Rapid Advances in Preventing Vertical Transmission
The decision to have a child can be a complicated one under any circumstances, but for an HIV-positive woman it may well be the most difficult decision she will ever face. Being HIV-positive does not automatically supplant the maternal instinct and the desire to have children. As new AIDS treatments are proving more successful and women are beginning to experience reductions in mortality and are living longer, many are facing the dilemma of whether or not to have a child. Treatments are as numerous for pregnant women as for the general population, but choices are more complex. The Public Health Service has recently published recommendations for pregnant women and antiviral use, but it is still not clear as to what is best for mother and fetus. There is still controversy over the use of AZT or other antivirals during pregnancy despite guidelines and recommendations from experts in the field. Access to emerging information is important and although more research is needed, some of the new data have proved encouraging.
Yvonne Bryson, M.D., of UCLA, stated at the May 1997 Pediatric HIV Symposium, a satellite meeting of the National Conference on Women and HIV, "I stand here today more optimistic than I've felt since I saw my first AIDS patient in 1981. Advances in the area of perinatal transmission give women the reproductive option if they wish to have a family." Progress in treatment and prevention can reduce the risk of vertical (mother-to-infant) transmission. AZT, which is the least effective of drugs, can decrease the risk by two-thirds, as demonstrated by ACTG 076. Dr. Bryson stated that there was potential for the rate of transmission to be reduced to below 2% with the use of improved strategies.
Some Factors That May Influence Transmission
The rate of vertical transmission has been shown by several investigators to be related to the status of the maternal immune system. According to an article Dr. Bryson published in the journal AIDS, "Women with advanced clinical disease and primary infection during pregnancy have a high risk of transmission" (AIDS 1996 (suppl 3):S33-42). Other predictive factors include lower CD4 counts, the mother's ability to produce neutralizing antibody, shedding of cervical virus and presence of p24 antigen.
Viral load is associated with transmission but it is not the only factor. Dr. Bryson stated that women she studied who did not transmit had a wide variation of viral load. There was also an overlap of viral load counts between some of the transmitters and the nontransmitters. Women with lower viral load had a lower risk of vertical transmission, though. There are studies that observed transmission at lower viral loads, but Dr. Bryson felt that many of those instances of transmission occurred at delivery. Viral load may be more useful in determining the mother's own treatment than in predicting if she will transmit the virus to her baby. The better the immune status of the woman, the better the chance that she will not transmit. For all of these reasons lowering maternal viral load is desirable.
Certain obstetrical factors may increase the risk of transmission by causing trauma to the newborn baby. These include some tests, instruments and procedures used during pregnancy. If possible, HIV-positive pregnant woman should avoid amniocentesis, chorionic villus sampling (CVs), fetal scalp sampling, cordocentesis, internal fetal and labor monitoring (external fetal monitoring is safe) and percutaneous umbilical blood sampling (PUBS). Procedures performed during delivery, such as episiotomy, urinary catheterization, shaving, forceps and vacuum extractors, should be utilized only if medically necessary for the safety of the mother and fetus.
It has been posited that Cesarean sections could have a protective effect. Numerous studies have examined this question and have come up with conflicting findings. A meta-analysis pooled the results of eleven studies and found that there was a higher risk of transmission for infants delivered vaginally versus infants delivered by C-section (Dunn, DT et al. Journal of Acquired Immune Deficiency Syndrome. October 1994; 7(10):1064-6). But it is difficult to control for covariants such as obstetrical emergencies, illness, condition of mother and type and amount of prenatal care. One study that was able to control for time of ruptured membranes (breaking of the "bag of waters") found no difference in transmission rate between C-sections and vaginal deliveries (Landesman S et al. The New England Journal of Medicine. June 20, 1996; 334(25):1617-23).
The increased risk of surgery for an immune-compromised woman must be balanced against the statistical difference in risk of transmission. A study in Italy found that HIV-positive mothers are at an increased risk of postoperative complications when delivered by C-section (Semprini A.E. et al. AIDS. August 1995, 8(9):913-7). Many obstetricians prefer antiviral drug treatment to C-sections.
Artificial rupturing of membranes should be avoided where possible. According to the Women and Infants Transmission Study (WITS), the risk of vertical transmission nearly doubles when the membranes rupture more than four hours before delivery (Landesman op. cit.). Women should be made aware of the symptoms of ruptured membranes so they can report them immediately to their health care provider. (However, having membranes ruptured for longer than four hours is not necessarily an indication for Cesarean section. Gina Brown, M.D., of Columbia Presbyterian, states that augmentation of labor may be helpful in such instances.)
Premature delivery (prior to 37 weeks) is also associated with a higher risk of vertical transmission (Greenberg BL. XI International Conference on AIDS. abstract Tu.C.2592). This finding was corroborated by a study conducted in France that found delivery prior to 34 weeks was independently associated with transmission and concluded that severe preterm labor should be prevented (L. Mandelbrot, XI International Conference on AIDS. abstract TuC.2603).
Another important consideration is whether any drug taken by the mother can cross the placenta (see the table "Drugs' Placental Passage in Humans") at sufficient levels to protect the baby. Marianne Garland, M.D., of Columbia University, presented her baboon studies on antiviral use and the fetus at the National Conference on Women and HIV held this May (abstract 204.2.). Neonatal drug levels will depend upon compartmentalization and metabolism of the drug in the fetus and placenta as well as elimination of the drug by the fetus. Dr. Garland stressed the importance of proper dosing of the mother so that the fetus would receive adequate levels of the drug.
It is thought that HIV can cross the placenta or a break in the placenta. In some cases HIV has infected the placenta but not the infant, or vice versa. For infection to take place, the viral genome needs to be replicated and inserted into the host genome of the fetus. This is where AZT and the reverse transcriptase agents are effective. They block the genome of the viral particle from being incorporated into the fetal cells. AZT has no effect on the release of the viral particles from the mother.
Although the exact mechanism of transmission is still unclear, it is known that it can be in utero (during pregnancy), intrapartum (at time of delivery) or postpartum (after delivery, by breast-feeding). The time when HIV is transmitted has a direct impact upon the types of interventions used.
HIV can infect human fetuses as early as eight weeks after conception. Interventions to prevent such transmissions are difficult. There appears to be an increased rate of spontaneous abortions when transmission occurs in the first trimester. Transmission occurring later in pregnancy is more responsive to interventions. The mother can be treated with antivirals that pass through the placenta to the fetus. Lynne Mofenson, M.D., of the NIH stated at the Women's Conference that the majority of transmission appears to occur during labor and delivery. Interventions that provide treatment directly to the baby are necessary for preventing transmission at that time.
The rationale for the protocol of ACTG 076 was to interrupt transmission at each of these stages. AZT was taken orally five times a day between 14 and 34 weeks, given intravenously during labor, and administered for six weeks to the newborn. The oral AZT was administered during pregnancy to target transmission that occurred in utero. Treatment began after the first trimester (the period during gestation of maximum organ development) so as to avoid a higher risk of birth defects. The infusion during delivery was able to cross the placenta and rapidly produce AZT levels in the baby that were viricidal. This was important because of the intense exposure to infected blood and cervico-vaginal secretions when the baby is passing through the birth canal. Oral AZT syrup was then administered to the newborn because of the possibility of microtransfusions of infected maternal blood cells into the fetal bloodstream during labor and delivery. In this way the AZT possibly switches from pre-exposure prophylaxis to postexposure prophylaxis for the baby.
The results of ACTG 076 demonstrated a 67% reduction in the risk of vertical transmission in the AZT-treated group at all levels of maternal viral load. Yet it is still unclear exactly how AZT reduced transmission (see Treatment Issues, April 1996), or indeed which components of the regimen were critical. Global studies of short-course AZT treatment are underway to answer the latter question.
Enrollment in another study on vertical transmission was stopped in March of this year. ACTG 185 looked at therapy with HIVIG (an immunoglobulin containing high levels of antibodies to HIV) versus IVIG (a standard immunoglobulin that does not contain HIV antibodies) in addition to the 076 regimen. All participants had more advanced disease than the 076 cohort and required antiviral therapy for their own health.
Researchers expected the transmission rate to be higher in such a group. Median CD4 count was 306 and 21% of the cohort had CD4 cell counts below 200. Twenty-three percent had received prior antiviral therapy, some for a prolonged period of time. Twenty-seven percent had a viral load above 50,000. Enrollment was halted when the transmission rate was found to be the same in both treatment arms, 4.8%, which made comparison impossible. This unexpectedly low rate was less than the 8% rate found in 076. Participants in ACTG 185 received AZT earlier in pregnancy by about two months, at 19.3 weeks as opposed to 11 weeks in ACTG 076.
Transmission was observed across all viral load levels including undetectable. Therefore, it did not appear that viral load was helpful in determining transmission in treated women. According to Dr. Mofenson, the 4.8% transmission rate found in this study is what is being reported now in the U.S. with the clinical implementation of the 076 regimen.
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.