NEONATAL THROMBOCYTOPENIA

SEVEN cases of thrombocytopenia have recently been reported in newborn infants whose mothers received a thiazide drug during the antepartum period. A cause-and-effect relation was unproved but was strongly suggested by the evidence. One of the seven infants died, a full-term infant girl born to a 24-year-old primigravida. At the time of her birth the amniotic fluid and placenta were meconium stained. The next morning cyanosis and apnea occurred and extensive petechiae and ecchymoses were noted on the lower abdomen. There was no jaundice. The liver edge was felt 3 cm. below the level of the xiphoid process. Continuous bleeding was noted from a puncture of the right heel. The platelet count was 13,000/ c.mm.; hemoglobin, 12.5 g. %; white cell count, 8660/c.num; and reticulocytes, 0.4%. Bone marrow examination revealed hypocellularity, decreased megakaryocytes, megaloblastic changes, and a myeloid:erythroid ratio of 1.6:1. The Coombs test, direct and indirect, was negative. Prothrombin activity was less than 10%. Total bilirubin was 5.6 mg., serum calcium 9.1 mg., and phosphorus 5.8mg. per 100 ml. Urine was normal. Despite intravenous infusions of steroids, antibiotics, vitamin K and folic acid, as well as two fresh blood transfusions, the infant died. The major postmortem findings were subdural and pulmonary hemorrhages and massive anoxic necrosis of the liver. In this series of seven patients, described by Rodriguez, Leikin and Hiller,1 characteristically petechiae and ecchymoses on the body, sometimes associated with mucosal and subconjunctiyal hemorrhages, were observed at birth or within a day thereafter. Bleeding from the gastrointestinal tract or other sites was noted. Platelet counts in these seven cases ranged from 4000 to 28,000 per c.mm. On bone marrow examination in five, there was evidence of hypocellularity in three and decreased numbers of megakaryocytes in four. Six of the infants recovered completely. There had never been a history of signfficant bruising or bleeding in any of the mothers in tl.is series, and in no instance were they found to have thrombocytopenia. An investigation was made of the drugs that the mother had received during the antepartum period. In every case it was ascertained that a thiazide drug (chlorothiazide, hydrochlorothiazide or methydothiazide) had been given for variable periods and in a wide range of doses up to the day of delivery. In most cases it was given for edema. In the past several years there have been scattered reports of purpura occurring in adult patients receiving chlorothiazide or hydrochlorothiazide.' In some cases this has been associated with a platelet deficit, whereas in others the platelet counts were normal. Neutropenia and agranulocytosis as isolated findings and in association with thrombocytopenia have also been recorded. Serum specimens, obtained from the mothers shortly after delivery, were used in complementfixation tests with a panel of platelets and leukocytes that would detect antibodies against all of the platelet and leukocyte isoantigens recognized so far; none of the sera contained detectable isoantibodies. Further, phenotyping for platelet antigens known to be the most frequent cause of isoimmune purpura revealed no incompatibility between mother and child for these antigens. There was no evidence of drug antibody in the mothers' sera that might be dependent on one of the thiazide drugs for activity. The explanation for the occurrence of these hematological side effects, presumed to be due to the thiazide drugs, is not clear. While a type of sensitivity involving an antigen-antibody reaction cannot be ruled out, there is as yet no confirming evidence for this possibility. A further possibility is that thrombocytopenia may be accounted for by an incompetent bone marrow. On the basis of four out of five cases studied the thrombocytopenia appeared to be caused by decreased megakaryocyte production and, moreover, three of these patients had additional evidence of bone marrow depression. Rodriguez, Leikin and Hiller concluded that this hematologic abnormality may be an unusual sensitivity on the part of the fetus to the thiazides and is most probably not immunologic. It would appear that, in respect of pregnant women, the administration of thiazide drugs should be reserved for situations that cannot be managed satisfactorily by other measures. In this connection, physicians are once again reminded of the request of the Food and Drug Directorate of the Department of National Health and Welfare that the Directorate be informed of any encounter with significant drug reactions, whether fetal or otherwise.

NEONATAL THROMBOCYTOPENIA AND THIAZIDE DRUGS SEVEN cases of thrombocytopenia have recently been reported in newborn infants whose mothers received a thiazide drug during the antepartum period. A cause-and-effect relation was unproved but was strongly suggested by the evidence.
One of the seven infants died, a full-term infant girl born to a 24-year-old primigravida. At the time of her birth the amniotic fluid and placenta were meconium stained. The next morning cyanosis and apnea occurred and extensive petechiae and ecchymoses were noted on the lower abdomen. There was no jaundice. The liver edge was felt 3 cm. below the level of the xiphoid process. Continuous bleeding was noted from a puncture of the right heel. The platelet count was 13,000/ c.mm.; hemoglobin, 12.5 g. %; white cell count, 8660/c.num; and reticulocytes, 0.4%. Bone marrow examination revealed hypocellularity, decreased megakaryocytes, megaloblastic changes, and a myeloid:erythroid ratio of 1.6:1. The Coombs test, direct and indirect, was negative. Prothrombin activity was less than 10%. Total bilirubin was 5.6 mg., serum calcium 9.1 mg., and phosphorus 5.8mg. per 100 ml. Urine was normal. Despite intravenous infusions of steroids, antibiotics, vitamin K and folic acid, as well as two fresh blood transfusions, the infant died. The major postmortem findings were subdural and pulmonary hemorrhages and massive anoxic necrosis of the liver.
In this series of seven patients, described by Rodriguez, Leikin and Hiller,1 characteristically petechiae and ecchymoses on the body, sometimes associated with mucosal and subconjunctiyal hemorrhages, were observed at birth or within a day thereafter. Bleeding from the gastrointestinal tract or other sites was noted. Platelet counts in these seven cases ranged from 4000 to 28,000 per c.mm. On bone marrow examination in five, there was evidence of hypocellularity in three and decreased numbers of megakaryocytes in four. Six of the infants recovered completely.
There had never been a history of signfficant bruising or bleeding in any of the mothers in tl.is series, and in no instance were they found to have thrombocytopenia. An investigation was made of the drugs that the mother had received during the antepartum period. In every case it was ascertained that a thiazide drug (chlorothiazide, hydrochlorothiazide or methydothiazide) had been given for variable periods and in a wide range of doses up to the day of delivery. In most cases it was given for edema.
In the past several years there have been scattered reports of purpura occurring in adult patients receiving chlorothiazide or hydrochlorothiazide.' In some cases this has been associated with a platelet deficit, whereas in others the platelet counts were normal. Neutropenia and agranulo-cytosis as isolated findings and in association with thrombocytopenia have also been recorded.
Serum specimens, obtained from the mothers shortly after delivery, were used in complementfixation tests with a panel of platelets and leukocytes that would detect antibodies against all of the platelet and leukocyte isoantigens recognized so far; none of the sera contained detectable isoantibodies. Further, phenotyping for platelet antigens known to be the most frequent cause of isoimmune purpura revealed no incompatibility between mother and child for these antigens. There was no evidence of drug antibody in the mothers' sera that might be dependent on one of the thiazide drugs for activity.
The explanation for the occurrence of these hematological side effects, presumed to be due to the thiazide drugs, is not clear. While a type of sensitivity involving an antigen-antibody reaction cannot be ruled out, there is as yet no confirming evidence for this possibility. A further possibility is that thrombocytopenia may be accounted for by an incompetent bone marrow. On the basis of four out of five cases studied the thrombocytopenia appeared to be caused by decreased megakaryocyte production and, moreover, three of these patients had additional evidence of bone marrow depression. Rodriguez, Leikin and Hiller concluded that this hematologic abnormality may be an unusual sensitivity on the part of the fetus to the thiazides and is most probably not immunologic.
It would appear that, in respect of pregnant women, the administration of thiazide drugs should be reserved for situations that cannot be managed satisfactorily by other measures. In this connection, physicians are once again reminded of the request of the Food and Drug Directorate of the Department of National Health and Welfare that the Directorate be informed of any encounter with significant drug reactions, whether fetal or otherwise. PAGES OUT OF THE PAST: FROM THE JOURNAL OF FIFTY YEARS AGO A MIND REMEDY Readers who are sick of the pessimism of modem medicine, and weary of its parade of learning, its pathology, diagnosis, and therapeutics, may at last find the rest the. crave in this little book. Dr. Ryerson has discovered that all diseases are one disease, and up to April, 1914, practically all were incurable. But now all are curable, and the master remedy is sugar of milk. Complete case reports are furnished, which cover all variations in disease from baldness, irregularity of teeth, and inferential apoplexy to locomotor ataxia and curvature of the spine. All great discoveries are essentially simple, and no treatment could be simpler than the administration of lactose.-Book Review, Caread. Med. Ass. J., 4: 529, 1914.