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Institute of Child Health
University College London
By January 2004, an estimated 38 million people were living with HIV/AIDS worldwide; 17 million of these were women, of whom 150,000 were living in western Europe.(1) During 2003, 630,000 children acquired infection, largely through mother-to-child transmission (MTCT), mostly in those parts of the world where the HIV epidemic has become generalised (mainly sub-Saharan Africa).
HIV-1 is an RNA virus targeting the cell-associated immune system, particularly CD4 cells. Risk of opportunistic infections and other serious clinical symptoms becomes great once immunodeficiency is established; AIDS is diagnosed according to specific clinical and immunological criteria.(2) Without antiretroviral therapy (ART), the median time to
AIDS is about 10 years and time from AIDS to death around two years.(3)
Use of highly active antiretroviral therapy (HAART) substantially delays disease progression, and HIV infection has now become a chronic infection in developed countries.(4,5) MTCT can occur during pregnancy, around the time of delivery or postnatally through breastfeeding. Without prophylactic interventions, including avoidance of breastfeeding, MTCT rates range from 15 to 40%.(6–9) Maternal plasma HIV RNA level is the best individual predictor of MTCT risk, and other factors increasing risk include AIDS, primary infection, vaginal delivery, low CD4 count and prematurity.(10,11) Breastfeeding is associated with an approximate doubling of overall MTCT risk, the risk remaining as long as breastfeeding continues.(12)
Antiretroviral prophylaxis reduces MTCT risk by decreasing viral replication, and thus viral load, in the pregnant woman and, for drugs which cross the placenta (such as zidovudine, nevirapine and lamivudine(13,14)), through postexposure prophylaxis of the neonate during and after exposure to the virus.
Table 1 highlights trends in strategies for prevention of MTCT in Europe. Although outside the scope of this review, a large number of trials have been performed in less developed countries (see Resources for further details).(15)
As Table 1 illustrates, HAART use has led to substantial declines in MTCT rates to below 2%. In the European Collaborative Study, antenatal HAART use is independently associated with around 85% reduced risk of MTCT.(16) Despite the undoubted effectiveness of HAART in prevention of MTCT, there remain few safety data from studies involving pregnant women, with all antiretroviral drugs having either a B or C FDA safety classification. Table 2 summarises the existing safety data relating to pregnancy outcome in women taking antiretroviral therapy in pregnancy.
Antenatal HAART use, particularly in the early weeks of pregnancy when organogenesis is taking place, has also raised questions relating to the safety of the exposed children, nearly all of whom are uninfected, both in the short and long term (see Table 3). A further issue needing consideration with regard to ART and prevention of MTCT relates to drug resistance. Little is known about the impact of HIV drug resistance on MTCT,(17) although there has been a case report of MTCT of multidrug-resistant HIV.(18) Use of single-dose nevirapine is associated with high levels of usually transient maternal resistance,(19,20) but the impact of this on subsequent response to ART among exposed women remains unclear.(15,20)
Increasing numbers of HIV-infected pregnant women are now taking HAART throughout pregnancy. With MTCT rates of around 1–2% in women on HAART, the vast majority of their infants will be uninfected, even though exposed to ART in utero and in early neonatal life. Continued monitoring of these children for potential adverse events is very important, but a considerable challenge, particularly as these are likely to be rare and may occur later in childhood.