Original Article
A Survey of Zidovudine Use in Pregnant Women with Human Immunodeficiency Virus Infection
N Engl J Med 1992; 326:857-861March 26, 1992
- Abstract
- Abstract
Background and Methods.
The expanding indications for zidovudine treatment make it important to elucidate the safety and toxicity of this drug for pregnant women and their fetuses. We asked pediatricians and obstetricians at the AIDS (acquired immunodeficiency syndrome) Clinical Trials Units to report information about pregnant women infected with the human immunodeficiency virus who were continuing their pregnancies and had received, or were receiving, zidovudine during gestation.
Results.
Reports of 43 women were received from 17 institutions. Doses of zidovudine ranged from 300 to 1200 mg per day, and 24 women took the drug for at least two trimesters. There were two reported instances of maternal toxicity (one gastrointestinal and one heatologic.) No teratogenic abnormalities occurred in the 12 infants with first-trimester exposure to zidovudine. All the infants, including two sets of twins, were born alive. The 38 singleton infants born at term for whom birth weights were reported had a mean birth weight of 3287±670 g; two cases of intrauterine growth retardation were reported among the infants delivered at term. Hemoglobin values, which were available for 31 newborns, ranged from 7.0 to 12.4 mmol per liter (11.2 to 20 g per deciliter); 3 of the 7 newborns with hemoglobin values of less than 8.4 mmol per liter (13.5 g per deciliter) were born prematurely.
Conclusions.
Zidovudine was well tolerated by the pregnant women and was apparently not associated with malformations in the newborns, premature birth, or fetal distress. No pattern of hematologic toxicity was observed in the newborns, but the anemia and growth retardation seen in a minority of the infants could, in part, have resulted from their mothers' treatment with zidovudine. (N Engl J Med 1992;326:857–61.)
Media in This Article
Table 1
Adverse Outcomes in the Cases of Newborns Whose Mothers Received Zidovudine during Pregnancy.*Table 2
Duration of Maternal Zidovudine Therapy and Associated Anemia in Newborns.*Article Activity
- Article
THE information available about the effects of zidovudine therapy during pregnancy on the mother and fetus is limited.1 , 2 As the number of women infected with the human immunodeficiency virus (HIV) increases3 and as the indications for treatment with zidovudine are broadened,4 , 5 more HIV-infected women are likely to be treated with zidovudine either intentionally or inadvertently during a pregnancy. Since this drug suppresses the replication of HIV type 1 (HIV-1) in vivo6 , 7 and crosses the placenta to the fetus,2 , 8 , 9 a combination of maternal therapy and early treatment of the newborn might theoretically reduce the risk of vertical transmission. Given the concern about the use of zidovudine for the mother during pregnancy, as well as concern about the safety of a proposed clinical trial of zidovudine to prevent vertical transmission during pregnancy, we undertook a retrospective survey of the short-term outcome of zidovudine use in pregnancy.
Methods
In the fall of 1990, all pediatricians and obstetricians participating in AIDS (acquired immunodeficiency syndrome) Clinical Trials Units funded by the National Institutes of Health were asked to report all known cases of HIV-infected pregnant women who had planned to continue their pregnancies and had received, or were currently receiving, zidovudine during gestation. Women who elected to terminate their pregnancies were not included. The information we collected included the mother's age; symptoms related to HIV infection in the mother; her antepartum T-lymphocyte count; the dose of zidovudine; the gestational age of the fetus during zidovudine treatment; fetal exposure to other drugs; the mother's use of cigarettes, alcohol, and illicit drugs; obstetrical ultrasound reports; complications of pregnancy; and evaluations of the newborn.
Results
Data on 43 women were reported by 17 institutions. Most of the case reports provided information about the mother's age, the dose of zidovudine, the mother's HIV disease status, use of other medications, antepartum fetal surveillance, and the outcome of the pregnancy (Table 1Table 1
Adverse Outcomes in the Cases of Newborns Whose Mothers Received Zidovudine during Pregnancy.*).Maternal age, reported for 41 patients, ranged from 20 to 43 years (mean ±SD, 29±5). For the 37 patients for whom data were reported, the nadir antepartum CD4+ cell count ranged from 0.008×109 to 0.87×109 per liter (8 to 870 per cubic millimeter). Of these, 17 had CD4+ cell counts below 0.20×109 per liter (200 per cubic millimeter), 13 had counts between 0.2×109 and 0.5×109 per liter (200 and 500 per cubic millimeter), and 7 had counts greater than 0.5×109 per liter (>500 per cubic millimeter). Among the 40 women for whom data were reported on HIV-related symptoms, 5 had AIDS, 21 had HIV-related symptoms, and 14 were asymptomatic. Thirteen women had participated in pharmacokinetic studies of zidovudine during pregnancy.
The dose of zidovudine was reported for 40 women and varied from 300 to 1200 mg per day. Varying zidovudine doses were reported in the cases of seven women; however, in only two cases were the indications reported for changes in the dose. One patient (the mother in Case 1 in Table 1) had grade 1 (mild) gastrointestinal toxicity, and another (Case 2 in Table 1) had grade II (moderate) hematologic toxicity. Twenty-four women took zidovudine for at least two trimesters.
Table 2Table 2
Duration of Maternal Zidovudine Therapy and Associated Anemia in Newborns.* summarizes the duration of zidovudine treatment according to trimester and whether zidovudine was given before conception. Of the 12 women who took zidovudine in the first trimester, 10 continued it throughout gestation.Information on medication use was reported for 39 women. Twenty-eight women had been treated with at least one other medication; concomitant therapies included trimethoprim–sulfamethoxazole (10 women), aerosolized pentamidine (9), antifungal agents (5), acyclovir (3), and additional antimicrobial medications (13). Illegal drug use by four women was reported.
All 45 newborns, including two sets of twins, were born alive. Of the 44 newborns for whom five-minute Apgar scores were provided, all had scores of 7 or more, and 36 had five-minute Apgar scores of 9 or 10. The infants of 40 women (including one set of twins) were delivered at or after 36 weeks of gestation. The preterm deliveries included those of two singletons born at 28 and 33 weeks and a set of twins born at 28 weeks. There were no cases of second-trimester pregnancy loss, fetal death, or stillbirth.
Birth weights were reported for 38 singleton term infants; they ranged from 1588 to 4800 g, with a mean (±SD) of 3287±670 g. Two cases of intrauterine growth retardation, defined as a birth weight below the third percentile for gestational age, were reported among the infants born at term. One infant weighed 1605 g and was born at 37 weeks' gestation to a 36-year-old woman who had used cocaine and who received zidovudine throughout the pregnancy (Case 3 in Table 1). The other infant, who weighed 1588 g, was born at 36 weeks' gestation to a 40-year-old woman with HIV-related symptoms who had received acyclovir, trimethoprim–sulfamethoxazole, nystatin, and erythromycin in addition to zidovudine (Case 4 in Table 1).
A complete blood count was reported for 30 newborns; for one additional infant only a hemoglobin value was reported. Anemia was identified on the basis of the newborn hemoglobin value. The mean hemoglobin level at birth was 9.3±1.4 mmol per liter (15.0±2.3 g per deciliter), with a range of 7.0 to 12.4 mmol per liter (11.2 to 20 g per deciliter). Cases 5 through 10 in Table 1 are those of the seven newborns (including one set of twins) who had hemoglobin values below 8.4 mmol per liter (13.5 g per deciliter); four of these infants had a hemoglobin count between 6.8 and 7.4 mmol per liter (11 and 12 g per deciliter), and three had a hemoglobin count between 7.4 and 8.1 mmol per liter (12 and 13 g per deciliter). Three of the depressed hemoglobin levels were measured in newborns delivered at 28 weeks' gestation. Hemoglobin values were available for 7 of the 10 newborns exposed to zidovudine throughout pregnancy; this group had a mean hemoglobin level of 9.2±1.1 mmol per liter (14.8±1.7 g per deciliter). Only one of these infants had a level below 8.4 mmol per liter (13.5 g per deciliter) (Case 5 in Table 1). Additional hematologic abnormalities reported in the newborns were thrombocytopenia in one infant (one of a pair of twins) who had bacterial sepsis and congenital cytomegalovirus infection (Case 10 in Table 1) and granulocytopenia in another infant who had also been exposed to acyclovir, trimethoprim–sulfamethoxazole, nystatin, and erythromycin during gestation (Case 4 in Table 1).
In addition to abnormalities in the newborns, Table 1 also lists any abnormal antepartum ultrasound observations. Results of ultrasound surveillance were reported for 40 cases. Abnormalities that were observed on ultrasonography after zidovudine was initiated included intrauterine growth retardation in one fetus (Case 4) and oligohydramnios in another (Case 11). No teratogenic abnormalities were reported in the 12 infants with first-trimester exposure. Birth defects noted on evaluation of the newborns included albinism (Case 12), polydactyly in a child with a familial history of polydactyly (Case 13), clitoral enlargement (Case 14), obstruction of the left ureteropelvic junction (Case 8), and an asymptomatic ventricular septal defect (Case 15). Two infections were seen at birth: mycoplasmal pneumonia (Case 16) and congenital cytomegalovirus (in one of the twins in Case 10).
Discussion
Zidovudine was well tolerated by the 43 pregnant women in our study, with only two maternal toxic reactions, one hematologic and the other gastrointestinal, that necessitated a reduction in the dose. In various clinical studies, the common dose-limiting toxic effects of zidovudine have included anemia, granulocytopenia, myopathy, nausea, dyspepsia, and constitutional symptoms.10 These reactions appear to be more prevalent with advanced HIV-related disease, as well as with an increasing dose and duration of therapy. It is likely that the infrequent occurrence of dose-limiting toxicity in this study (4 percent) reflects the relatively early stage of disease and the short duration and lower dose of zidovudine therapy in our population.
Among the 12 newborns with first-trimester exposure to zidovudine, no malformations were reported. Although this observation is encouraging, such data cannot be used to infer that zidovudine does not have some degree of teratogenicity. In mice, zidovudine has a direct toxic effect on the embryo, resulting in early resorption.11 In addition, any small series of negative case reports may be misleading, since even well-established teratogens, such as isotretinoin, are associated with malformations in only 20 percent of exposed fetuses.12
No increased risk of premature birth, intrauterine growth retardation, or newborn asphyxia was found. Forty-one of the 45 infants were born at term. The preterm birth rate of 9 percent is less than expected in this generally high-risk population.13 The mean birth weight of infants in this report was more than 3000 g and was not significantly different from the overall mean birth weight for term neonates, reported to be in the range of 3280 to 3400 g.14
No pattern of serious hematologic toxicity was observed in the infants. The transplacental passage of zidovudine observed in pharmacokinetic studies in pregnant women2 , 8 , 9 and the anemia resulting from zidovudine therapy in children in clinical trials10 , 15 have raised concerns that the drug could cause clinically important bone marrow suppression in the developing fetus. Hemoglobin concentrations at birth are a function of gestational age, increasing from about 6.2 mmol per liter (10 g per deciliter) at 32 weeks to an average of 10.4 mmol per liter (16.8 g per deciliter) at term, with 8.4 mmol per liter (13.5 g per deciliter) the lowest limit of normal for term infants.16 In this series, the mean hemoglobin level at birth of the zidovudine-exposed newborns was 9.3 mmol per liter (15.0 g per deciliter); seven values fell below 8.4 mmol per liter (13.5 g per deciliter), of which three occurred in premature neonates. The low hemoglobin levels in the three premature infants may reflect prematurity rather than zidovudine toxicity. Anemia did not occur more often in the infants who were exposed to zidovudine throughout gestation.
There have been only limited reports of the outcomes of newborns after maternal zidovudine treatment,1 , 2 and our series includes four cases (Cases 10, 11, and 15 and one uncomplicated case) that have been reported previously.1 , 2 No important adverse effects on mothers or newborns have been described in two other recent series.17 , 18
Attributing complications in the fetus or newborn to zidovudine toxicity alone may be incorrect. The patients who take zidovudine during pregnancy make up a unique population with many additional conditions that could also adversely affect the outcome of pregnancy; these include HIV-1 infection itself, opportunistic infections, the use of multiple concomitant medications, and use of illicit drugs. In addition, the retrospective study design we used has limitations. Early adverse outcomes of pregnancy (such as first-trimester losses and teratogenic effects) may have been unintentionally underreported, since these cases may have been unknown to the obstetricians and pediatricians we surveyed. Moreover, the case reports, which in many instances were abstracted from medical records, lacked information, including a missing CD4+ cell count in 16 percent and a missing newborn hemoglobin value in 28 percent.
In summary, our data are reassuring in that we observed no pattern of adverse outcomes of pregnancy that could be attributed directly to maternal zidovudine therapy. The use of zidovudine by the mothers during pregnancy was not associated with malformations in their newborns, premature birth, or fetal distress. It is possible, however, that maternal zidovudine therapy contributed to other abnormalities that were present in small numbers, such as oligohydramnios, anemia, and growth retardation. Although the number of cases we describe is limited, these data provide useful information for physicians who must counsel patients about zidovudine use during pregnancy.
The opinions expressed in this article are those of the authors and do not represent the official position of the Public Health Service.
Supported in part by a grant (U01-AI-27667) from the National Institute of Allergy and Infectious Diseases.
We are indebted to the following clinicians, who reported cases of zidovudine use in HIV-infected pregnant women: William Crumbleholme, M.D., Department of Obstetrics and Gynecology, University of California at San Francisco; John P. Johnson, M.D., Department of Pediatrics, University of Maryland, Baltimore; Harold Lischner, M.D., Division of Immunology, St. Christopher's Hospital for Children, Philadelphia; John Modlin, M.D., Department of Pediatrics, Johns Hopkins Hospital, Baltimore; Alan Salinger, M.D., Department of Obstetrics, University of Cincinnati College of Medicine, Cincinnati; Neil Silverman, M.D., Department of Obstetrics and Gynecology, Thomas Jefferson University, Philadelphia; and Janet Stein, M.D., Department of Obstetrics and Gynecology, Beth Israel Hospital, New York.
Source Information
From the Department of Obstetrics, Gynecology, and Reproductive Science, Mount Sinai Medical Center, New York (R.S.S.); the Pediatric, Adolescent and Maternal AIDS Branch. National Institute of Child Health and Human Development, Bethesda, Md. (P.S.); the Department of Obstetrics and Gynecology, University of Miami School of Medicine, Miami (M.J.O.); the Department of Obstetrics and Gynecology, UCLA School of Medicine, Los Angeles (P.B.); the Department of Obstetrics and Gynecology, University of Washington, Seattle (D.H.W.); the Department of Medicine, University of Rochester Medical Center, Rochester, N.Y. (J.S.L.); the Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston (H.H.); the Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, N.C. (E.G.L.); the Department of Obstetrics and Gynecology, Albert Einstein College of Medicine. Bronx, N.Y. (D.J.G.); the Department of Obstetrics and Gynecology, State University of New York Health Science Center at Brooklyn (H.M.); and the Department of Obstetrics and Gynecology, Columbia—Presby terian Medical Center, New York (H.E.F.). Address reprint requests to Dr. Sperling at the Department of Obstetrics, Gynecology, and Reproductive Science, Mount Sinai Medical Center, Box 1173, 1 Gustave Levy PI., New York, NY 10029.
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