Protecting Mothers and Children

"Mothers are keen to know how to prevent their babies from becoming infected,” says Poloko Kebaabetswe, health educator and co-director of the Botswana–Harvard Partnership for HIV Research and Education, a collaborative research and training initiative involving the Harvard AIDS Institute and the Botswana Ministry of Health. “They want their children to have a chance to survive.”

The problem of mother-to-infant, or perinatal, transmission is central to the HIV crisis in developing countries—particularly in sub–Saharan Africa, which is home to four out of five women with HIV, most of them of child-bearing age. While the incidence of perinatal infections in the United States and other developed countries has declined in the past few years—attributable in large part to the widespread use of zidovudine (ZDV) among pregnant women—developing countries have not been as fortunate.

Work to decrease transmission rates internationally, and sustain their downward move in the United States, falls into three fundamental areas: primary prevention, medical intervention, and changes in cultural and behavioral issues, such as breastfeeding and social stigmatization.

Worldwide, almost two and a half million women are newly infected with HIV each year. Many of these women subsequently transmit the virus to their infants during pregnancy, during labor and delivery, or through breastfeeding. “We know that the vast majority of these infections can be avoided with low-cost treatments,” says Richard Marlink, executive director of the Harvard AIDS Institute. “The fact that these easily preventable infections continue to occur is one of the worst tragedies of the HIV epidemic.” Each year, more than 600,000 infants are born HIV infected.

Preventing Infection in Women
HIV transmission from mother to child can be best avoided by first preventing infection of women. “We’re working on the end of the equation—perinatal transmission. But it would all be unnecessary if we addressed the first part—primary prevention,” says Art Ammann, president of Global Strategies for HIV Prevention and clinical professor of pediatric immunology at the University of California San Francisco.

Perinatal transmission can be reduced by providing women with education about HIV and pregnancy, voluntary HIV counseling and testing, free or low-cost prenatal care, and access to anti-HIV drugs during pregnancy. Encouraging mothers with HIV not to breastfeed and providing feasible feeding alternatives can also help to reduce mother-to-infant transmission of HIV.

“A lot of education is necessary,” says Kebaabetswe of her efforts to get mothers, and communities, to participate in and support perinatal transmission prevention programs. “I go to churches. I talk to key people in communities, such as chiefs and councilors, and to mothers in clinics. It’s the only way these programs will succeed.”

While information about pregnancy and HIV is widely available in developed countries, women in resource-scarce countries are not as well informed about the dangers of perinatal transmission. “We’re finding in some towns that women still don’t have a good understanding of what HIV is. They don’t know how they were infected, or how they might infect their babies,” says Geeta Rao Gupta, president of the International Center for Research on Women in Washington, DC.

Voluntary counseling and testing for HIV is crucial to the successful implementation of transmission prevention programs. More than 90 percent of women living with HIV in developing countries do not know they are infected. People who can provide testing and counseling services are generally not available or are not adequately prepared.

“Women living in many cities in Africa suffer great damage [from family and friends] after finding out they are HIV positive,” says Catherine Hankins, associate professor in the departments of epidemiology, biostatistics, and occupational health at Montreal’s McGill University and associate director of the McGill AIDS Centre. “Most women feel it is much better for them not to know their HIV status.”

Says Kebaabetswe, “It is critical that people be trained to serve as counselors. Women need to know what it means to be tested for HIV, what it means if the results are positive or negative, what the implications of this action are to their lives, even before their test. It is important that women who must face the decision [to test] and the consequences know where their sources of strength are.”

Even in the United States, where voluntary HIV testing and counseling is widely available, many women first find out they are HIV positive during prenatal screening or once their child is born and tests positive for HIV. This is especially true for women in groups at high risk for HIV infection—injection drug users, urban dwellers, and minority populations.

Treatment Protocols
Treatment to prevent mother-to-child transmission of HIV is a complicated issue, not only because of the feasibility of implementing adequate treatment regimens in developing countries, but because research is ongoing and protocols change quickly. There currently are three basic protocols for prevention of perinatal transmission: the 076 protocol, in which ZDV is administered; the Thailand protocol, in which ZDV is administered for a shorter period than called for in the 076 protocol; and the nevirapine regimen, in which nevirapine, not ZDV, is administered.

The 076 protocol is the result of a 1994 clinical trial, the AIDS Clinical Trials Group 076, that was conducted in the United States to test the effectiveness of ZDV as a preventive to perinatal transmission. The trial called for HIV-infected pregnant women to receive ZDV five times daily during the last six weeks of their pregnancies and during their deliveries. Following delivery, treatment shifted to the infants who received ZDV for six weeks. In addition to this medical management, the babies were fed formula; breast-feeding was strictly avoided. Incidence of perinatal transmission was reduced threefold among infants in this study, from 26 percent to 8 percent. Only a few months after these results were obtained, the U.S. Public Health Service published guidelines recommending the use of ZDV for all pregnant women infected with HIV.

In developed countries, the results of implementing the 076 protocol have been impressive. In 1995, for example, 1,800 new HIV infections were reported among infants in the United States. By 1999, there were fewer than 300 HIV-infected infants born in this nation. In the United States and other developed nations that implement the protocol, incidence of perinatal transmission often remains at 5 percent or less.

Controlled studies on ZDV conducted after the 076 trial reinforce the drug’s utility as an agent that prevents transmission. “As a monoprophylaxis [single drug treatment],” says Kenneth McIntosh, professor of pediatrics at Harvard Medical School and in the Harvard School of Public Health Department of Immunology and Infectious Diseases, “no other drug is as good as ZDV. It offers maximum benefit with a minimum of risk to mother and infant.”

Although the 076 protocol is extremely effective, it is also expensive (as high as $1,000 per treatment regimen) and requires lengthy monitoring and treatment for women and their infants. In 1998, in an effort to determine whether a shorter (and, at $50, less expensive) regimen of ZDV would be equally effective at dropping transmission rates, a controlled study was conducted in Thailand. Pregnant women in the study received ZDV only twice a day during the final four weeks of their pregnancy and during their labor. The women were provided safe alternatives to breast milk and did not breastfeed. When rates of transmission among infants in the control group were compared with those for infants whose mothers were given ZDV, researchers found a 51 percent reduction in incidence.

This halving of transmission was a welcome result, especially when variables such as cost and ease of administration were factored in. Yet, many proponents of ZDV who compare these results (halving of transmission rates) with those realized from studies of full course of ZDV (threefold reduction) are not quite sure if the savings are worth the cost—a greater number of infants who will become infected.

“The short ZDV course is clearly not as effective,” says McIntosh. “For ZDV as a single drug, the long course remains the best for preventing transmission.”

In tandem with these studies are those investigating the efficacy, and practicality, of the drug, nevirapine. Using this drug in a study involving pregnant HIV-infected women in Uganda, Laura Guay, an assistant professor of pathology and pediatrics at Johns Hopkins University School of Medicine in Baltimore, and colleagues achieved a 48 percent reduction in perinatal transmission rates, while holding the drug treatment costs to a mere $4.

“In the developing world,” says Guay, “nevirapine is a better option than ZDV. It is inexpensive, simple to administer, and does not demand use of high-cost resources such as hospitals.”

The controlled study pivotal to Guay’s statement was conducted from 1997 to 1999. In it, pregnant women gave themselves one dose of nevirapine at the onset of labor. Their infants received a single dose of the drug within three days of their birth. Trial results for the nevirapine group showed a transmission rate of 8.2 percent among the infants at birth, 13.1 percent after the infants were fourteen weeks old. This compared favorably with percentages achieved in a similar group of infants whose mothers received ZDV at the onset of labor. Their transmission rates were 10.4 percent and 25.1 percent, respectively. Unlike most studies involving ZDV, the nevirapine trial achieved its results among infants who were breastfed.

The Question of Breastfeeding
Whether HIV-infected mothers who participate in ZDV trials should refrain from breastfeeding their infants is a hotly debated issue in much of the developing world. Uninfected infants who are breastfed by HIV-infected mothers are at substantial risk for becoming infected. Bottle-feeding or use of breast milk substitutes may prevent infection in 10 percent of perinatally exposed children, if implemented safely. But safe implementation can be challenging when tradition and physical circumstances are considered.

Breastfeeding has long been described as the safest and healthiest choice for both infants and mothers. For an infant, breastfeeding has nutritional and psychological benefits and can confer immunity to many diseases and infections. For a mother, breastfeeding is convenient; can affect her ability to conceive, effectively lengthening the periods between conceptions; and can protect her against ovarian and breast cancers. Bottle-feeding, in contrast, demands the mother use expensive, hard-to-find formula. In addition, she must make sure the water she uses to mix the formula is clean and safe, a difficult task in many developing countries.
In countries where breastfeeding is the norm, bottle-feeding is often a red flag on a woman’s HIV status. “Breastfeeding is not just a medical issue, it is a social issue as well,” says Gupta. “We need to think about what we are doing to an HIV-positive mother. We have to help her return to her community, help her family and neighbors understand, help ease the stigma for her.”

photo: Human Issues Collaborative

In Botswana, the Harvard AIDS Institute is working in partnership with that country’s government to determine more precisely the role breastfeeding has in transmission, and how drug treatment may modify that role. Throughout the next three years, the Botswana–Harvard Partnership for HIV Research and Education will treat 1,500 pregnant HIV-infected women using several drug regimens. The women will begin treatment at 34 weeks using ZDV. Some of the women will also be given nevirapine at birth to see if the two drugs have an additive effect. At birth, some of the infants will receive a prophylactic regimen of ZDV syrup for six months; other infants will be bottle-fed formula. The results of this study should help researchers decide whether strict avoidance of breastfeeding is necessary if infants, and mothers, receive medication to stem transmission.

“We need to know if we can say okay to breastfeeding and still protect the babies,” says Kebaabetswe. “It is hoped the research will provide guidelines on the safety of breastfeeding while a baby is on ZDV.”

The Role of Fathers
Preventing perinatal transmission by necessity focuses on mothers and infants. Yet the ramifications of the work go far beyond these two groups. “It’s interesting that all the arguments have been about mother-child transmission and not parent-child,” says Hankins. “We’ve ignored the role of the father.” Studies have shown that providing HIV counseling and testing to both members of a couple at the same time can lead to greater acceptance and less abuse and abandonment of the HIV-infected woman. Only a few African countries do offer couple counseling and testing, mostly as part of research studies.

“If we saw this as an issue for both parents, routinely offered HIV testing and counseling to couples at the same time, and discussed treatment decisions during pregnancy with both parents,” says Hankins, “we might be doing a lot better at reducing perinatal transmission.”

“People often ask why we are focusing on babies,” says Ammann. “But perinatal transmission can be the wedge that opens up discussions on other health care issues. Perinatal transmission is loaded with all kinds of other issues such as confidentiality, women’s inequality, stigma, inheritance laws, orphans, mothers, primary prevention. Hopefully, starting with perinatal transmission will trigger these other questions that need to be addressed.”

—Pamela DeCarlo is communications specialist at the Center for AIDS Prevention Studies, University of California San Francisco; Ann Menting is associate editor of the Harvard AIDS Review.