PROFOUND ANEMIA IN A NEWBORN INFANT OF A MOTHER RECEIVING ANTIRETROVIRAL THERAPY (1998)

Pediatric AIDS has affected >7000 children in the United States.1 New cases of pediatric HIV infection are almost exclusively acquired through perinatal transmission. In 1994 the ACTG 076 study report demonstrated a significant decrease in perinatal transmission of HIV when pregnant women and their newborns received zidovudine (ZDV).2 The adverse effects of ZDV to the newborn and infant, mild transient anemia, were minor compared with the great benefit of decreased disease transmission derived from the therapy. Many experts now feel that pregnant women should be given combination therapy with multiple agents in addition to ZDV, if indicated by criteria applicable to nonpregnant women.3 Although the infants in the 076 study were carefully monitored, the effects of other antiretroviral drugs on the fetus have not been studied in large and closely controlled trials. It is possible that the newer medications and novel combinations of existing antiretrovirals now being used in pregnant women may produce adverse events in the fetus and neonate. In this case report we describe a newborn with severe anemia who was delivered by a mother receiving the antiretroviral combination of ZDV, lamivudine (3TC) and zalcitabine (ddC). A cause for the anemia was investigated and no etiology other than drug suppression of fetal erythroid tissue could be identified. Case report. A term male infant was delivered by cesarean section for fetal distress after spontaneous rupture of membranes to a 30-year-old primiparous woman with a diagnosis of HIV infection. At delivery the infant was pale and developed respiratory distress shortly after birth. Physical examination revealed a male infant with respiratory distress, a hyperactive precordium and hepatomegaly. There was no evidence of hydrops. Initial laboratory data included: a hematocrit of 11% with an elevated MCV of 134 fl; a white blood cell count of 7000/mm3 with a normal differential; and a platelet count of 181 000/mm3. An evaluation for sepsis was performed and intravenous ampicillin and gentamicin were given. The infant was diagnosed with high output congestive heart failure secondary to profound anemia, and he was transferred to our regional intensive care nursery where he received a partial volume exchange transfusion to restore the hematocrit to 40%. The prenatal history was significant for a diagnosis of HIV infection in the mother 5 years before the pregnancy. She had no history of opportunistic infections, other than recurrent vaginal candidiasis and genital herpes. During the first trimester the mother's medications included: ZDV, 100 mg three times a day (TID); didanosine (ddI), 167 mg twice a day (BID); and trimethoprim-sulfamethoxazole, one double strength tablet three times per week. Five months before delivery the ZDV dosage was increased to 200 mg TID. Three months before delivery the ddI was discontinued and replaced with 3TC, 150 mg BID, and ddC, 0.375 mg TID. At that time the HIV viral load was found to be 43 000 copies/mm3 (Roche Amplicor PCR, Laboratory Corporation of America, Research Triangle Park, NC), and the CD4 count was 224/mm3 with 23% CD4 cells. Two weeks before delivery the HIV viral load was undetectable. Routine prenatal laboratory testing of the mother demonstrated O/Rh- blood type and a negative Coombs test. At delivery maternal laboratory studies revealed a leukocyte count of 11 200/mm3, the hematocrit was 33% with a normal mean corpuscular volume and the platelet count was 276 000/mm3. Laboratory studies were performed to evaluate the etiology of the infant's anemia. The reticulocyte count was 0. A blood smear was remarkable only for macrocytosis without nucleated red blood cells; no evidence of hemolysis was seen. The infant's blood type was O/Rh+. A direct Coomb's test of the baby's blood was negative. A Kleihauer-Betke smear of maternal blood revealed no evidence for fetal-maternal hemorrhage. Hemoglobin (hgb) electrophoresis was normal for a newborn (82% hgb F, 18% hgb A1). Parvovirus B19 IgG was elevated as determined by enzyme-linked immunosorbent assay (SmithKline Beecham Laboratories, Norristown, PA), with an undetectable IgM titer. These titers were interpreted as being consistent with past infection, probably maternal in origin with transplacental transfer to the infant. PCR for parvovirus B19 in the baby's serum did not detect viral DNA (Viromed Laboratories, Minneapolis, MN). Urine viral culture did not grow cytomegalovirus or other viruses. The infant's blood culture showed no bacterial growth. The infant's hematocrit stabilized at 37% after the transfusion, and reticulocyte count recovered to 1.1% by 8 days of age. The baby steadily improved and was discharged home at 11 days of age. The infant received a 6-week course of ddI. Hematocrit at 10 weeks of age was 30% with a reticulocyte count of 1.2%. A repeat parvovirus IgG titer at 11 months of age was undetectable. Testing of the patient's blood by PCR failed to detect the HIV virus and the patient is now seronegative. Discussion. The cause of the life-threatening anemia in our infant is presumed to be in utero erythroid marrow suppression by one or more of the antiretroviral agents administered to the mother. The differential diagnosis of neonatal red blood cell hypoplasia includes infection, nutritional deficiencies, congenital leukemia and congenital red blood cell aplasia (Diamond-Blackfan anemia), as well as exposure to erythroid suppressive agents. There was no sign of infection, including parvovirus B19 infection which has been reported to cause a neonatal erythroblastopenic anemia.4 Nutritional deficiency is rare and the mother of the case patient received close prenatal care and vitamin supplementation. The timely response of the reticulocyte count and absence of any further episodes of anemia makes Diamond-Blackfan anemia or congenital leukemia unlikely. However, the infant's response is consistent with the withdrawal of a marrow-toxic agent. Antiretroviral therapy has been associated with anemia in both adults and children. ZDV has been most frequently implicated as a cause of bone marrow suppression of myeloid and erythroid cells. Although severe idiosyncratic anemia can occur, the anemia is most often ZDV dose-dependent.5 The effects of ZDV on the fetus and newborn were analyzed in the 076 study.2 The only significant difference in safety profiles between the ZDV-treated group of infants and the placebo group was the hemoglobin values in the first 6 weeks of life. The maximal difference, 1 g/dl, was noted at 3 weeks of age; by 12 weeks of age there was no difference in hemoglobin values in either group. The mean hemoglobin of infants in the ZDV group at birth was approximately 16 g/dl, compared with 17 g/dl in the placebo group, suggesting that prenatal exposure to ZDV monotherapy has a detectable but small effect on fetal hematopoiesis. The effects of other antiretroviral drugs have not been studied in a formal manner in pregnant women and their infants. The overall occurrence of anemia in clinical trials with various combinations of ZDV, ddI, ddC and 3TC does not appear to be significantly increased over ZDV alone.6, 7 A report of severe anemia in adults given ZDV and 3TC was recently presented.8 Eight patients whose hematocrits were stable while receiving ZDV (n = 5) or 3TC (n = 1) monotherapy or no therapy developed significant anemia after treatment with a combination of ZDV and 3TC. The mother of our patient did not have anemia at the time of delivery. However, fetal erythroid precursors may be more sensitive to the effects of antiretrovirals than adult precursors.9 The Antiretroviral Pregnancy Registry, a collaborative project of the National Institutes of Health, the Centers for Disease Control and pharmaceutical companies, collects data on the outcomes of pregnancies with prenatal antiretroviral exposure from ACTG trials and voluntary reports by practitioners.10 From January 1, 1989, to December 31, 1996, seven other infants were reported to the registry with neonatal anemia after prenatal therapy [ZDV (n = 5), ZDV and ddI (n = 1), ZDV and 3TC (n = 1)]. Because there is a paucity of prospective data on large numbers of patients, the true incidence of neonatal anemia after any maternal antiretroviral therapy remains unknown. Since the time of the 076 study the approach to treating HIV-infected patients has become significantly more aggressive, using two or three drug combinations at a time and monitoring viral RNA load as well as T cell markers to direct therapy.3 A careful balance must be maintained between the medical needs of the mother, the need for interruption of vertical transmission of HIV and the potential adverse effects of novel antiretroviral therapies on the fetus. It is of increasing importance to closely monitor pregnant women receiving antiretroviral therapy and carefully evaluate the newborns resulting from these pregnancies. In addition practitioners should be vigilant in registering patients in the Antiretroviral Pregnancy Registry10 and reporting suspected adverse events so that vital information may be disseminated in a timely fashion. Wendy J. Watson, M.D. Timothy P. Stevens, M.D. Geoffrey A. Weinberg, M.D. Department of Pediatrics; Division of Infectious Diseases; Children's Hospital at Strong; University of Rochester Medical Center; Rochester, NY (WJW, GAW) St. Joseph's Hospital Health Center; Syracuse, NY (TPS)