Birth Outcomes Following Zidovudine Therapy in Pregnant Women

Approximately 100,000 childbearing-aged women in the United States are infected with human immunodeficiency virus (HIV), and an estimated 7000 infants are born to HIV-positive mothers each year (1). In the United States, the rate of perinatal transmission of HIV among mothers who do not receive antiretroviral therapy is 15%- 30% (2). Results from a recent multicenter randomized double-blind clinical trial suggest that treatment of HIV-positive mothers and their infants with zidovudine (ZDV) may substantially reduce the risk for perinatal HIV transmission (3). However, any potential risk for adverse outcomes associated with use of antiretrovirals during pregnancy should be considered. This report summarizes data from the Antiretroviral Pregnancy Registry regarding use of ZDV and the occurrence of structural birth defects reported for pregnancies registered during January 1989-December 1993.

In January 1989, the Zidovudine in Pregnancy Registry was established by the Wellcome Foundation, in conjunction with CDC, and has been managed by the Burroughs Wellcome Co. (Research Triangle Park, North Carolina), * the manufacturer of ZDV. In January 1993, the Zidovudine in Pregnancy Registry was expanded to include zalcitabine and became the Antiretroviral Pregnancy Registry. Although ZDV is not yet approved for use during pregnancy, physicians and other health professionals have provided to the registry reports of women who received antiretroviral therapy during pregnancy. The purpose of the worldwide registry is to measure the incidence of infants with structural defects among prospectively registered cases (i.e., those registered predelivery) and to monitor potential patterns of defects by collecting data on outcomes of pregnancies registered retrospectively (i.e., cases reported post- delivery). A prenatal exposure to ZDV is defined as inadvertent or intentional use of oral or intravenous ZDV at any time during pregnancy. The registry follows CDC guidelines for definitions of major birth defects (4).

Physicians provide information regarding pregnancy dates, lowest CD4+ T-cell count, CDC classification of HIV disease, dosage, length of therapy, and trimester of exposure to antiretroviral drugs. At the expected delivery date, a follow-up form is sent to the physician to ascertain the pregnancy outcome and occurrence of concurrent illnesses.

From 1989 through 1993, 198 prenatal exposures to ZDV were reported prospectively. As of December 31, 1993, 30 women were still awaiting delivery. Of the other 168 women, 47 (28%) were lost to follow-up -- 39 (83%) because the initial reporting physician did not respond to inquiries after the date of expected delivery. Reports are considered lost to follow-up only after efforts to obtain information have been made by sending at least three monthly letters and making one telephone call after the expected delivery date or if the reporting physician can no longer locate the patient.

Of the 121 prospectively registered women, four delivered infants with structural birth defects. ZDV therapy in 54 pregnancies occurred during the first trimester: among these 54 women, one infant was born with a birth defect (agenesis of the right kidney), and 45 infants were born without defects; eight pregnancies were terminated by induced abortions. Among 47 women who received ZDV therapy during the second trimester, three infants were born with birth defects (pectus excavatum, atrial septal defect, and fetal alcohol syndrome), and 44 infants were born without defects. No birth defects occurred among infants born to the 20 women who received ZDV therapy during the third trimester.

Indications for ZDV treatment of the 121 women included asymptomatic HIV infection with low CD4+ count (97), treatment for acquired immunodeficiency syndrome (AIDS) (nine), symptomatic HIV infection (six), and prophylaxis following needlestick injury (six); indications were unknown for three women.

Of the pregnancies registered retrospectively, four infants were born with defects following third trimester ZDV therapy (extra digits; asymptomatic ventricular septal defect; left hydronephrosis and ureteral pelvic junction obstruction; and two-vessel cord, hypoplastic left heart and mitral atresia).

Reported by: A White, PhD, E Andrews, PhD, R Eldridge, M Dickerson, H Tilson, MD, International Div of Surveillance, Epidemiology, and Economics Research; M Elkins, Infectious Diseases, Burroughs Wellcome Co, Research Triangle Park, North Carolina. W Dai, MD, Div of Drug Safety, Hoffmann-LaRoche, Inc, Nutley, New Jersey. B Hurn, MD, Clinical and Safety Surveillance Svc, Wellcome Research Laboratories, Beckenham, England. ER Alexander, Seattle-King County Health Dept, Seattle. H Fox, Dept of Obstetrics and Gynecology, Columbia Presbyterian Medical Center, New York. P Garcia, MD, Prentice Hospital, Chicago. A Rogers, Pediatric, Adolescent, and Maternal AIDS Br, Center for Research for Mothers and Children, National Institute of Child Health and Human Development, National Institutes of Health. Div of Sexually Transmitted Diseases and HIV Prevention, National Center for Prevention Svcs; Div of HIV/AIDS; National Center for Infectious Diseases; Div of Birth Defects and Developmental Disabilities, National Center for Environmental Health, CDC.

Editorial Note

Editorial Note: Based on findings in the registry, the observed proportion of birth defects among infants of women who received ZDV therapy during the first trimester of pregnancy (when the fetus is most sensitive to teratogens {5}) was 2% (1 of 46). This does not differ from the expected proportion in the general population (3%) (4). Neither the prospective nor retrospective reports indicated a consistent pattern of defects. In addition, cases of birth defects from the AIDS Clinical Trial Group 076 clinical trial (3) do not suggest an increase or unusual pattern of birth defects. Public Health Service agencies are evaluating possible recommendations for use of ZDV to reduce the risk for perinatal transmission of HIV.

The findings in this report are preliminary, and the sample size was limited. Other potential limitations of this and other registries include differential reporting of pregnancy outcomes, losses to follow-up, and underreporting. In general, cases lost to follow-up are more common for observational registries than for cases obtained from registries using active ascertainment methods. Retrospective reports may include cases with more unusual or severe features and may be less representative of the population.

Because the number of HIV-positive women who use ZDV during pregnancy may increase, the registry must be sustained to monitor for possible teratogenicity among infants of women receiving ZDV or other antiretroviral therapy during pregnancy. Physicians who provide care for women treated with ZDV or zalcitabine can register patients by calling the registry, (800) 722-9292, extension 8465, in the United States or by calling (919) 315-8465 for registrations from countries outside the United States. Copies of the semiannual registry report are available to health professionals by calling these numbers or by writing to the Antiretroviral Pregnancy Registry, P.O. Box 12700, Research Triangle Park, NC 27709.

References

1. CDC. National HIV serosurveillance summary: results through 1992. Vol 3. Atlanta: US Department of Health and Human Services, Public Health Service, CDC, 1994.

2. CDC. 1993 Sexually transmitted diseases treatment guidelines. MMWR 1993;42(no. RR-14).

3. CDC. Zidovudine for the prevention of HIV transmission from mother to infant. MMWR 1994;43:285-7.

4. CDC. Congenital malformations surveillance report, January 1982- December 1985. Atlanta: US Department of Health and Human Services, Public Health Service, CDC, 1988.

5. Tuchmann-Duplessis H. Drug effects on the fetus. New York: Adis Press, 1977.

• Use of trade names and commercial sources is for identification only and does not imply endorsement by the Public Health Service or the U.S. Department of Health and Human Services.

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