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                   AIDS INFORMATION NEWSLETTER
                   Michael Howe, MSLS, Editor
                     AIDS Information Center
                VA Medical Center, San Francisco
                     [phone] 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, [phone], extension 8465,
in the United States or by calling [phone] 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 [phone],
extension 8465, within the United States and [phone] 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.

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Copyright (c) 1994 - Bulletin of Experimental Treatments for AIDS
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