Elizabeth Letsky

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 Charlottes 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.

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 babys 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.

Erythropoietic suppression in fetal anemia because of Kell alloimmunization.

OBJECTIVE Our purpose was to test the hypothesis that maternal anti-Kell alloimmunization produces fetal anemia by erythroid suppression. STUDY DESIGN Erythropoiesis in 11 anemic fetuses from maternal anti-Kell alloimmunization was compared with that in 11 fetuses where the mother was alloimmunized to RhD; each was matched for hematocrit, gestational age, hydrops, and perinatal outcome. Comparisons of the difference were performed by either paired t or Wilcoxon tests. RESULTS The anti-Kell group had reduced reticulocytosis (p = 0.007) and erythroblastosis (p = 0.045) and lower amniotic fluid bilirubin concentrations (p = 0.02) in comparison with the anti-D group. No correlation was found between hematocrit and reticulocytosis in the anti-Kell group, whereas the anti-D group had a significant linear relationship (r = 0.63, p < 0.05), indicating a progressive reticulocytosis in response to the degree of anemia. CONCLUSION These findings suggest that erythroid suppression, rather than hemolysis, is the predominant mechanism in producing fetal anemia related to maternal Kell alloimmunization. Fetal blood sampling is the investigation of choice in the evaluation of anemia related to maternal Kell alloimmunization, because reduced hemolysis means amniotic fluid bilirubin concentrations correlate poorly with anemia.

The risks of antenatal subcutaneous heparin prophylaxis: a controlled trial

Summary. The risks of long‐term antenatal subcutaneous heparin therapy were assessed in a small controlled trial of prophylaxis of thromboembolism. Forty patients with a documented history of previous thromboembolism were randomly allocated either to receive heparin (10 000 i.u. subcutaneously twice daily) throughout pregnancy and labour or to receive no treatment (control group). All patients were treated with heparin (8000 i.u. twice daily) for 6 weeks after delivery from the first postnatal day. There appeared to be no increased risk of antenatal or postnatal bleeding associated with subcutaneous heparin, but one patient in the control group developed a deep vein thrombosis and one in the treatment group developed severe debilitating osteopenia. The withholding of epidural analgesia may have contributed to both maternal and fetal morbidity in the treatment group. There was one abortion in each group but no other fetal or neonatal losses although more babies from the treated group entered the special care baby unit. Although the numbers are too small for statistical analysis, the findings indicate that the use of long‐term low‐dose subcutaneous heparin is not without complications and there is need for a larger, multicentre trial to allow precise quantification of fetal and maternal risks against the risk of recurrent thromboembolism.

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

Summary Platelet transfusions are frequently given to neonatal intensive care unit (NICU) patients with severe thrombocytopenia (platelets less than 50 × 109 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 × 109 L−1 (all patients), or less than 50 × 109 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.

Prolonged heparin therapy in pregnancy causes bone demineralization

Summary. The relation of heparin therapy to osteoporosis was assessed in a retrospective analysis of 20 women treated during and after pregnancy with subcutaneous heparin for thromboembolism prophylaxis. The phalangeal cortical area ratio was significantly less after long term therapy (>25 weeks) compared with that after short term therapy (<7 weeks). The same trend was found in the metacarpal area ratio, although this did not reach statistical significance. The changes were most marked in a woman who had received heparin also in a previous pregnancy. No correlations were found between duration of therapy and back pain, conventional radiology of lumbar spine or the Singh index of femoral trabecular pattern which were within the normal range in all patients. The findings indicate a dose‐related demineralization process associated with prophylactic heparin therapy in pregnancy. The correct methods of and criteria for thromboembolism prophylaxis in pregnancy need critical re‐examination.

Middle cerebral artery peak systolic velocity in the prediction of fetal anemia

Objective The fetal middle cerebral artery peak systolic velocity (MCA PSV) has been suggested as a potential test to predict the fetal hematocrit level. We tested the hypothesis that a low fetal hematocrit is associated with an increase in MCA PSV in a prospective study of normal and alloimmunized pregnancies.

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.

Haematological indices at fetal blood sampling in monochorionic pregnancies complicated by feto-fetal transfusion syndrome

36 MCDA twin pregnancies with FFTS investigated by fetal blood sampling (FBS) were studied over a 10‐year period (1988–1997). The haematological data obtained at FBS were compared between the donor and recipient fetuses. It was shown that the donor fetus had a significantly lower haematocrit (35·7 per cent versus 47·2 per cent; p<0·001), haemoglobin (12·2 gs/dl versus 15·8 g/dl; p<0·001), and red blood cell count (2·9×1012/l versus 3·8×1012/l; p=0·006) compared with the recipient fetus. A haematocrit discordancy of >15 per cent, however, was found in only 25 per cent of twin pairs. There were no significant inter twin differences in the remaining indices. The study concluded that although there are significant differences in haematocrit and red cell mass between the donor and recipient fetuses, only a minority of fetuses will have degrees of discordancy suggested in the literature to be diagnostic. We suggest that FBS does not have a role in establishing the diagnosis of FFTS, although its role in determining the degree of haematocrit discordancy to assist in timing of delivery remains to be evaluated.

Continuing controversy in alloimmune thrombocytopenia: Fetal hyperimmunoglobulinemia fails to prevent thrombocytopenia

Two patients with severe alloimmune thrombocytopenia were managed by weekly intrauterine platelet transfusions at 25 to 36 weeks. In one patient high-dose immunoglobulin was also administered weekly to the mother, and high maternal and fetal immunoglobulin levels were achieved. Fetal platelet counts were similar in both patients. The only variable that affected fetal platelet concentration was the posttransfusion platelet count from the previous transfusion.