Pregnancy and HIV infection: A european consensus on management

The number of adults becoming infected in Europe continues to increase, with heterosexual contact accounting for a growing proportion of cases in Western Europe. There is particular concern for the increasing numbers of infected people reported from Eastern Europe, where the current infrastructure may be unable to cope with a rapidly evolving epidemic. HIV infection and transmission thus remains an important issue in Europe. The risk of mother-to-child transmission of HIV infection can be substantially reduced from 15-20% without interventions to less than 2% with the use of antiretroviral therapy during pregnancy, during labour and in the neonatal period, with an elective caesarean section delivery and refraining from breastfeeding. Potent and effective antiretroviral therapy [highly active antiretroviral therapy (HAART)] to delay progression of disease in HIV-infected adults has become the standard of care, and is usually applied before serious disease has developed. There is anecdotal evidence to suggest that HIV-infected women may now positively choose to become pregnant and that those who do become pregnant are less likely to have this pregnancy terminated, because their own disease is well managed and interventions to reduce the risk of vertical transmission are available. Given the current situation in Europe, where the vast majority of paediatric HIV infections acquired from mother to child are preventable, the standard of care should be that all pregnant women, and even those planning a pregnancy, are not only offered, but recommended to have, an HIV test. Furthermore, a test should also be offered to their sexual partners. If a woman is treated with antiretroviral drugs before becoming pregnant, a second trimester fetal anomaly scan may be reassuring. There are no data to suggest that these drugs are associated with an increased risk of teratogenicity, with the exception of efavirenz, zalcitabine and hydroxyurea, which are contraindicated during pregnancy. An elective caesarean section delivery substantially reduces the risk of mother-to-child HIV transmission, with an independent effect on vertical transmission even in women with a low viral load and in those on effective antiretroviral therapy. HIV-infected women should therefore be given the option of delivering their child through a caesarean section performed before labour and before rupture of membranes. Advantages and disadvantages of this option should be discussed. All HIV-infected women should be offered therapy during pregnancy, taking into account that it involves two different people; the infected pregnant woman and her infant, who is usually not infected. The choice of therapy and timing of initiation will depend on the clinical status of the woman and has to balance delaying disease progression and prevention of vertical transmission. The decision should be based on the woman's treatment history, clinical status and the available prognostic markers, CD4 lymphocyte counts and plasma HIV-RNA levels. These markers are related to the likelihood of disease progression in the mother and also to the risk of vertical HIV transmission. For the prevention of mother-to-child transmission, zidovudine (ZDV) monotherapy remains the standard prophylaxis. Data from the 076 trial and observational studies indicate that selection of ZDV-resistant virus rarely occurs with the 3- to 6-month regimen used in pregnancy. Some clinicians suggest the use of HAART for all women to reduce the risk of vertical transmission, but there is no evidence to substantiate this suggestion and the issue remains controversial. Although the objective of achieving the lowest possible viral load in pregnancy may be appealing, even with maternal plasma HIV-RNA levels above 1000 copies/ml, more than 95% of infants will be uninfected with ZDV prophylaxis alone. Early in utero transmission appears to be rare, although a few cases have been reported. Therefore, the impact of prophylaxis can be expected to be greatest in the third trimester and around delivery. There are also arguments for not starting therapy too early in pregnancy to avoid exposure of the fetus at early stages of development and because partial suppression of viral replication may lead to the emergence of drug-resistant strains over a longer period of time. This is of particular concern with monotherapy or double combinations. Deferring antiretroviral prophylaxis until late-second trimester may be considered, unless there is an increased risk of preterm delivery, such as with recurrent genital tract infections, cervical incompetence, uterine malformations, or twin pregnancy. In these cases, antiretroviral therapy should be introduced mid-second trimester. When a woman becomes pregnant while receiving therapy, it is generally recommended to continue the same therapy. HAART should never be replaced by suboptimal combinations. Concerns about teratogenicity may lead to consider temporary, but complete, discontinuation of HAART during the first trimester. The risks and benefits of this approach are not known, and the decision should only be taken after a discussion between the pregnant women and the treating expert physician. ZDV should be included in all antiretroviral regimens during pregnancy. However, many women with prior therapy have already received ZDV in the past and switched to HAART without ZDV. In these cases, and where there was an informed decision to move away from ZDV, the current HAART should be continued. For women who need treatment for their own health, HAART should be initiated after the first trimester, and should include ZDV. If there is a risk of preterm delivery, HAART should be started soon after the first trimester, and earlier than mid-second trimester. Women who do not require antiretroviral therapy for their own health should be started on the three-part ZDV regimen in the beginning of the third trimester, at 28-32 weeks, with an elective caesarean section at 38 weeks. Again, an earlier start is recommended for women at risk of preterm labour. If a caesarean section is not an option, ZDV + lamivudine (3TC) may be considered. The addition of a two-dose nevirapine (NVP) regimen to the three-part ZDV regimen once labour is established should, in theory, reduce the risk of transmission. Women not requiring antiretroviral therapy for their own health but with HIV-RNA > 10000 copies should be offered HAART, including ZDV, starting after the first trimester. Women presenting in late pregnancy without therapy should be started on a three-part ZDV regimen (including 1 week post-partum) as soon as possible. Although the addition of the two-dose peri-partum NVP regimen is likely to reduce transmission, triple combination therapy of ZDV, 3TC and NVP may be a better approach to keep future options for the mother open. Antiretroviral therapy should be continued as per normal right until the time of delivery, including the morning dose of the day of the scheduled caesarean section delivery. Regardless of the maternal antenatal antiretroviral regimen, ZDV is recommended intravenously during the intrapartum period and orally for the newborn for 4-6 weeks. If stavudine (D4T) is part of the ongoing regimen in the mother, this should be interrupted for the duration of the delivery, as D4T and ZDV are antagonists. Women who received previous prophylactic ZDV may or may not have an indication for therapy for their own health at present. If the only indication is again prophylactic, the 076 trial regimen remains the standard of care. If ZDV drug-resistant virus is present, a decreased antiretroviral efficacy is to be expected. In these cases, HAART or a combined nucleoside reverse transcriptase inhibitor (NRTI) regimen without ZDV may be advisable. For infants born to mothers receiving ZDV monotherapy or ZDV-containing combination therapy in pregnancy, treatment with ZDV should be started as soon as possible after delivery, regardless of maternal viral load. In very premature infants, intravenous ZDV is the only available choice. Adding NVP to ZDV neonatally is not recommended, as there is no evidence of additional effect. For infants born to mothers receiving antiretroviral therapy not including ZDV in pregnancy, ZDV may still be the option for the infant, but the reasons why the mother is not taking ZDV need consideration. If the mother has documented resistance to ZDV, the infant should receive one of the NRTI from the maternal regimen. If the mother uses D4T and is not resistant to ZDV, one dose of D4T should be omitted near the time of delivery (as D4T cannot be taken simultaneously with ZDV), intravenous ZDV should be administered during delivery, and ZDV given to the neonate. After delivery, maternal D4T could be resumed. For infants born to mothers who did not receive any therapy during pregnancy, one dose of NVP to the mother during labour plus one dose to the infant at 48-72 h could be combined with 6 weeks of ZDV. Alternatively, HAART as a post-exposure prophylaxis (ZDV + 3TC + NVP) for 6 weeks has been suggested on a theoretical basis, although currently there are no data available to substantiate this recommendation. If infants identified some time after delivery as being at risk of vertical transmission are breastfed, the mother should be advised to cease breastfeeding immediately to avoid further transmission risk. Although the window of opportunity is small relative to the duration of exposure, consideration could be given to initiating treatment immediately. If treatment is given in such circumstances, it is recommended to be HAART. Pneumocystis carinii pneumonia prophylaxis should be initiated immediately and continued until the child has been confirmed not to be infected.