AIDS INFORMATION NEWSLETTER Michael Howe, MSLS, Editor AIDS Information Center VA Medical Center, San Francisco (415) 221-4810 ext 3305 December 2, 1994 Women and HIV Infection (Part XIV) Epidemiologic Notes and Reports: 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 hydronephrosisand 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: 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. (Centers for Disease Control and Prevention. Morbidity and Mortality Weekly Report. 1994;43(22):409,415-16.) Addendum In the article "Birth Outcomes Following Zidovudine Therapy in Pregnant Women," the second sentence of the first full paragraph should read "In January 1993, the Zidovudine in Pregnancy Registry was expanded to include zalcitabine and became the Antiretroviral Pregnancy Registry jointly managed by Burroughs Wellcome Co. and Hoffmann-LaRoche Inc." Any pregnancies exposed to either zidovudine or zalcitabine should be reported to the registry, telephone (800) 722-9292, extension 8465, within the United States and (919) 315-8465 for registrations from outside the United States. (Centers for Disease Control and Prevention. Morbidity and Mortality Weekly Report. 1994;43(24):450.) AZT Seen Helping To Lower Transmission During Pregnancy by Edward Stim [CONFERENCE NEWS: Published by the Organizing Committee of the Tenth International Conference on AIDS/International Conference on STDs 1994 - Yokohama, Japan. Distributed electronicaly by GENA/Hivnet Amsterdam - ISSUE 4, Wednesday 10 august 1994.] At Tuesday's Special Recent Report Session, data on mother-to-child HIV transmission and in particular on a recently-completed AZT vs. placebo trial in HIV+ pregnant women and their newborns, were presented by Drs Y. Bryson of UCLA and James F. Balsley of U.S. NIH. Dr. Bryson said the rate of perinatal transmission varied; from 50% in Kenya, to 25-30% in the U.S. and 13% in Europe. As most cases appear to occur intrapartum, this is an important point of intervention with antiretrovirals and of increased attention to preventing prolonged labor and limiting newborn contact with maternal blood and secretions. Dr. Bryson also noted that studies of HIV+ pregnant women who did not transmit HIV to their infants revealed them to have significantly higher HIV neutralizing antibody than transmitters, which suggested the possible usefulness of passive antibody immunotherapy during pregnancy to prevent HIV transmission. Dr. Balsley then presented the recent and much-publicized study which showed that AZT reduced perinatal transmission of HIV. The study, involving a large number of cooperating hospitals in Europe and the U.S., sought to find out whether standard dose AZT started between 14 and 34 weeks gestation in previously untreated pregnant HIV+ women with CD4 counts above 200 and including 6 weeks of newborn treatment could affect HIV vertical transmission. The results at 18 months showed a transmission rate of 25. 5% in placebo cases , and 8.3% in AZT cases, a 67.5% reduction in relative risk. Toxicity was low during treatment and up to the 18-month follow-point. This pathfinder study has proved that antiretroviral treatment in pregnancy can reduce rates of transmission. But unfortunately, cost and logistical problems will make it impossible for pregnant women in developing countries to receive such AZT treatment. Dr. Joep Lange, chief of clinical research at WHO's Global Programme on AIDS and co-moderator of the session, said: "Even if we could prevent thousands of perinatal infections in industrialized countries, the real problem lies in the developing world-where millions are at risk. Dr. Lange also summarized the outcome of a meeting recently held by WHO in Geneva in the prevention of perinatal HIV transmission by AZT. AZT Decreases HIV Transmission from Mother to Newborn Harvey S. Bartnof, MD [TREATMENT UPDATES from tlhe X International Conference on AIDS in Yokohama, Japan: BETA (Bulletin of Experiment Treatments for AIDS) Online - No. 22. Published by the San Francisco AIDS Foundation - September 1994.] While the results of ACTG 076 had already been released before Yokohama, the CDC published their recommendations for AZT therapy in HIV-infected pregnant women and their newborns during the week of the Yokohama Conference. Hence, several sessions addressed different aspects of the study and the recommendations. An African study showed that HIV transmission from mothers to their newborns occurs: 31% intrauterine (during pregnancy), 58% intrapartum (during delivery), and 11% postpartum (after delivery). Increasing risk of transmission is associated with maternal viral burden, higher p24 antigenemia and lower CD4 lymphocyte counts. As of December 1993, an interim analysis of ACTG 076, a Phase III, double-blind, placebo-controlled trial were as follows. Four hundred seventy-seven (477) women with a median age of 25 years, a median CD4 count of 550 cells/mm3, and no prior AZT exposure (during the current pregnancy) were enrolled. The race/ethnic background was 50% African-American, 29% Hispanic and 19% Caucasian/non-Hispanic. Daily oral AZT 500 mg (100 mg 5 times a day) was given to the pregnant women after 14 weeks gestation and continued until the onset of labor. At the start of labor, an IV loading dose of 2 mg/kg of AZT was given, followed by a continuous IV infusion at the rate of 1 mg/kg/hour. The infant was treated with 2 mg/kg orally 4 times a day until age 6 weeks. There were 364 infants born with known HIV status. Of the 180 other/infant pairs who received AZT, there were 13 HIV-infected infants, an 8.3% transmission rate. Of the 184 mother/infant pairs who received placebo, there were 40 infected infants, a 25.5% transmission rate. Therefore, there was a 67.5% reduction in HIV transmission from mother to newborn in the treatment group. This result was highly statistically significant (p=0.000056). Dr. Yvonne Bryson from UCLA School of Medicine stated that there was no significant toxicity in either the mothers or their infants. A slightly decreased hemoglobin in some infants resolved by age 3 months. There were no obvious teratogenic effects. Based on these results, the U.S. Public Health Service, via the CDC, has published the recommended guidelines for AZT treatment of HIV-infected mothers after the 14th week of gestation, during labor, and to their infants up to age 6 weeks. The doses are the same as those used during the ACTG 076 Study above. Mothers and fathers need to understand that the long-term effects to the infant are unknown, including possible future carcinogenic and/or reproductive effects, as well as physical and mental growth abnormalities. Several comments were voiced in Yokohama that the expense of AZT precludes the vast majority of HIV-infected women or their infants in developing countries from access to the drug. Balsey J. Mother-to-child infection. X International Conference on AIDS. Special recent report session SR-2. Yokohama, August 1994. Oral presentation. Blanche S. Materno-fetal HIV transmission. X International Conference on AIDS. Yokohama, August 1994. Abstract PS11 and plenary session oral presentation. Bryson Y. Protective role of zidovudine in reduction of maternal-fetal HIV transmission during pregnancy. Presented at New Strategies for Treatment and Prevention of HIV Disease, a Wellcome Foundation satellite symposium. X International Conference on AIDS. Yokohama, August 1994. Rogers M. Prevention of maternal-fetal transmission of HIV. Presented at Treatment of HIV Disease: Advances and Future Challenges, University of California at Los Angeles (UCLA) satellite symposium. X International Conference on AIDS. Yokohama, August 1994. U.S. Department of Health and Human Services. Recommendations of the U.S. Public Health Service Task Force on the use of zidovudine to reduce perinatal transmission of human immunodeficiency virus. Morbidity and Mortality Weekly Report 43(RR-11). August 5, 1994. DISTRIBUTED FOR GENA by AEGIS/San Juan Capistrano - 714.248.2836: Copyright (c) 1994 - Bulletin of Experimental Treatments for AIDS (BETA), a quarterly publication of the San Francisco AIDS Foundation (SFAF). Reproduced with permission. Reproduction of this article (other than one copy for personal reference) requires written consent from the SFAF. For subscription information contact the BETA Subscription Office at 1.800.959.1059 or 1.510.549.4300, or via the internet at beta@sfsuvax1.sfsu.edu.