Information About the Safety of Combination Antiretroviral Treatment for Human Immunodeficiency Virus Infection During Pregnancy
During the early 1990's, before perinatal preventive treatments were available, an estimated 1,000-2,000 infants were born with HIV infection each year in the United States. Today, the United States has seen dramatic reductions in mother-to-child, or perinatal, HIV transmission rates. These declines reflect the widespread implementation of Public Health Service (PHS) recommendations made in 1994 and 1995 for routinely counseling and voluntarily testing all pregnant women for HIV in the United States, and for offering zidovudine (AZT, also called ZDV) to infected women during pregnancy and delivery, and for the infant after birth. (MMWR - July 7, 1995).
Soon after, the use of combination therapy including a new class of HIV drugs known as protease inhibitors (PIs) became available. Combination treatments for people with HIV/AIDS now usually include three or four antiretroviral drugs (such as AZT, 3TC, ddI, d4T combined with PIs). (MMWR - April 24, 1998) Thus, many HIV-infected pregnant women may need to take combination therapy (including a PI) for their own health. In 1998, the PHS provided health care providers with information for discussion with HIV-infected pregnant women to make informed decisions regarding the use of antiretroviral drugs during pregnancy. (MMWR - January 30, 1998) The use of antiretroviral drugs during pregnancy requires unique considerations, including 1) the potential need to change dosing as a result of changes associated with pregnancy, 2) the potential for adverse short- or long-term effects on the fetus and newborn, and 3) the effectiveness for reducing the risk for perinatal transmission. Data to address many of these considerations were not yet available at the time those recommendations were made; most are still not available. Clinical studies that looked at the use of HIV combination treatment among pregnant HIV-infected women were already underway.
Recent Reports of Premature Births and Birth Defects
Recently, results from a few small studies showed that some HIV-infected women on combination therapy were reported to have had higher than expected rates of premature births. Other ongoing studies have not shown these results. It is not known if the premature births are due to the women's use of HIV therapy. These women may have had other risk factors for premature births or birth defects in their children. A summary of some of these studies follows; not all studies have yet been published in the medical literature.
- Phase I studies of the Pediatric AIDS Clinical Trials Group (PACTG) - Clinical trials conducted by the National Institutes of Health (NIH) identified a greater than expected number of premature births among HIV-infected pregnant women who were participating in two of three studies of PI-containing combinations of antiretroviral drugs. It is not clear if the premature births are due to maternal anti-HIV therapy, the severity of maternal HIV diseases, other risk factors for premature births, or a combination of these.
- A Swiss study of 37 pregnant women with HIV infection, 16 of whom received combination therapy including one or two PIs revealed several medical problems. Adverse reactions occurred among 21 of 37 women. The most common toxicity was anemia, which was seen among 15 (41%) of women--14 of whom were receiving AZT/3TC. At the time of the report, 10 of 30 (33%) newborns were born prematurely. The rates of prematurity did not differ between women who received combination therapy without PIs (6/17, 35%) and women who received combination therapy that included PIs (4/13, 31%). There was one report of biliary atresia, a rare birth defect.
- The Antiretroviral Pregnancy Registry - Data collected from January 1, 1989-December 31, 1997 did not show an increase in the number of birth defects with exposure to AZT in the first-trimester (1.1%) or any-trimester (3.4%) when compared with the expected percentage (rate) of birth defects in the general uninfected population. Also, there was no pattern of defects that would suggest a common cause among reported birth defects. Only very limited data are yet available on possible effects from PIs. There were no statistically significant differences in the low birth weight (<2500 grams) or gestational age (<37 weeks) among HIV-infected women receiving combination therapy with PIs versus women receiving AZT single therapy or combination therapy without PIs.
- CDC Perinatal AIDS Collaborative Transmission Studies (PACTS) - Most recent data show that seven out of 40 births (18%) were premature among women receiving PIs during pregnancy. This compares to a 17% prematurity rate among women exposed to AZT during pregnancy and a 22% prematurity rate among women who were not taking any antiretroviral therapy. Based on a fairly small number of women who received PIs during pregnancy (only 2% of the total cohort and this almost exclusively during the past year), there was no evidence of an increased risk of premature births among women taking PIs.
- The CDC Perinatal Guidelines Project - This study included 17 women who took PIs during pregnancy (while 97% of 197 women enrolled took AZT during pregnancy). Three out of these 17 women experienced premature births, but none before 36 weeks.
- A search of the medical literature revealed 81 additional reports of adverse effects of PIs in non-pregnant individuals. The reports showed that metabolic effects usually occur after an estimated 1 year on PI treatment. None of the literature specifically addressed adverse effects of PI use during pregnancy, even though it is mentioned as a risk factor for gestational diabetes, which has been associated with certain birth defects.
Perinatal Prevention Saves Lives!
Studies continue to show that perinatal HIV prevention is making a difference, both in terms of lives and resources saved:
- Between 1992 and 1996, perinatally acquired AIDS cases declined 43% in the United States. A downward trend continued into 1997.
- Among women in the CDC PACTS, AZT use increased following the publication of PHS recommendations, and the rate of perinatal transmission dropped from 21% to 11%. The PACTS study includes women from four cities -- New York City, Newark, Atlanta, and Baltimore.
- In North Carolina, perinatal HIV transmission dropped from 2l% in 1993 to 6.2% in the first half of 1996.
- Prenatal care that includes HIV counseling and testing and AZT treatment for infected mothers and their children saves lives and resources. Without intervention, a 25% perinatal transmission rate would result in the birth of an estimated 1,500 HIV-infected babies each year in the United States, with lifetime medical costs for treating an HIV-infected child of $491,936.
Where Do We Go From Here?
It is important to note that the cause of the premature births and birth defects among HIV-infected women who are on combination therapy is not known. Risks of premature births are known to be associated with multiple risk factors such as young maternal age, concurrent sexually transmitted diseases, drug use, and socioeconomic risk factors. Among HIV-infected women who have a number of these risk factors, the severity of their HIV illness is also likely to contribute to prematurity risk. Recent small studies have raised the question of whether combination therapy might be associated with this risk. Scientists are currently reviewing the combination treatment studies involving several cohorts to evaluate any maternal factors including therapy that may have contributed to the premature births. One such study is a collaboration with investigators from PACTS, NIH, CDC, and other institutions, which will consist of a meta-analysis of prematurity and combination therapy among HIV-infected women enrolled in U.S.-based cohort studies.
Until further information is known, it is recommended that HIV-infected pregnant women who are receiving combination therapy (with or without PIs) for treatment of their HIV infection should continue their regimens as recommended by their health care provider. These women should receive careful, regular monitoring of their pregnancies and for potential toxicities.
No changes have been recommended to the current treatment guidelines for pregnant women infected with HIV.
These recommendations include the use of AZT primarily for the prevention of transmission of HIV to the baby.
PHS will provide updated information on this Web Site as it becomes available over the next several months.