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.

Platelet transfusion in the management of severe thrombocytopenia in neonatal intensive care unit patients.

Platelet transfusions are frequently given to neonatal intensive care unit (NICU) patients with severe thrombocytopenia (platelets less than 50 x 10(9) L(-1)) but no study has assessed whether this is clinically appropriate. To address this we conducted a retrospective review of platelet transfusion practice in patients developing severe thrombocytopenia over 3 years in a single NICU. Out of 901 admissions, 53 (6%) developed severe thrombocytopenia. Twenty-seven neonates received a total of 63 platelet transfusions, the main triggers being: platelet count less than 30 x 10(9) L(-1) (all patients), or less than 50 x 10(9) L(-1) in those with previous haemorrhage or clinical instability. No major haemorrhage occurred during severe thrombocytopenia either in neonates in whom platelet transfusions were withheld (26/53) or in neonates given platelets who survived to discharge (22/27). Five preterm neonates given platelets died but all had overwhelming sepsis or necrotizing enterocolitis and none died directly as a result of haemorrhage. Although the widely used liberal triggers for neonatal platelet transfusion highlighted in this review reflect available guidelines, and represent cautious ('safe') haemostatic practice, they are likely to result in unnecessary transfusion for a significant number of NICU patients. Improved practice requires definition of a safe lower limit for platelet count in stable neonates; effective platelet transfusion strategies for sick neonates; and improved therapies for conditions precipitating severe thrombocytopenia.

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.

Intrauterine rescue transfusion in monochorionic multiple pregnancies with recent single intrauterine death.

To assess the role of fetal blood sampling and intrauterine transfusion in monochorionic (MC) multiple pregnancy complicated by single intrauterine death (IUD), we reviewed ten cases over a 4-year period in a tertiary referral centre which underwent fetal blood sampling within 24 h of death of its MC co-twin. Intrauterine rescue transfusion was performed in all seven anaemic fetuses (hematocrit; Hct < 30%) to raise the fetal Hct to > or = 40%. The rationale was to prevent death and/or brain injury. Two fetuses, which were severely acidaemic at blood sampling, died in utero within 24 h of the procedure. In two cases, the surviving twins manifested abnormal sonographic findings of the fetal brain 2-5 weeks later and underwent late termination. In two cases, the pregnancies continued uneventfully until delivery at 35 and 40 weeks' gestation with good neonatal outcome. In one case the co-twin delivered 1 week later at 29 weeks but died within 12 h. Fetuses without anaemia were not transfused and had normal clinical outcomes. We suggest that intrauterine rescue transfusion before the development of severe acidaemia in anaemic surviving MC co-twins may prevent fetal death, but does not necessarily prevent brain injury. Until its role becomes clearer, we recommend that its use be restricted to situations in which the parents and the local jurisdiction allow late termination as an option if brain injury subsequently manifests on ultrasound.

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.

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.

Iron status in pregnant women: which measurements are valid?

Anaemia in pregnancy in developing countries continues to be a public health problem of significant proportion. At least 50% of the anaemia has been blamed on iron deficiency. In populations where chronic inflammation and iron deficiency anaemia coexist, the criteria to accurately define iron status are not always clear. Similarly, in pregnancy, with marked physiological changes, cut-off points for biochemical parameters need to be re-examined. In this study we examined the diagnostic accuracy of iron parameters including mean cellular volume (MCV), serum iron, transferrin, total iron binding capacity (TIBC) and its saturation, zinc protoporphyrin (ZPP), ferritin and serum transferrin receptor (TfR) for the assessment of iron status in a population of anaemic pregnant women in Malawi. Stained bone marrow aspirates were used as the standard for comparison. Results show that for the purpose of screening, serum ferritin is the best single indicator of storage iron provided a cut-off point of 30 microg/l is used. A number of other commonly used parameters of iron status were shown to have limited diagnostic accuracy. Logistic regression was used to obtain mathematical models for the prediction of bone marrow iron status using a combination of available parameters.

Inhibition of erythroid progenitor cells by anti-Kell antibodies in fetal alloimmune anemia.

BACKGROUND: In alloimmune anemia of the newborn, the level of hemolysis caused by the presence of antibodies to antigens of the Kell blood-group system is less than that caused by antibodies to the D antigen of the Rh blood-group system, and the numbers of reticulocytes and normoblasts in the baby's circulation are inappropriately low for the degree of anemia. These findings suggest that sensitization to Kell antigens results in suppression of fetal erythropoiesis as well as hemolysis. METHODS: We compared the growth in vitro of Kell-positive and Kell-negative hematopoietic progenitor cells from cord blood in the presence of human monoclonal anti-Kell antibodies and anti-D antibodies and serum from women with anti-Kell antibodies. RESULTS: The growth of Kell-positive erythroid progenitor cells (erythroid burst-forming units and colony-forming units) from cord blood was markedly inhibited by monoclonal IgG and IgM anti-Kell antibodies in a dose-dependent fashion (range of concentrations, 0.2 to 20 percent), but monoclonal anti-D antibodies had no effect. The growth of these types of cells from Kell-negative cord blood was not affected by either type of antibody. Neither monoclonal anti-Kell antibodies nor monoclonal anti-D antibodies inhibited the growth of granulocyte or megakaryocyte progenitor cells from cord blood. Serum from 22 women with anti-Kell antibodies inhibited the growth of Kell-positive erythroid burst-forming units and colony-forming units but not of Kell-negative erythroid burst-forming units and colony-forming units (P<0.001 for the difference between groups). The maternal anti-Kell antibodies had no inhibitory effects on granulocyte-macrophage or mega-karyocyte progenitor cells from cord blood. CONCLUSIONS: Anti-Kell antibodies specifically inhibit the growth of Kell-positive erythroid burst-forming units and colony-forming units, a finding that supports the hypothesis that these antibodies cause fetal anemia by suppressing erythropoiesis at the progenitor-cell level.

Activated protein C resistance in normal pregnancy.

This prospective cross-sectional (10 women on each occasion) and longitudinal (20 women) study investigated activated protein C (APC) ratio in normal pregnancy. The APC ratio was measured at booking, 20, 30 and 36 weeks of gestation, and compared with a sample of normal nonpregnant women. No significant difference was found between APC ratios for pregnant women at any gestation and those of the nonpregnant population in either the longitudinal or cross-sectional studies. There was a significant decrease in APC ratios throughout pregnancy, but in all but one case values remained within the normal nonpregnant range. The APC ratio can therefore be used as a screening test for the factor V Leiden mutation during pregnancy.

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.

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.

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.

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)

Clinical utility of fetal RhD typing in alloimmunized pregnancies by means of polymerase chain reaction on amniocytes or chorionic villi.

OBJECTIVE: Our purpose was to describe the clinical utility of a deoxyribonucleic acid amplification method for determining fetal RhD status in alloimmunized pregnancies STUDY DESIGN: Six RhD-negative women with alloimmunized pregnancies and heterozygous partners underwent amniocentesis (n = 5) or chorionic villus sampling (n = 1). Fetal RhD type was determined by polymerase chain reaction and results disclosed to the attending physicians. RESULTS: Knowledge of the fetal RhD status avoided further invasive procedures in two pregnancies and facilitated the timing or performance of intrauterine transfusions in the remainder. CONCLUSIONS: In alloimmunized pregnancies the ability to RhD-type the fetus in amniotic fluid avoids the risks of fetomaternal hemorrhage and increased sensitization associated with fetal blood sampling or chorionic biopsy. This allows more rational pregnancy management, avoiding invasive procedures in the presence of an RhD-negative fetus, or planning therapeutic interventions or offering termination of pregnancy in the presence of an RhD-positive fetus.

Direct fetal administration of immunoglobulins: another disappointing therapy in alloimmune thrombocytopenia.

Current management strategies to prevent fetal intracranial haemorrhage in perinatal alloimmune thrombocytopenia (PAIT) include serial platelet transfusion and/or maternal high-dose intravenous immunoglobulin (IVIG) administration. The former involves multiple invasive procedures, while the latter is both expensive and of questionable efficacy. We report the use of direct fetal IVIG in 2 fetuses with PAIT, undergoing serial intrauterine platelet transfusions. Fetal IVIG had no effect on fetal platelet count. We conclude that direct fetal IVIG administration does not appear to have a role in the management of PAIT, and that current management strategies remain far from ideal.