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Abstract

This article reviews current understanding of the management of mother-to-child transmission of HIV-1 infection in the context of developed-country settings. The advent of highly active antiretroviral therapy has facilitated the virtual elimination of mother-to-child transmission of HIV infection in developed countries, reducing transmission rates to approximately 1–2%. This review describes the epidemiology of HIV infection among women of child-bearing age and the risk factors, timing and mechanisms of mother-to-child transmission, followed by a discussion of the identification of pregnant HIV-infected women and their therapeutic and obstetric management.

Keywords

antiretroviral prophylaxis breastfeeding elective cesarean section HIV mother-to-child transmission pregnancy

This review will focus on the management of mother-to-child transmission (MTCT) of HIV-1 in developed-country settings. However, the vast majority of pediatric HIV infections acquired from mother to child take place in developing-country settings, mainly in sub-Saharan Africa, which is home to 60% of people living with HIV infection worldwide. The World Health Organization (WHO) has published extensive guidelines on the use of antiretroviral drugs for treating pregnant women and preventing MTCT in resource-constrained settings [1] and on infant feeding, together with the United Nations International Children's Emergency Fund (UNICEF) and the United Nations Programme on HIV/AIDS (UNAIDS) [2]. Although evidence from clinical trials and studies in developing countries have identified effective interventions for prevention of MTCT in such settings, implementation of these and expansion of prevention of MTCT services remains a substantial challenge [3 –6], as does prevention of HIV infection in women of childbearing age (Box 1).

Epidemiology of HIV infection among women of childbearing age

By the start of 2004, an estimated 38 million adults and children were living with HIV/AIDS, of whom 17 million were women, with 640,000 children acquiring HIV infection in 2004 alone, mostly through MTCT [7,8]. Most of these HIV infected individuals live in sub-Saharan Africa, where, in some parts of South Africa, seroprevalence among pregnant women exceeds 30% (Table 1) [8].

Table 1.

HIV statistics, end of 2003*.

	Number of women living with HIV/AIDS	As % of total adults living with HIV/AIDS
Sub-Saharan Africa	13.1 million	57%
North America	250,000	25%
Latin America	560,000	35%
Western Europe	150,000	26%
Eastern Europe and Central Asia	440,000	31%
South and South East Asia	1.8 million	29%

Adapted from [7].

Most women with HIV infection are in their prime childbearing years, with most worldwide having acquired their infection through heterosexual contact. In Western Europe, 58% of new reports of HIV infections in 2003 among men and women were acquired heterosexually, largely due to a rising number of cases among people originating from countries with generalized HIV epidemics (particularly sub-Saharan Africa) [9,10].

Identification of HIV infection in pregnant women

Interventions to prevent MTCT can only be applied if HIV-infected women are promptly identified in pregnancy. Antenatal HIV testing is therefore an integral component of strategies to prevent MTCT. National and international guidelines state that all pregnant women should not only be offered, but actively recommended, an antenatal HIV test [11,12], the benefits being not only the prevention of vertical HIV infections but also the monitoring and management of the woman's own HIV disease and health.

Universal antenatal HIV screening with an opt-in strategy, involving obtaining specific informed consent for the HIV test, tends to be the most common approach in Europe and the USA: in some settings, an opt-out antenatal screening strategy is followed, whereby all pregnant women are automatically tested for HIV along with the other antenatal tests, such as those for syphilis or hepatitis, unless they specifically decline the test. This strategy tends to result in a higher level of uptake of screening compared with opt-in strategies [13]. In the UK in 1999, national targets were adopted for the universal offer and recommendation of antenatal HIV testing, reflecting concerns that, within London, an estimated 35% of maternal HIV infections were not diagnosed until after delivery at this time, rising to 74% outside London [14]; subsequently there have been significant improvements over time in the uptake of antenatal HIV testing, with more than 80% of infected pregnant women in London in 2001 aware of their HIV status before delivery [Tookey P. Pers. Comm. 2005].

Box 1.

United Nations General Assembly Declaration of Commitment on HIV/AIDS, 2000*.

25% reduction in the percentage of pregnant women aged 15–24 years who are HIV infected by 2010

20% reduction in infant HIV infection by 2005

50% reduction in infant HIV infection by 2010

Adapted from [125]

General recommendations for antenatal HIV testing are that:

It should be voluntary (that is, women should be allowed to refuse testing)

It should be performed as early in pregnancy as possible

Retesting of women testing negative in areas of high seroprevalence or from high-risk groups may be considered to identify women acquiring infection during pregnancy

Rapid testing in labor

Rapid HIV antibody tests are now used in a variety of clinical settings, including use in labor for women who have not been tested previously, usually due to late or inadequate antenatal care. This then allows immediate provision of prophylactic antiretroviral therapy (ART) and for avoidance of breastfeeding postnatally. Initiation of zidovudine prophylaxis in labor and/or providing it as postexposure prophylaxis to the newborn very soon after birth can substantially reduce MTCT risk, and this is also the case for single-dose nevirapine, which crosses the placenta very rapidly [15,16]; use of highly active antiretroviral therapy (HAART) as postexposure prophylaxis in such situations is currently under investigation.

The Mother Infant Rapid Intervention at Delivery (MIRIAD) study [17] assessed the acceptance and feasibility of rapid HIV testing among women in labor in the USA: a total of 8% of women in the 16 US hospitals in the study were eligible for rapid testing in labor. Nearly 6000 women with undocumented HIV status were offered rapid testing in labor and 84% consented, with a very high specificity and sensitivity of the test found. The US Centers for Disease Control and Prevention now recommends routine rapid HIV testing with an opt-out approach for women with undocumented HIV status [12].

Mother-to-child transmission of HIV: risks, rates, timing & mechanisms

MTCT of HIV infection can take place in utero, during labor and delivery and postnatally through breastfeeding. Early in utero transmission appears to be rare, although a few cases have been reported [18]. Mechanisms of in utero transmission include fetal exposure to cell-free and/or cell-associated HIV in amniotic fluid and infection of the placental cells and/or disruption of the integrity of the placenta (as suggested by the increased risk of MTCT associated with chorio-amnionitis and high-density placental malarial infection [19 –21]). Intrapartum transmission may occur through direct contact between the infant passing through the birth canal and infective genital secretions and blood, through microtransfusions from maternal to fetal blood due to uterine contractions and via ascending infection from the genital tract to the amniotic fluid after rupture of membranes [22 –25]. Reported MTCT rates prior to the introduction of interventions ranged from 15–20% in Europe, 16–30% in the USA, 25–40% in Africa to 13–48% in South and South East Asia [26]. Some of these geographical differences were due to different underlying risk factor prevalences, particularly breastfeeding, while others were probably due to different methodology.

Maternal plasma HIV RNA level is the strongest individual predictor of the risk of MTCT of HIV infection [27 –29]. Women with symptomatic HIV disease, including AIDS, with primary infection during pregnancy and with severe immunodeficiency (indicated by low CD4 counts), are at increased risk of transmission [30]. Documentation of vertical transmission, even at very low plasma HIV viral loads, reflects the possibility that levels and detectability of viral load in the genital tract and in plasma are not necessarily concordant, and also highlights that other risk factors are important. Viral load in the genital tract has indeed been shown to be an independent risk factor for MTCT [25,31], and factors associated with shedding of HIV in the genital tract include plasma RNA viral load, coinfection with sexually transmitted infection and CD4 count [32,33]. Obstetric and infant factors increasing MTCT risk include vaginal delivery (see later section on obstetric management) and prolonged duration of rupture of membranes and, possibly, certain invasive obstetric procedures and prematurity [34 –41]. Various behavioral factors have been found to be associated with an increased risk of MTCT, including use of illicit drugs [42,43] and a high frequency of unprotected sex [42,44].

In 2000, the results of a clinical trial in Kenya of breastfeeding versus formula feeding confirmed earlier observational data that postnatal transmission through breast milk is a major contributor to the overall likelihood of infection in children of HIV-infected mothers [45]. In the trial, the estimated absolute rate of postnatal transmission was 16% at 24 months after delivery. Specific risk factors for breastfeeding transmission relate to mode of infant feeding, virus shedding and breast health [32,46,47]. Nonexclusive breastfeeding (which is common worldwide) is associated with a higher risk of postnatal transmission [48,49].

Therapeutic management in pregnancy

Antiretroviral drugs, which exert their effect through inhibition of viral replication, were first approved for use in adults to prevent clinical and immunologic disease progression in 1987. Since 1996, the therapeutic management of HIV has been transformed by the use of potent combinations of antiretroviral drugs or HAART: rapid uptake and widespread use of HAART in resource-rich settings have transformed HIV infection into a chronic disease, with significant improvements in AIDS-free survival and quality of life [50,51].

Women identified as HIV-infected in pregnancy should be clinically and immunologically evaluated to determine whether or not they require therapy for their own health. Decisions regarding initiation of ART in infected adults are usually based on clinical and immunologic status and, increasingly, HIV RNA viral load, although policies and practices vary within and between countries (see Information resources). The standard of care for HIV-infected individuals is for HAART: in Western Europe and other resource-rich settings such as the USA, a large proportion of HIV-infected women are already receiving HAART when they become pregnant. For example, in the European Collaborative Study, the proportion of women already receiving HAART when they become pregnant was shown to have increased from 5% in 1997 to 63% in 2000 and 85% in 2003 [52].

All women who do not need to initiate HAART for their own health should be offered antiretroviral prophylaxis for prevention of MTCT: antiretroviral prophylaxis reduces MTCT risk by decreasing viral replication and, thus, viral load in pregnant women and, for those drugs that cross the placenta, such as zidovudine, nevirapine and lamivudine [53,54], through postexposure prophylaxis of the neonate during and after exposure to the virus. In 1994, the results of the AIDS Clinical Trials Group (ACTG) 076 trial were published, showing for the first time that antiretrovirals could be used as prophylaxis to prevent MTCT (Box 2). Subsequent to the ACTG 076 trial, there have been a substantial number of other clinical trials investigating long- and short-course antiretroviral prophylaxis in breastfeeding and nonbreastfeeding populations, with a variety of different antiretroviral regimens [1]. The Pediatric AIDS Clinical Trials Group (PACTG) 316 trial (Box 2) found that, in a setting with a high use of antenatal HAART, addition of single-dose nevirapine to mother and infants did not provide any extra prophylactic effect [55]. However, it has not been possible to evaluate antenatal HAART use for the prevention of MTCT in a randomized, placebo-controlled clinical trial in developed-country settings, although data from observational studies have confirmed its substantial effectiveness [56]. For example, transmission rates of 1.2% were reported among women on HAART in both the Women and Infants Transmission Study [29] and the European Collaborative Study [52] while, in the French Perinatal Cohort, a MTCT rate of 0.7% was reported among the subgroup of women with viral loads below 1000 copies/ml [57].

Box 2.

Summary of ACTG 076 and PACTG 316 randomized placebo-controlled clinical trials†.

ACTG 076

Setting: USA and France

Intervention:

– Three-part regimen of zidovudine monotherapy

– Antenatal oral zidovudine started at between 14 and 34 weeks' gestation

– Intravenous zidovudine during labor

– Neonatal oral zidovudine for 6 weeks after delivery

Efficacy: MTCT rate of 8.3% in intervention arm versus 25.5% in the placebo arm

PACTG 316

Setting: USA, Europe and Brazil

Women received non-study ART antenatally (mainly HAART)

Intervention:

– Intrapartum: single nevirapine dose (200 mg) or placebo plus intravenous zidovudine

– Neonatal: single nevirapine dose (2 mg/kg) or placebo within 72 h of delivery plus non-study ART (usually zidovudine)

Efficacy: MTCT rate of 1.4% in nevirapine arm versus 1.6% in placebo arm

Single-dose nevirapine did not confer an additional protective effect in this population

ACTG: AIDS Clinical Trials Group; ART: Antiretroviral therapy; HAART Highly active antiretroviral therapy; MTCT: Mother-to-child transmission; PACTG: Pediatric AIDS Clinical Trial Group.

†

Adapted from [55,126].

Safety considerations

The increasing use of HAART in pregnancy, particularly during the early weeks of pregnancy when organogenesis is taking place [29,55,58], has raised many questions relating to pregnancy outcome and safety issues for the exposed children, both in the short and longer term. To date, there are insufficient safety data from studies involving pregnant women, such that all antiretroviral drugs are classified by the US Food & Drug Administration (FDA) as safety level B or C [201].

Teratogenicity

Some animal studies have suggested an increased risk of malformations associated with use of certain antiretroviral drugs [202]. CNS malformations were observed in cynomolgus monkeys with in utero exposure to efavirenz [59,202] and there have been a few case reports of neural tube defects with exposure to efavirenz in the first trimester of pregnancy [60,61,202]. It is therefore recommended that the use of this drug should be avoided in the first trimester of pregnancy, and that women of child-bearing age should be offered pregnancy testing before initiating therapy with this drug and use adequate birth control for the duration of treatment [1]. On the basis of a small number of case reports of malformations in fetuses/infants of women receiving a combination of antiretroviral therapy and Pneumocystis carinii pneumonia prophylaxis in the first trimester [62], folic acid supplementation should be recommended and the need for folate antagonists assessed for women receiving HAART [203].

Human data have shown no evidence of an increased risk of congenital malformations associated with exposure to zidovudine prophylaxis [63], but there are fewer data available with regard to first-trimester exposure to HAART. In a large European birth cohort study, the prevalence of congenital abnormalities by earliest exposure to and type of treatment regimen were investigated in nearly 2000 infants with in utero ART exposure, including approximately 600 exposed to HAART: the overall prevalence of congenital abnormalities was 1.5%, with no evident increase in any particular abnormality with the use of ART or HAART during pregnancy. Prevalence of congenital abnormalities in infants exposed to ART in the first trimester was similar to that in infants with exposures later in pregnancy, at 1.8 versus 1.4% [56].

The Antiretroviral Pregnancy Registry was established by the pharmaceutical industry in 1988 and depends on voluntary reports from clinicians of exposures to antiretroviral drugs in pregnancy and pregnancy outcomes [204]. The registry has not identified any specific teratogenic risk associated with any specific class of antiretrovirals among over 4500 exposures reported to date. Comparison of first-trimester exposures with exposures in the second and/or third trimesters has shown no significant difference in the risk of congenital abnormalities [64].

Antiretroviral toxicity

Existing safety data relating to pregnancy outcome in women taking antiretroviral therapy in pregnancy are summarized in Box 3. With regard to adverse effects among exposed children, anemia (usually mild and reversible) is the major toxicity usually associated with exposure to prophylactic zidovudine to reduce vertical transmission [63,65,66]. However, a more prolonged effect on hemopoiesis has recently been suggested. In the French Perinatal Study, ART-exposed uninfected children had small but significantly reduced levels of platelets, lymphocytes and neutrophils at 18 months compared with unexposed infants [67], while in the European Collaborative Study, children with ART exposure (mainly zidovudine monotherapy) in utero had significantly lower neutrophil counts for up to 8 years compared with unexposed children [68]. These two large European cohorts were consistent in their findings of an apparently greater effect of combination antiretroviral therapy and prolonged duration of exposure on hemopoiesis. Although these findings are of concern, it is important to note that it is uncertain whether there are, or will be, any clinical consequences of slightly reduced lymphocytes, neutrophils and platelets in childhood in this population.

Animal studies have suggested the potential for mutagenic and carcinogenic effects of zidovudine [69,70]. Zidovudine has been demonstrated to incorporate into the DNA of leukocytes in infants with in utero zidovudine exposure [71], but persistence and the clinical significance is unknown [72]. Observational studies have been reassuring regarding lack of cancers in ART-exposed children [63,73,74]. However, evidence to date does not exclude the possibility of a risk of mutagenic and carcinogenic effects at older ages.

Drugs belonging to the nucleoside reverse transcriptase inhibitor (NRTI) class are well recognized as inducing mitochondrial depletion and dysfunction. Among uninfected children exposed to NRTIs in utero or neonatally, a small number of cases of mitochondrial dysfunction have been reported in France [75,76], with additional reports of temporary hyperlactatemia among ART-exposed uninfected infants reported, which are also likely to indicate mitochondrial toxicity [77 –79]. Large observational studies in the USA have not been able to confirm an excess of deaths attributable to mitochondrial disease in uninfected, ART-exposed children [72,80]. There is a need for improved estimates of the incidence of mitochondrial dysfunction among ART-exposed uninfected children born to HIV-infected mothers, and a clearer understanding of the clinical significance and natural history of such abnormalities.

Resistance

Emergence of viral resistance to antiretroviral drugs may occur through selection for any preexisting resistant viral populations or by the development of new mutations, and occurs when viral replication is only partially suppressed; for example, with suboptimal therapy or nonadherence to drug regimens. Resistance can be detected both by genotype and phenotype assays, but clinical implementation is complex and demanding. International and national recommendations have been made relating to drug-resistance testing, including indications and quality control issues [81].

With regard to antiretroviral prophylaxis for the prevention of MTCT, current evidence suggests that the long-term impact in terms of future HAART regimens for women exposed to short-course zidovudine for the prevention of MTCT is minimal, with a low prevalence of zidovudine resistance reported [82 –84]. However, use of single-dose nevirapine is associated with high levels of usually transient maternal resistance [85,86]; the impact of such resistance on the subsequent response to ART among exposed women is under investigation; however, findings thus far indicate that use of single-dose nevirapine-boosted zidovudine prophylaxis reduces viral response to non-NRTI (NNRTI)-based ART when initiated shortly after delivery. What happens if there is a longer interval before treatment initiation requires further research [86,87].

Box 3.

Safety aspects for antiretroviral therapy-exposed pregnancies.

Metabolic complications

Glucose intolerance and gestational diabetes risk may be increased among women on highly active antiretroviral therapy (HAART), particularly in those receiving protease inhibitors, and reduced serum insulin levels have been reported in HAART-exposed newborns [104 –107]

Lactic acidosis

This is a rare but life-threatening toxicity, thought to be related to nucleoside reverse transcriptase inhibitor (NRTI)-induced mitochondrial toxicity

There have been case reports (some fatal) in pregnant women on didanosine and stavudine-containing HAART [108,109,205]

This combination of drugs should be avoided in pregnancy

Nevirapine-related hepatotoxicity

It is uncertain whether pregnancy is associated with an increased risk of hepatotoxicity over and above the increased risk associated with female gender

The degree of immunosuppression is strongly associated with the risk of hepatotoxicity [110,111]

Deaths from fulminant hepatitis in pregnant women receiving nevirapine have been reported [112,113]; other less severe adverse effects have also been reported [114,115]

Nevirapine should be used with caution for pregnant women with CD4 cell counts above 250 cells/mm³ starting prophylaxis to prevent mother-to-child transmission (MTCT)

Single-dose nevirapine has not been found to be associated with hepatotoxicity

Prematurity

Substantial and consistent evidence exists from European observational studies of an increased risk of premature delivery associated with antenatal HAART use, particularly if prolonged [58,90,116]

No such association is reported from US studies [29,91,92]

Preliminary evidence suggests an immunologic mechanism may be behind the association between pregnancy duration and HAART exposure [117]

Pre-eclampsia

There are reports of increased risk of pre-eclampsia among women receiving HAART from the UK and Spain [118,119]

Findings require confirmation in a large data set

Little is known about the impact of HIV drug resistance on vertical transmission of HIV [83], but a case report of MTCT of multi-drug-resistant HIV has been reported from the USA [88].

Obstetric management

Mode of delivery

Key findings relating to mode of delivery are summarized in Box 4. With the success of HAART in reducing maternal viral load and, thus, MTCT risk, the added benefit of elective cesarean section (CS) as an intervention among women on HAART has been questioned. However, this is difficult to assess given their low MTCT risk, as a large number of mother–child pairs are needed for a meaningful analysis, and a large meta-analysis of observational data is required. National and local policies vary regarding recommendations for mode of delivery in infected women receiving HAART without obstetric indications for elective CS (see Information resources). However, it is strongly recommended that women with detectable viral loads at delivery and those not receiving HAART (i.e., instead receiving zidovudine monotherapy as per the 076 regimen) should be advised of the effectiveness of elective caesarean section in reducing the risk of MTCT and offered this mode of delivery. Furthermore, the infected woman herself should be involved in all decision-making regarding the mode of delivery.

There is a consistent body of evidence from European studies supporting an association between antenatal HAART use and premature delivery (<37 weeks) [58,89,90]. In the most recent analysis of the European Collaborative Study, involving more than 1000 infants with in utero HAART exposure of a total of 4372 mother–child pairs, antenatal HAART use inititated pre-pregnancy or during early pregnancy was associated with a 1.88– and 2.05-times greater risk of prematurity, respectively, compared with any mono or dual therapy after adjustment for maternal CD4 count, injecting drug use, maternal age and mode of delivery [58]. However, other studies in the USA have not identified an increased prematurity risk associated with HAART use [29,91,92], which may be due to differences between the populations studied and different availability of precise data on the timing of initiation of ART [93].

Box 4.

Key findings relating to mode of delivery.

Effectiveness of elective cesarean section (CS) in reducing mother-to-child transmission (MTCT)

1994: observational evidence for protective effect of elective CS [120]

1999: results of the mode of delivery randomized trial [37] and meta-analysis [38]:

– Elective CS before labor and before rupture of membranes associated with a two-thirds reduction in MTCT risk

Highly active antiretroviral therapy (HAART) era: uncertainty regarding the additional benefit of elective CS in women with low or undetectable plasma viral loads receiving HAART [52,203,121]

Postpartum complications

CS is associated with a higher rate of postpartum complications among HIV-infected women than vaginal delivery [122,123]

HIV-infected women have an increased risk of complications compared with uninfected women regardless of mode of delivery [124]

HIV-infected women having CS deliveries should receive antibiotic prophylaxis, which may also be of benefit to women undergoing vaginal deliveries [124]

The issue of timing of elective CS in HIV-infected women is another area lacking in consensus. With the finding that shorter duration of pregnancy is associated with prolonged HAART use in pregnancy [58,94], it is now generally recommended that elective CSs be scheduled for between 37 and 38 weeks' gestation [203], although the German–Austrian guidelines recommend 36 weeks. Emergency CS, particularly if this occurs with prolonged duration of rupture of membranes, is associated with an increased risk of MTCT and postpartum complications compared with elective CS. However, avoidance of the risk of emergency CS by early scheduling of elective CS needs to be balanced by issues regarding neonatal wellbeing.

Prenatal diagnosis of chromosomal abnormalities

Prenatal diagnosis of congenital abnormalities among the HIV-infected obstetric population has become increasingly important, as infected women are becoming pregnant at increasingly older ages [95]. There is no evidence to suggest that antenatal procedures should be contingent on antenatal testing for HIV; however, as all pregnant women should be offered testing for HIV at their first antenatal visit, centers should have a clinical policy in place regarding prenatal diagnosis among HIV-infected women. An increased risk of MTCT associated with invasive diagnostic procedures such as amniocentesis were reported in the pre-HAART era [96,97]. Coll and colleagues recently reported the impact of a prenatal diagnosis program in HIV-infected pregnant women in their tertiary hospital, involving screening all women with a combined test and nuchal translucency assessment, with mid-trimester amniocentesis under the cover of HAART offered to those screening positive [98]. The screen-positive rate for chromosomal anomalies or neural tube defects was 11.2%, with ten women opting to have amniocentesis, of whom two had fetuses with chromosome abnormalities. Although there were no vertical HIV infections documented, the study was too small to evaluate whether or not amniocentesis carries an additional risk of MTCT in the HAART era. However, the study does highlight the need for obstetric health providers to have a policy for management of prenatal diagnosis in HIV-infected women.

Other obstetric management issues

Pregnant women with HIV infection are also at increased risk of other sexually transmitted and blood-borne infections and, thus, antenatal screening for such infections is recommended, although the type of infections routinely screened for varies locally and nationally as for non-HIV-infected women. On the basis of what is known regarding the epidemiology of hepatitis infections, injecting drug users should be routinely offered hepatitis C testing, while hepatitis-B testing should be offered to women from high prevalence areas, if these tests are not already universally offered antenatally. On the basis of reports of an increased risk of glucose intolerance and gestational diabetes in women receiving protease inhibitor-containing HAART (Box 3), antenatal care providers might consider screening for gestational diabetes among this group of women (particularly those on long-term HAART) if it is not already part of routine care.

An increased risk of MTCT associated with episiotomy and/or forceps/vacuum delivery was reported in the pre-HAART era [96]. In a recent analysis of the European Collaborative Study a non-statistically significant increased risk was associated with these types of delivery, but numbers were small in this subgroup [52].

Postnatal management

Neonatal prophylaxis

In line with the findings of the ACTG 076 trial, most neonates born to HIV-infected mothers receive 6 weeks of zidovudine syrup as the postnatal component of antiretroviral prophylaxis. However, policies and practices vary with regard to the type of prophylaxis given and the duration of prophylaxis, with some pediatricians routinely prescribing 4 rather than 6 weeks of zidovudine prophylaxis, while others have a policy of giving combinations of two or more drugs, usually for 4 rather than 6 weeks [94,99]. No evidence from clinical trials is available to guide clinicians regarding the optimum regimen and duration of neonatal prophylaxis for infants whose mothers received HAART during pregnancy, and clinicians may tailor the prophylaxis given on the basis of a variety of factors, including the type and duration of antenatal HAART.

With regard to postexposure prophylaxis for infants not exposed to any antiretroviral prophylaxis antenatally or intrapartum, postexposure prophylaxis with a combination of zidovudine for 1 week and single-dose nevirapine has been shown to be more effective in reducing the risk of acquisition than single-dose nevirapine alone in the NeVirApine plus Zidovudine (NVAZ) trial in an African setting [100]. On the basis of HAART being an effective approach to postexposure prophylaxis in adults [101], HAART is generally used in this situation in Europe with neonates [99]; however, there are insufficient numbers currently to properly evaluate this approach. The PACTG 1043 trial, investigating the use of HAART as postexposure prophylaxis in situations where mothers received no ART, is currently underway.

Mode of infant feeding

In developed-country settings where formula feeding is acceptable, feasible, affordable, sustainable and safe, HIV-infected women should be advised to avoid breastfeeding, as recommended in the WHO/UNICEF/UNAIDS guidelines [2]. Even among women receiving HAART, these guidelines hold true, as although HAART may result in undetectable viral loads in plasma, there is only a limited understanding of its effect on breast-milk viral load, which is known to be highly variable [102].

Diagnosis of HIV-exposed newborns

All infants born to HIV-infected mothers will be seropositive for HIV antibodies as a result of passive acquisition in utero. Diagnosis of the infant is thus dependent on identification of the virus itself, most frequently in polymerase chain reaction (PCR) tests (usually HIV DNA PCR, although HIV RNA PCR may also be used). A diagnosis of HIV infection is usually made on the basis of two positive viral assays on separate specimens and testing of peripheral blood lymphocytes at 1 day, 1 month and 3 months is effective in detecting nearly all infections. For infants with negative PCR tests, confirmation of loss of maternal antibodies should take place at 15–18 months of age. There is no clear evidence that exposure to HAART delays diagnosis in infected children.

Postnatal therapy for the mother

Therapeutic management and monitoring of HIV disease is a complex and rapidly changing field, and infected women are best managed in referral centers with specific expertise available. Multidisciplinary management of women in pregnancy, involving HIV/infectious diseases specialists, will allow continuity of care in the postnatal period.

Future perspective

Effective interventions for prevention of MTCT are now widely available in developed-country settings, with very low MTCT rates now being reported (below 1–2%), and a public health goal of elimination of vertically acquired HIV infection is now on the agenda. Widespread use of HAART has led to greatly improved AIDS-free survival and quality of life which, with the very low MTCT rates achievable, has given HIV-infected women both greater opportunity to become pregnant and also an increased desire to do so. Therefore, there is likely to be an increasing number of HIV-infected women becoming pregnant, and an increasing number of infants, although mainly uninfected (in up to 98% of cases), exposed to antiretroviral drugs in utero and in early life. Although the benefits of HAART both for prevention of progression of disease and for prevention of MTCT are enormous, reports of adverse pregnancy outcomes associated with prolonged use of antenatal HAART are of concern and highlight the need for continued monitoring and research. The potential short- and long-term impact of exposure in fetal and early life to HAART among uninfected children is a further area requiring vigilance and research, although continued long-term monitoring of such children represents a considerable challenge.

Box 5.

Summary of therapeutic management of pregnant HIV-infected women.

Monitoring of HIV disease:

Follow-up every 4 weeks, with more intensive monitoring if woman is severely immunosuppressed or has clinical disease

Quantification of CD4 cell count and plasma RNA viral load at least every trimester and before delivery

HIV RNA viral load should be measured after initiating or changing antiretroviral regimen (approximately 2 weeks later)

Antiretroviral therapy:

All HIV-infected women should be offered antiretroviral therapy (ART) to prevent mother-to-child transmission (MTCT) and for their own disease progression if required on the basis of maternal clinical status, CD4 cell count and plasma HIV RNA levels

When a woman becomes pregnant while receiving ART, it is generally recommended to continue with the same therapy

ART should be continued as normal right up to the time of delivery

Pregnancy management:

A multidisciplinary approach is best

Psychosocial support, including support with antiretroviral treatment adherence, is recommended

Pediatric HIV infections continue to occur in those parts of the world where interventions are widely available [52,103]. This may be due to a variety of factors, including inadequate or late access to antenatal care, inadequate public health system infrastructure, late or nonidentification of HIV infection in pregnant women, suboptimal application of prevention of MTCT interventions and poor uptake of and/or adherence to prevention of MTCT interventions. Recent advances in rapid HIV testing and postexposure prophylaxis may result in at least some vertical infections being prevented from women with no or limited antenatal care; however, this should not be seen as an alternative to improving antenatal HIV screening programs. Research is needed regarding the processes involved in implementation of prevention of MTCT policies to clarify the barriers to successful implementation and identify potential solutions.

Questions remain regarding the optimum approach to management of pregnancy in HIV-infected women in developed-country settings, including the additional benefit of elective CS for women receiving HAART with undetectable plasma viral loads; however, these are difficult to answer when MTCT rates are so low and cannot be addressed by clinical trials. It is uncertain how MTCT rates will be affected by trends in the epidemic and in clinical management in developed-country settings, for example, the increasing number of heavily pretreated women becoming pregnant and the increases in prevalence of primary drug resistance. Continued monitoring of rates and risk factors for MTCT in the HAART era will therefore be essential.

A summary of therapeutic management of pregnant HIV-infected women can be found in Box 5.

Information resources

All accessed October 2005.

German/Austrian: Robert Koch Institute

www.rki.de/infekt/aids_std/az_en/preg0305.htm

World Health Organization: monthly surveys of prevention of MTCT publications and abstracts

www.who.int/reproductivehealth/rtis/mtct/monthly_publications/listing_mtct_reports.htm

World Health Organization: antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. Guidelines on care, treatment and support for women living with HIV/AIDS and their children in resource-constrained settings.

www.who.int/reproductive-health/rtis/docs/arvdrugsguidelines.pdf

Women, Children and HIV: general information and research updates

www.womenchildrenHIV.org

Executive summary

Epidemiology of HIV infection among women of childbearing age

By the beginning of 2004, an estimated 38 million adults and children were living with HIV/AIDS, 17 million of whom were women.

A total of 640,000 children acquired HIV infection in 2004 alone, mostly through mother-to-child transmission (MTCT).

Identification of HIV infection in pregnant women

Universal antenatal testing is an integral component of prevention of MTCT strategies.

Opt-out strategies tend to have higher uptake levels than opt-in strategies.

Antenatal HIV testing should be voluntary and carried out as early in pregnancy as possible.

MTCT of HIV: risks, rates, timing & mechanisms

MTCT can take place in utero, intrapartum and postnatally through breastfeeding.

Maternal plasma HIV RNA level is the strongest individual predictor of MTCT risk.

Other risk factors include symptomatic HIV disease, low CD4 counts and obstetric and infant factors such as prolonged duration of rupture of membranes and prematurity.

Therapeutic management in pregnancy

Highly active antiretroviral therapy (HAART) is now the standard of care for HIV-infected individuals with clinical and immunologic indications for treatment.

HIV-infected pregnant women, if not already receiving HAART, should be evaluated to determine whether they need therapy for their own health.

All pregnant HIV-infected women who do not need to initiate HAART for their own health should be offered antiretroviral prophylaxis to prevent MTCT (which is likely to be HAART, but may also be zidovudine monotherapy in some cases).

MTCT rates below 1–2% have been reported from observational studies among women receiving HAART.

Human data have shown no evidence of increased risk of congenital abnormalities associated with in utero antiretroviral exposure, including HAART.

Adverse pregnancy outcomes reported to be associated with HAART include prematurity, gestational diabetes, lactic acidosis and preeclampsia.

Nevirapine should be used with caution in pregnant women with CD4 counts above 250 cells/mm³ starting antiretroviral therapy (ART) in pregnancy.

There are concerns that such in utero ART exposure may have adverse effects in the medium to long term on uninfected children, including immunologic, hematologic and mitochondrial functioning and potential genotoxicity.

Obstetric management

Elective cesarean section is an effective intervention to prevent MTCT.

However, the additional benefit of elective cesarean section among women with undetectable viral loads receiving HAART is uncertain.

Women should be involved in decision-making regarding mode of delivery.

Obstetric providers should have a policy for management of prenatal diagnosis in HIV-infected women, particularly as this population is becoming pregnant at increasingly older ages.

Postnatal management

Neonatal prophylaxis is an important component of a prevention of MTCT strategy.

Policies and practices vary with regard to type and duration of prophylaxis.

Postexposure prophylaxis with HAART for infants whose mothers received no ART in pregnancy may be used on the basis of this approach being effective in adults.

Formula feeding should be strongly recommended for all infected women in developed-country settings.

References

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

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Managing Mother-to-Child Transmission of HIV Infection in Developed-Country Settings

Abstract

Keywords

Epidemiology of HIV infection among women of childbearing age

Identification of HIV infection in pregnant women

Rapid testing in labor

Mother-to-child transmission of HIV: risks, rates, timing & mechanisms

Therapeutic management in pregnancy

Safety considerations

Teratogenicity

Antiretroviral toxicity

Resistance

Obstetric management

Mode of delivery

Prenatal diagnosis of chromosomal abnormalities

Other obstetric management issues

Postnatal management

Neonatal prophylaxis

Mode of infant feeding

Diagnosis of HIV-exposed newborns

Postnatal therapy for the mother

Future perspective

Information resources

References