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• W2051464900 abstract "Introduction Mother-to-child (vertical) transmission of HIV-1 can occur before, during or after birth, although the relative contribution of each of these routes remains poorly quantified [1–4]. There is clinical and laboratory evidence to support several possible mechanisms for infection, including maternal disease state and viral load, fetal exposure to infected maternal body fluids during gestation and delivery, and breastfeeding [3,5–14]. Knowledge about the timing of mother-to-child transmission of HIV is sought in order to determine the period of greatest risk for the infant, as this would suggest approaches to help prevent HIV infection and suggest the optimum time of their initiation. If infection occurs mainly during early gestation, interruption of transmission may be difficult, whereas intervention may be more feasible if transmission occurs mainly during late gestation or at the time of delivery. If transmission at the time of delivery occurs through exposure of the fetus to infected maternal secretions, Caesarean section delivery or reduction of viral load in the birth canal would be beneficial. On the other hand, if transmission at the time of delivery occurs through maternal–fetal transfusion during labour, prophylactic antiretroviral treatment of the infant would be appropriate. Knowledge about postnatal transmission through breastfeeding would inform guidelines regarding infant feeding practices [15]. Intrauterine transmission Although there is evidence to suggest that HIV can infect the placenta at all stages of pregnancy, and infected placental cells may be passed to the fetus during the birth [16,17], the relevance of HIV transmission to the fetus is unclear. When the amniotic sac is intact, transmission may occur through placental tears with transfusion of infected blood into the fetal circulation either through transplacental cellular traffic (which may be important towards the end of pregnancy) or by progressive infection of different placental layers until the virus reaches the fetoplacental circulation. Some placental cells, such as Hofbauer and possibly trophoblast cells, appear to express CD4, and in vitro infection of both cell types has been reported [18]. The cellular composition of the placenta changes with gestation, and the risk of placental infection could vary over pregnancy. Placental disruption, by for example, chorioamnionitis, or through cigarette smoking and illicit drug use, has been associated with increased transmission risk [14,19–21]. Evidence to support intrauterine transmission includes case reports of detection of virus in fetal material from as early as 12 weeks' gestation [22–24], the intrauterine onset of symptomatic HIV disease [25], and the identification of HIV in amniotic fluid [26]. Additionally, the findings that a proportion of HIV-infected children tested during the first few days of life have detectable virus in their blood [27–29] and the rapid progression of disease in some infected infants [30–34] also suggest intrauterine transmission. However, in a carefully conducted French study of tissue from 100 first and second trimester fetuses, only two thymuses showed evidence of HIV infection [24]. A similar lack of virological evidence of intrauterine infection was reported from Sweden and elsewhere [16,35], and on balance it appears that early in utero infection is rare, and is thought to be more common towards the end of pregnancy. Intrapartum transmission Transmission during labour and delivery could occur via direct contact of the fetus/infant with infectious maternal blood and genital secretions during passage through the birth canal, through ascending infection from the vagina or cervix to the fetal membranes and amniotic fluid, and through absorption in the fetal-neonatal digestive tract [36]. Alternatively, during uterine contractions in labour, maternal–fetal micro–transfusion may occur. It is therefore important to determine the dominant mode of transmission of paediatric infection with regard to intervention approaches: elective Caesarean section delivery would be appropriate to avoid exposure in the birth canal, although prophylaxis of the fetus/infant with antiretrovirals would be the intervention of choice to prevent infection through microtransfusions. HIV-1 has been cultured from cell-free and cellular fractions of vaginal and endocervical secretions of HIV-1-infected women [37], and HIV-1-infected cells have been found in female genital tract secretions by polymerase chain reaction amplification [38–40]. Henin et al. [41] showed that excretion of HIV was significantly higher in pregnant than in non-pregnant women. The presence of HIV in cervicovaginal secretions [42] may be a risk factor for perinatal transmission. However, in a trial in Malawi [43] on the use of cleansing of the birth canal with chlorhexidine, cleansing had no significant impact on HIV transmission rates, except when membranes were ruptured for more than 4 h before delivery. It is unknown whether the effect of genital virus shedding on vertical transmission is distinct from the effect of plasma viraemia on transmission, and the association between plasma viraemia levels and viral load in the birth canal remains to be established. It has been suggested that the reduction of the rate of vertical transmission associated with the use of zidovudine in pregnancy and at the time of delivery may be primarily due to a prophylactic effect in the newborn, rather than to the decrease of maternal viral load [3]. The occurrence of intrapartum transmission is supported by various strands of indirect evidence, including the finding that more than 50% of HIV-infected infants have negative virological tests in the first few days of life [27–29], that there is a rapid increase in the rate of viral detection in the first week of life [28], and that some neonates show virological and immunological patterns similar to those of adults with primary infection [34,44]. Further supporting evidence comes from studies showing a relationship between mode of, and circumstances during, delivery and risk of vertical transmission [2,4,6–8]. A meta-analysis of data from 11 prospective studies showed only a 20% reduction in the risk of vertical transmission after operative delivery, but no allowance was made for emergency versus elective Caesarean section or for any other variables known to be associated with vertical transmission. This meta-analysis is currently being updated using data from 15 perinatal cohort studies in Europe and the United States, and is likely to confirm the reduction in vertical transmission rate associated with elective caesarean section (J. Read, personal communication, 1997). Long labour and prolonged membrane rupture may increase the risk of transmission [2,7,8], although this has not been found in all studies. In the French perinatal cohort, haemorrhage during labour and the presence of bloody amniotic fluid substantially increased the risk of vertical transmission [2], and in one small study, bloody neonatal gastric aspirate was associated with infection in the infant [36]. Prepartum and intrapartum bleeding may expose the fetus to maternal blood, but could also be associated with placental disruption and transplacental transmission. Evidence to date suggests a lack of association between transmission and management of labour and delivery [2,4]. Breastfeeding It is unclear whether infection takes place through cell-free HIV in breastmilk or through HIV-infected cells. Cell-free virus could penetrate the mucosal lining of the gastrointestinal tract of infants by infecting cells, or by direct entry into the bloodstream via mucosal breaches. If HIV infection only occurs through cell-associated virus, then colostral milk may be more infectious because of its high cellular content, although the other components of colostrum may have a protective effect. It is unclear whether damage to the intestinal tract of the infant, caused by the early introduction of other foods, could increase its permeability and thus result in increased rates of infection for the infant [45]. The immature gastrointestinal tract of the newborn may facilitate transmission, although transmission has been reported in infants who begin breastfeeding outside the neonatal period [46]. Transmission of HIV through breastmilk can occur in situations where the mother was HIV-infected shortly after delivery, but also in established maternal infection. Based on a meta-analysis of limited evidence, it has been estimated that the additional risk of infection through breastfeeding is between 7 and 22%, and in observational studies from South Africa, Brazil and Europe breastfeeding doubled the overall vertical transmission rate [1,5,13,45,47]. Transmission may be less related to the amount of exposure and more to the time of exposure, infectivity of milk or specific susceptibility of the infant. It has been suggested that the risk of vertical transmission may be particularly high for infants who receive other foods as well as breastmilk, and there is little evidence to suggest that the risk of transmission is associated with duration of breastfeeding [45,48]. Hypothesis of timing of transmission A working definition of the timing of vertical transmission in non-breastfeeding populations has been proposed by Bryson et al. [49] in which an infant is defined as infected intrauterine if there is a positive culture or DNA polymerase chain reaction (PCR) test on a sample drawn during the first 48 h after birth. Intrapartum infection is assumed if there is a negative culture or PCR test in the first week of life, followed by a positive sample before 3 months of age. However, this definition is not based on experimental data, and the underlying assumption may not hold true if negative early specimens could be due to sequestration of the virus in an inaccessible location (such as lymph nodes or central nervous system). Furthermore, in breastfeeding populations, infants are also exposed to HIV through breastmilk. Estimated timing of vertical transmission in non-breastfeeding populations There have been several attempts to quantify the relative contribution of each of these routes, using different methodological approaches. One of the first modelling exercises was that of Rouzioux et al. [50], who, using a Markov model and results from 95 HIV-infected, non-breastfed infants born to HIV-infected women, estimated the timing of transmission, the time from birth to the emergence of detectable virus, and the time from birth to seroconversion. The model indicated that 17% of infected children would be virus culture-positive or PCR-positive at birth, rapidly rising to 50% by 10 days of age, and 95% by 2 months. The model indicated that less than 2% of infected infants acquired the infection more than 2 months before birth, approximately 35% of vertically infected infants were infected in utero less than 2 months before delivery, and in the remaining 65% of cases [95% confidence interval (CI), 22–92] the date of infection was estimated as the date of birth. The estimated median period between birth and the emergence of viral markers of infection was 10 days (95% CI, 6–14), with 95% of infected children having shown markers of infection by 56 days [51]. Using a different methodological approach, Dunn et al.[28] derived age-specific estimates of the sensitivity of PCR using distribution-free methods for interval censored data (Table 1). Data on 271 infected children from 12 perinatal studies were combined for analysis. PCR detected HIV DNA in an estimated 38% (90% CI, 29–46) of HIV-infected children tested on the day of birth or the day after birth. The estimated sensitivity was relatively constant from birth to day 8, increased rapidly in the second week of life, and reached 93% (90% CI, 76–97) by 14 days of age. Only seven children had negative PCR test results after the neonatal period, with the age at the last negative test ranging between 65 and 183 days.Table 1: . Time to first positive polymerase chain reaction or culture for non-breastfeeding populations.Similar results, based on the non-parametric method developed by Turnbull [52], were obtained by others (Table 1). Kuhn et al. [27] estimated the sensitivity of HIV DNA PCR in the neonatal period at 22% between birth and day 3, rising to more than 95% by 39 days of age. Chouquet et al. [53] who like Rouzioux used information on children enrolled in the French Perinatal cohort, but with a non-parametric method of analysis, showed a PCR positivity at birth of about 25%, rapidly rising to 80% by week 2. Using viral culture rather than PCR, data from 140 infected children in the multicentre Women and Infants Transmission Study suggested an estimated probability of being positive at birth of 27%, and 89% by 1 month [29]. These results are consistent with the estimates derived by others based on DNA PCR. The statistical method used does not yield a classification of intrauterine or intrapartum transmission for each infant, only an estimate of the population distribution of times at which a viral test would first be positive if monitored continuously. However, these results could be taken to suggest that, in non-breastfeeding populations, about one-quarter to one-third of vertical infection is acquired intrauterine. This is probably a lower estimate because the observed proportion positive at birth will underestimate the true proportion with intrauterine infection because a transmission event shortly before delivery may not have sufficient time for infection to be established and to produce a positive culture at birth, or because of sequestration of the virus [29,54,55]. These relative rates of timing of vertical transmission are confirmed indirectly by observations from the twin registry, where the first-born twin was significantly more likely to be infected than the second-born twin, and vaginal delivery was independently associated with increased transmission risk [56]. An indirect measure of the proportion of infections occurring intrapartum was obtained by comparing infection rates in twins by mode of delivery and presentation. First-born vaginally delivered infants have potential exposure both in utero and intrapartum, whereas second-born Caesarean-delivered infants theoretically have exposure confined to the intrauterine period. The vertical transmission rate in first-born vaginally delivered twins was 35% compared with 8% in second-born Caesarean-delivered infants. Thus, the absolute rate for intrauterine transmission was 27%, indicating that approximately three-quarters of transmission occurred intrapartum [56]. In a study by Kuhn et al. [57], using results of DNA PCR tests in 276 infants born to HIV-infected mothers and following the working hypothesis of Bryson et al.[49], timing of transmission was associated with intrapartum risk factors. Infants with greater intrapartum exposure, such as prolonged membrane rupture and vaginal mode of delivery, were more likely to have virological evidence of infection during delivery than those with less intrapartum exposure, but were equally likely to have presumed intrauterine infection [57]. Furthermore, in the Women and Infant Transmission Study infants with early positive virological tests had evidence of immune stimulation, which suggested intrauterine infection [44]. In addition, results from several observational studies, including the European Collaborative Study, showed a stable transmission rate after about 34 weeks gestation, and where there was a mode of delivery effect this was constant over gestational age [2,4]. The association between prematurity and increased vertical transmission risk may be mediated by premature membrane rupture and subclinical bacterial infections [2]. The increased risk of infection in very premature infants is likely to be due to increased susceptibility to intrapartum infection as a result of immaturity of the immune system and low levels of maternally derived HIV antibodies. Breastfeeding populations The estimates suggesting that three-quarters of vertical transmission occurs during delivery were based on studies in non-breastfeeding populations. However, in populations where breastfeeding is common it is not only impossible to distinguish between late intrauterine and intrapartum transmission, but also between intrapartum transmission and transmission via breastfeeding occurring in the first few weeks of life. Simonon et al. [58] estimated the contribution of intrauterine, intrapartum and postnatal transmission in 47 infected children born to HIV-infected mothers in Kigali, Rwanda, using non-parametric methods similar to those used by Dunn et al. [28]. In this prospectively followed cohort, 30% of infected children showed evidence of infection at birth, and 81% at 3 months of age. At 24 months, all infected children had received at least one positive PCR result. In the study by Bertolli et al. [59] in Kinshasa, Democratic Republic of the Congo (DRC; former Zaïre), PCR test results for HIV DNA on venous blood drawn from children aged 0–2 days and 3–5 months were used to estimate the relative contribution of the three routes. Among 41 infected children, 22% were PCR-positive at birth, 83% by 3 months, and all by 24 months. In Kigali, the overall rate of vertical transmission was 25.3% (95% CI, 19–32) [58] (Table 2). The estimated rate of intrauterine transmission was 7.7% (taking the 30% of infected children who were PCR-positive at birth) and the intrapartum plus postnatal transmission rate was 17.6%. On the other hand, if the sensitivity of PCR was assumed to be only optimal at 3 months, the intrauterine, intrapartum and early postnatal transmission rate would be 20.4% and the late postnatal transmission rate (after 3 months of age) would be 4.9%. This would give a range of 4.9–17.6% of transmission attributable to breastfeeding and a likely relative contribution of each period of 30, 50 and 20% (before birth, during and immediately after birth, and after 3 months of life, respectively). In Kinshasa [59], 23% of HIV-infected children were estimated to have had intrauterine, 65% intrapartum/early postpartum, and 12% late postpartum transmission. The estimated absolute rates for intrauterine, intrapartum/early postpartum and late postpartum transmission (after 3 months of age) were 6, 18 and 4% (Table 2). These results again suggest that the risk of transmission is likely to be higher during labour and delivery than during gestation, and also that breastfeeding beyond 3 months results in a substantial additional risk of transmission.Table 2: . Estimates of timing of transmission for breastfeeding populations.Late postnatal transmission of infection through breastfeeding Acquisition of infection after 3–6 months of age through breastfeeding may contribute substantially to the overall rate of infection in breastfeeding populations. The results from Rwanda and the DRC have already suggested that about 5% of children born to HIV-infected mothers only became infected after 3 months of age, and the relative contribution of this to the overall rate of vertical transmission was 12–20% [58,59]. Late postnatal infection was further confirmed in a study in Côte d'Ivoire by Ekpini et al. [60], who defined late postnatal transmission to have taken place when a child had a negative PCR at 3 or 6 months or age, followed by either a positive PCR at 9 months or older, or by persistently positive serology beyond 15 months of age, or both. Among the 45 children born to HIV-1-positive mothers whose PCR results were negative at or before 6 months of age, four (9%) became HIV-infected. The estimated rate of late postnatal transmission with account taken of loss to follow-up and weaning patterns was 12% (95% CI, 3–23) or 9.2 per 100 child-years of breastfeeding [60]. To provide a more reliable estimate of late postnatal transmission of HIV through breastfeeding, a metaanalysis of data from four cohorts from industrialized countries and four cohorts from developing countries was undertaken by the Ghent International Working Group on Mother-to-Child Transmission of HIV-1 [61]. Results from this analysis indicated an overall risk of infection after 3 months of age of about 3 per 100 child-years of breastfeeding, with the similarity between individual studies strengthening the reliability of the overall estimate [61]. In a modelling exercise, assuming different infant feeding practices, infant mortality rates, varying antenatal HIV seroprevalence and HIV incidence postnatally, and HIV transmission rates through breastfeeding. Kuhn and Stein [15] contributed to the debate about feeding alternatives for infants born to HIV-infected women in less developed countries. Complete avoidance of breastfeeding by the whole population always produced the worst outcome. The lowest frequency of adverse outcomes (HIV infection or infant deaths) occurs if no HIV-infected women breastfeed and all HIV-negative women breastfeed optimally, when infant mortality rates are less than 100 per 1000 and assuming a relative risk of dying in non-breastfed infants of 2.5 compared with breastfed infants. If the absolute rate of late postnatal transmission of HIV infection through breastfeeding is 7% or more, early cessation of breastfeeding (3 months after the delivery) by HIV-infected mothers would be beneficial, even at high infant mortality rates [15]. However, they clearly show that where HIV-infected women are not identified antenatally, sustained promotion of breastfeeding is desirable. Conclusion Mother-to-child HIV transmission through breast-feeding is an important consideration when discussing therapeutic interventions to reduce the risk of mother-to-child transmission at the time of delivery. Ekpini et al. [60] calculated that had the AIDS Clinical Trials Group 076 protocol [3] been used in their African population with the same effectiveness as demonstrated in the United States, there would have been an overall reduction in the rate of vertical transmission of 54% rather than 67%, because some children in whom intrapartum infection was prevented by zidovudine therapy would have become infected through breastfeeding [60]. However, it is currently not known whether the risk of HIV infection through breastfeeding in infants exposed to antiretroviral drugs around the time of delivery is the same as for those who were not treated. There is now sufficient evidence to suggest that transmission during late pregnancy and the intrapartum period contributes relatively more to the overall rate of vertical transmission than the early intrauterine period, even in populations where breastfeeding is the norm, and that postnatal transmission through breastfeeding poses a substantial additional risk of infection. Current approaches to interventions to reduce vertical transmission, partly through practical necessity, target the late intrauterine and intrapartum periods, but their application in populations where breastfeeding is the norm poses still unanswered questions." @default.
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• W2051464900 title "Mechanisms and timing of mother-to-child transmission of HIV-1" @default.
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