetal procedures.

OBJECTIVE: To investigate the effect of needle size and siliconization on fetal blood sampling, transfusion, and electrocardiography. METHODS: Standard needles were modified by increasing the internal (but not the external) diameter and either siliconization of the bore or external Teflon coating. The siliconized needles were subjected to a series of flow experiments with either blood or saline at various driving pressures, and assessed in clinical use during fetal transfusion and fetal blood sampling. The Teflon-coated needles were used for fetal transfusion to try and facilitate the fetal electrocardiogram (ECG). RESULTS: Under conditions simulating fetal transfusion, the siliconized needle allowed a 93% increase in flow rate compared to the standard needle (P < .05). Samples obtained after fetal transfusion with the siliconized needles were free of clots, whereas 50% of the post-transfusion samples with the standard needle had clots present. Similarly, samples taken for fetal platelet count were free of platelet clumping and clots with siliconized needles, but not with standard needles. Fetal ECG recordings were recorded successfully when Teflon-coated needles were used to access the fetal circulation via the intrahepatic vein. CONCLUSIONS: Modifications to standard needles improved blood flow and reduced the activation of coagulation during both fetal intravascular transfusion and platelet count measurement. Direct fetal ECG recording was facilitated by Teflon coating the external surface of the needle, insulating the fetal signal from maternal electrical signals.

The effect of intrauterine intravascular blood transfusion on iron metabolism in fetuses with Rh alloimmunization.

Fetal plasma ferritin concentrations were measured in 43 normal fetuses at 18-36 weeks and in 78 blood samples collected before transfusion from 23 fetuses with Rh alloimmunization. Among controls, there was a significant correlation between fetal serum ferritin and gestational age (r = 0.39, P = .009), consistent with an increase in fetal storage of iron during normal pregnancy. In Rh-alloimmunized fetuses, the ferritin concentration was above the reference range in 63% of the samples. Before the first transfusion, the fetal ferritin concentration was increased compared with controls (mean multiples of the mean = 2.6, range 1-26) and showed a negative correlation with fetal hematocrit (r = -0.43, P less than .05), suggesting that the worse the fetal anemia, the higher the iron store. Serial transfusions were associated with further increase in serum ferritin, which correlated primarily with the total volume of blood transfused. Three fetuses had plasma serum ferritin concentrations above 1 mg/L, a level compatible with a diagnosis of iron overload in children. These observations suggest that there is a potential risk of iron overload in Rh-alloimmunized fetuses undergoing intrauterine blood transfusion.

Disseminated intravascular coagulation.

Healthy pregnancy is accompanied by changes in the haemostatic system which convert it into a hypercoagulable state vulnerable to a spectrum of disorders ranging from venous thromboembolism to disseminated intravascular coagulation (DIC). This latter is always a secondary phenomenon triggered by specific disorders such as abruptio placentae and amniotic fluid embolism due to release of thromboplastin intravascularly or endothelial damage resulting from pre-eclampsia and sepsis. In modern obstetric practice the most common cause is haemorrhagic shock with delay in resuscitation leading to endothelial damage. The initial management of massive obstetric haemorrhage is the same whether associated with coagulopathy initially or not. Low-grade DIC, associated with pre-eclampsia, is monitored haematologically by serial platelet counts and serum fibrin degradation products (FDPs). Supportive measures and removal of the triggering mechanism are the key to successful management. Outcome depends primarily on our ability to deal with the trigger and not on direct attempts to correct the coagulation deficit.

Consequences of fetomaternal haemorrhage after intrauterine transfusion.

Fetomaternal haemorrhage was studied after 68 consecutive fetal intravascular transfusions performed in 20 patients with Rh isoimmunisation. alpha Fetoprotein concentration was assayed in maternal blood taken before, and immediately after each transfusion and three and 24 hours later. An increase of 50% or more in the concentration in any of the samples after transfusion was considered to indicate fetomaternal haemorrhage. Fetal alpha fetoprotein concentration in blood sampled before transfusion was also assayed and the amount of fetomaternal haemorrhage calculated. Fetomaternal haemorrhage occurred in 21 of 32 patients with an anterior placenta and in six of 36 with a posterior or fundal placenta. The mean estimated volume of haemorrhage was 2.4 ml, which was on average equal to 3.1% of the total fetoplacental blood volume. When the volume of fetomaternal haemorrhage at the first transfusion was greater than 1 ml there was a greater increase in maternal Rh (D) antibody titres and a greater fall in fetal packed cell volume. Sampling of fetal blood should not be routinely done early in patients with Rh isoimmunisation, and intrauterine transfusion should be delayed as long as possible. Sampling sites other than the placental cord insertion reduces the risk of fetomaternal haemorrhage.

Randomised trial of vitamin A supplementation in pregnant women in rural Malawi found to be anaemic on screening by HemoCue.

OBJECTIVE: To assess the effects of vitamin A supplementation in women with anaemia during pregnancy. DESIGN: Single-centre randomised controlled trial. SETTING: Rural community in southern Malawi, central Africa. POPULATION: Seven hundred women with singleton pregnancies at 12-24 weeks measured by ultrasound scan and with haemoglobin <11.0 g/dl by HemoCue screening method. Analysis was by intention to treat. All received iron and folate, and sulphadoxine/pyrimethamine for antimalarial prophylaxis. METHODS: Women were randomised to receive oral supplementation with daily 5000 or 10,000 iu vitamin A, or placebo. MAIN OUTCOME MEASURES: Anaemia, as assessed by Coulter counter, severe anaemia, iron status and indices of infection. RESULTS: Vitamin A deficiency was, in this rural population, less common than predicted. Vitamin A supplementation had no significant impact on anaemia, severe anaemia, iron status and indices of infection. Vitamin A stores were less likely to be depleted at the end of pregnancy in supplemented groups. CONCLUSIONS: Vitamin A supplementation programmes to reduce anaemia should not be implemented in similar antenatal populations in rural sub-Saharan Africa unless evidence emerges of positive benefit on substantive clinical outcomes. Introducing public health interventions of unknown benefit and with unclear biological mechanisms can divert scarce resources from clinical and social interventions more likely to impact maternal mortality.

Erythropoiesis in pregnancy.

There is a dramatic increase in total blood volume during healthy pregnancy. The disproportionate expansion in plasma volume (50%) and red cell mass (18-25% depending on iron status) results in a decrease in haemoglobin concentration maximal at 32 weeks gestation. This should not fall below 11 g/dl at any time during pregnancy. Deficiency of essential haematinics arising from increased requirements and inadequate intake may have far reaching effects on mother, fetus and neonate which bear no relationship to the impaired oxygen carrying capacity of the reduced cell mass. Pathological anaemia of pregnancy is due to over 90% of cases to iron deficiency associated with depleted stores and deficient intake. The single largest demand for iron arises from the increased red cell mass under the influence of erythropoietin. Tissue enzyme malfunction occurs even in the very first stages of iron deficiency before significant anaemia develops. Increased blood loss at delivery and preterm birth are observed associated complications. Off-spring of iron deficient mothers have decreased iron stores and may develop anaemia in the first year of life. Studies have shown behavioural abnormalities in children with iron deficiency and poor performance in the Bayley Mental Developmental Index. The poor performance in mental and motor development can be improved to the level of iron-sufficient infants by treatment with ferrous sulphate. Folate deficiency often accompanies iron deficiency as they are both associated with a poor diet. The haematological effects of folate deficiency are usually masked by iron deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Peripartum prophylaxis of thrombo-embolism.

It is important to continue or introduce prophylaxis of thrombo-embolism before elective delivery or during labour if the incidence of post partum thrombo-embolism is to be reduced. Women with previous thrombo-embolism, genetic or acquired thrombophilia should receive intrapartum and post partum prophylaxis for at least six weeks. Those having operative delivery may require prophylaxis for a shorter period if there are no other risk factors. Subcutaneous unfractionated or low molecular weight heparins are the anticoagulants of choice. Available evidence shows that the use of prophylactic heparin during the course of epidural or spinal anaesthesia does not increase the risk of local haematoma although this remains an actively controversial area. To reduce the risk of osteopenia associated with long-term therapy and relieve the women of the onus of self-administered injections, heparin may be replaced by warfarin post-partum even if the mother is breastfeeding but warfarin dosage, unlike heparin, will require careful monitoring.

Pregnancy and the erythrocyte sedimentation rate.

OBJECTIVES: To determine the range of erythrocyte sedimentation rate values obtained in healthy pregnant women. To examine the effect of gestational age and haemoglobin concentration on erythrocyte sedimentation rate. SETTING: Queen Charlotte's Hospital, London, UK. DESIGN: Cross sectional descriptive study. Population Healthy pregnant women attending for routine outpatient antenatal visits at Queen Charlotte's Hospital in London. METHODS: Erythrocyte sedimentation rate was determined by the Westergren method, haemoglobin concentration by automated cell counter and gestational age by ultrasonography. The median and 95% reference range was determined for erythrocyte sedimentation rate values obtained. Linear regression analysis was used to determine the influence of haemoglobin concentration and gestational age on erythrocyte sedimentation rate. RESULTS: For 1,019 women examined, the range of erythrocyte sedimentation rate values obtained was 4-112 mm/ h. Gestational age and haemoglobin concentration both significantly influenced erythrocyte sedimentation rate. (P < 0.0001). For non-anaemic women the 95% reference range rose from 18-48 mm/h in the first half of pregnancy to 30-70 mm/h in the second half of pregnancy. For anaemic women the corresponding reference ranges were 21-62 mm/h and 40-95 mm/h, respectively. CONCLUSION: For the correct interpretation of erythrocyte sedimentation rate values obtained during pregnancy gestational age and haemoglobin concentration must be taken into account.

Low-molecular-weight heparin for obstetric thromboprophylaxis: experience of sixty-nine pregnancies in sixty-one women at high risk.

OBJECTIVE: Our purpose was to investigate the use of low-molecular-weight heparin (enoxaparin, Clexane) for thromboprophylaxis in pregnancy. STUDY DESIGN: A prospective consecutive cohort of 61 pregnant women at high risk of thromboembolism receiving antenatal thromboprophylaxis with enoxaparin (usually 40 mg, subcutaneously daily) in a total of 69 pregnancies was identified from the obstetric medicine clinic at Queen Charlotte's Hospital. Bone density measurements of the hip and lumbar spine were taken in 26 women after 28 pregnancies within 16 months post partum. Nonparametric statistics were used for comparisons. RESULTS: There were no episodes of antenatal thromboembolism. One woman (1.6%) (receiving 20 mg of enoxaparin) had a pulmonary embolus post partum. Heparin levels (anti-Xa assay) were greater with the 40 mg dose (median 0.09 U/ml) than with the 20 mg dose (median 0.03 U/ml) (p = 0.0006) but were not affected by gestational age (r = -0.1, p = 0.14). Enoxaparin had no effect on platelet count or on in vitro coagulation tests. Nine (32%) women had bone density in the spine or hip > 1 SD below the mean for age- and sex-matched controls. CONCLUSION: This, the largest study to date of low-molecular-weight heparin use in pregnancy, confirms previous reports that it is a safe and effective alternative to unfractionated heparin for obstetric thromboprophylaxis in high-risk women. Effects on bone demineralization require further investigation.

Intrauterine death due to fetomaternal hemorrhage despite successful treatment of fetal anemia.

A case of hydrops fetalis caused by massive fetomaternal hemorrhage was initially successfully treated by intrauterine intravascular transfusion. Unexplained intrauterine death occurred 2 weeks afterwards. The investigation of fetomaternal hemorrhage by fetal blood sampling and the management are discussed.

Survival and desferrioxamine in thalassaemia major.

A small randomised trial and observation of all patients homozygous for beta-thalassaemia in Britain born in or before 1963 indicated that those patients who had received average weekly doses of more than 4 g of desferrioxamine over the previous few years were less likely to die in the near future than were patients of similar ages who had received less, or no, desferrioxamine.