MOTHER-CHILD HIV-1 TRANSMISSION

0889-8545/97 $0.00

HIV DISEASE IN PREGNANCY

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MOTHER-CHILD HIV-1 TRANSMISSION Timing and Determinants Lynne M. Mofenson, MD

Globally, the World Health Organization (WHO) estimates that 3.5 million women have been infected with HIV-1, most of whom are of childbearing age. More than 1 million of the children born to these women have acquired infection perinatally. An estimated 3000 additional women become infected every By the year 2000, it is projected that as many as 5 to 10 million children will be infected, with over three quarters of these cases occurring in the developing world, particularly sub-Saharan Africa. Thus, perinatal HIV-1 infection constitutes a significant global public health problem, and the prevention of transmission is a high public health priority. An understanding of the pathogenesis of perinatal transmission is crucial for the design of new preventive and therapeutic interventions. RATES OF PERINATAL TRANSMISSION

Early in the HIV-1 epidemic, the risk of perinatal transmission from an infected woman to her infant was estimated to be as high as 65%. However, these early studies focused on infected women identified because of clinical symptoms or the prior birth of a child with AIDS. Studies of more representative populations of HIV-1-infected women followed in a prospective fashion have provided lower estimates of perinatal transmission rates. Transmission rates have ranged from 14% to

From the Pediatric, Adolescent, and Maternal AIDS Branch, Center for Research for Mothers and Children, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA VOLUME 24 * NUMBER 4 DECEMBER 1997

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33% in studies performed in industrialized countries such as the United States and Europe (Fig. 1). In the developing world, particularly Africa, rates as high as 43%have been reported. The reasons for these differences are likely to be multifactorial and include geographic variation in the prevalence of cofactors influencing transmission. Important potential cofactors include geographic differences in maternal clinical status, virulence of circulating viral strains, and the frequency of breast-feeding. TIMING OF HIV-1 TRANSMISSION

The timing of HIV-1 transmission has a direct impact on the design of preventive interventions. If transmission occurs during early gestation, interruption may be difficult. However, if transmission occurs during the early preembryonic (3 to 5 weeks’ gestation) and embryonic (6 to 10 weeks’ gestation) phases of gestation, fetal demise and pregnancy loss may result. In a study of 14 fetal losses experienced by HIV-1-infected women, HIV-1 was detected by in situ hybridization in placental and fetal tissues from 7 of 14 fetuses.5oIf transmission occurs in utero but later in gestation, intervention may be more feasible. For example, treatment of the mother and fetus during late pregnancy with antiviral agents could hypothetically prevent late in utero transmission. Interventions are also possible if transmission occurs primarily during

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HIV TRANSMISSION RATE Figure 1. Rates of perinatal HIV-1 transmission in studies from industrializedand nonindustrialized countries. ECS = European Collaborative Study. Open bar = industrialized; solid bar = nonindustrialized.

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the intraparturn period. If transmission occurs via direct contact of the infant with infectious maternal secretions, operative delivery or vaginal viricides may be protective. If, however, significant transmission occurs by maternal-fetal transplacental microtransfusions during labor, interventions that include prophylaxis of the infant may be necessary. Current data support HIV-1 transmission during the intrapartum as well as intrauterine and postpartum periods (Table 1). However, the relative proportion of transmission that occurs intrapartum versus intrauterine remains controversial. The bimodal age of symptom onset in infected children suggests the existence of two subsets of children. In a recent analysis of a French cohort, rapid onset of AIDS in the first few months of life, consistent with the clinical outcome of other viral infections transmitted in utero, was uncommon, occurring in 17% of infected infants.57AIDS did not develop in the majority of infants until several years of age, suggesting that as much as 80% of transmission may occur intrapartum. Other clinical findings suggestive of in utero infection, such as intrauterine growth retardation, are uncommon in HIV-1 infection. Table 2 Text continued on page 766 Table 1. TIMING OF PERINATAL TRANSMISSION Intrauterine Transmission

lntrapartum Transmission

Postpartum Transmission (Breast-Feeding)

HIV isolation from cervicovaginal HiV isolation from cellular and cell-free portions of breast milk secretions Case reports of infants infected by lntrapartum exposure to blood breast-feeding from mothers who become HIV-infected postpartum or from an infected “wet nurse” HIV identified in fetal tissue, Increased infection rates in first- Meta-analysis of pooled data indicates increased attributable risk of fetal blood samples, and born twin infection by breast-feeding amniotic fluid Intrauterine growth Acute primary infection virologic and immunologic pattern retardation observed in some HIV-infected infants? Positive viral studies in Negative viral studies at birth, followed by positive studies at 20°/. to 60% of infected infants at birth first month of life in 40% to 80% of infected infants Bimodal onset of symptoms, Bimodal onset of with late onset (>I2 months) symptoms, with early onset (112 months) in in 70% 130% HIV p24 antigen in cervicovaginal secretions associated with increased risk of infection Association of duration membrane rupture with risk of infection Possible protective effect of cesarean delivery HIV identified in placental tissue In vitro infection of placenta-derived cells

Modified from Mofenson LM: Epidemiology and determinantsof vertical HIV transmission. Semin Pediatr Infect Dis 5~252-265. 1994.

~

Prospective

Retrospective Twin registry

NYCiLandesman et a P (19961

MultinationalDuliege et al" (1995) sets)

20% (115 twin

20% (104)

24% (127)

Prospective

NYCiMinkotl el alM (1 995)

24%

(351)

Prospective

Type of Study

United States NYCiAbrams et all (1995)

Site/Study/Year

Transmission Rate (No. Infants)

> 15 mo

> 6 mo

> 15mo

> 6 mo

Length of Infant Follow-up

Infected Seropositive > 15 mo HIV-related disease Uninfected Seronegative > 12 mo No symptoms

Infected 2 2 @ PCR @ antibody > 15 mo AIDS-defining illness Symptoms and 1 @ PCR Uninfected 2 2 0PCR (1 > 6 mo) 2 0antibody tests No symptoms Infected Seropositive 2 15 mo AIDS-delining illness @ HIV-IgA x 2 at 2 6 mo Uninfected No symptoms and either Seronegative x 2 2 6 mo HIV-IgA- x 2 at 2 6 mo Infected 2 2 @ culture Uninfected 2 2 0Culture (1 > 1 mo&l r6mo)

Definition of Infant Infection Status

~

Table 2. VERTICAL TRANSMISSION RATES: REVIEW OF SELECTED STUDIES

Associated Duration of membrane rupture 2 4 h Low birth weight Illicit drug use CD4+ count Not associated Mode of delivery Maternal age Associated First-born twin Vaginal delivery AIDS

Associated Low CD4 + Duration of membrane rupture 2 4 h

Associated Maternal AIDS CD4+ < 500 Zidovudine (protective)

Risk Factors for Transmission

Infected second-born twins have more rapid development of symptoms

Infected infants more likely to be low birth weight than uninfected infants

NS

Higher rates of prematurity and intrauterine growth retardation in infected vs uninfected infants

Infant Outcome

(1994, 1996)

33

European Collaborative

(1996)

France/Mandelbrot et a P

Europe Italian Multicenter Cdlaborativefiovo el a103 11gw

Caribbean HaitiMalsey et a138 (1990)

Prospective

Prospective

Registw

Prospective Case-control (308 HIV @ P 3360 HIV 09 )

16% (1945)

19.0% (1632)

18.5% (975)

(230)

24%

> 18 mo

> 18 mo

> 18 mo

> 12 mo

Infected 2 2 @ Cultures or p24 antigen Seropositive > 18 mo AIDS HIV-related death Uninfected Seronegative > 18 mo 0Culture, p24 antigen

Infected Seropositive > 18 mo or 2 2 positive cultures Uninfected Seronegative > 18 mo No symptoms Infected Seropositive > 18 mo AIDS-related death Uninfected Seronegative > 18 mo

Infected Seropositive > 12 mo Excess mortality (13% excess at 3 mo) Uninfected Seronegative > 12 mo

Associated p24 antigenemia Premature rupture of membranes Procedures during pregnancy Bloody amniotic fluid Hemorrhage in labor Low CD4+ count Not associated Mode delivery Associated AIDS CD4+ count Vaginal delivery Prematurity

Associated Vaginal delivery Maternal symptoms Prematurity

Not associated Breast-feeding

Table continued on following page

No difference congenital defects, prematurity, or birth weight in infected vs uninfected infants

NS

No difference in birth weight in infected vs uninfected infants

Birth weight < 2500 g, < 37 weeks gestation, and excess mortality more likely in infants born to HIV @ P vs HIVG P No difference birth weight in infected vs uninfected infants

Kenyatlemmerman el ala1 (1995)

Prospective Case-control (315 HIV 0 P 311 HIV@ 9 )

Prospective

Africa Soulh A f r i c d b bat et ai9

(1996)

Prospective

Type of Study

Asia IndidKurner et ai(1995)

SiteStudyRear

(94)

31%

34% (181)

48% (143)

Transmission Rate (No. Infants)

Infected Seropositive 2 15 mo AIDS HIV-related death Uninfected Seronegative 2 9 mo Non-HIV-related death

Infected 0PCR Uninfected @ PCR

> 3 mo

Infected Seropositive > 18 mo @ Culture, p24 antigen Uninfected Seronegative > 18 mo

Definition of infant Infection Status

> 18mo

> 18 mo

Length of Infant Follow-up

Table 2. VERTICAL TRANSMISSION RATES: REVIEW OF SELECTED STUDIES (Continued).

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Associated Vaginal delivery Anemia Not associated Maternal age Parity Duration membrane rupture Preterm delivery Breast-feeding @ Syphilis serology Associated Sexually transmitted disease Chorioamnionitis Low CD4+ count Higher CDB count Low CD4+/8+ ratio infant gender (female)

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Associated Placental membrane inflammation Prematurity CDC stage Iii/IV Low CD4 Low birth weight

Risk Factors for Transmission

Prematurity and postpartum endometritis but not intrauterine growth retardation more likely in infants born to HIV 0 P than HIV 0 P No difference in birth weight and gestational age in infected vs uninfected infants

NS

Low birth weight and prematurity more common in infected than uninfected infants

Infant Outcome

Prospective Case-control (323 HIV 0 P 341 H I V O 0 )

Prospective Case-control (324 HiV @ 0 254 HIV @ 0 )

Prospective Case-control (318 HIV @ 0 309 HIV 0 9 )

WrelSi. Louis et atw

RwandaiBuitery et alq2,’4 (1993, 1994) 20% to 29% (162)

42.8% (257)

> 12 mo

> 12 mo

Infected Seropositive > 12 mo AIDS HIV-related death Uninfected Seronegative > 12 mo

Infected 2 2 @ Culture or PCR Seropositive > 15 mo Uninfected Seronegative > 15 mo All cultures/PCR @

Infected Seropositive 2 12 rno HIV-related death Uninfected Seronegative z 12 mo

Associated Marital status (married) Breast-feeding: duration (x 15 mo) Not associated Disease stage (most were healthy) Mode of delivery Associated @ p24 antigen CD4+ < 15% CDB+ 2 1800/mm3 Chorioamnionitis Fever 2 30 days Hb 5 0.85 giL? Preterm/postterm? Associated 2 3 recent sex partners CD4+/CD8+ < 0.5

Intrauterine growth retardation, placental weight more likely in infants born to HIV @ P vs HIV 0 P No difference in gestational aae or neonatal mortalitv in iGants born to HIV @ f vs HIV@ P

2.4% vs 1.2% stillbirths in HIV @ vs HIV 0 P

Low birth weight and death at < 12 mo more likely in infants born to HIV @ 0 than HIV @ 0 No difference in birth weight in infected vs uninfected infants

CDC = Centers lor Disease Control; PCR = polymerase chain reaction; STD = sexually transmined disease; NS = not specified; @ = positive; 0 = negative. Modified from MoFenson LM: Epidemiology and determinants of vertical HIV transmission. Sernin Pediatr Infect Dis 5:252-265, 1994.

(1 993)

(1994)

KenyaiDaHa et alp’

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MOFENSON

summarizes the data from selected cohort studies performed between 1993 and 1996. Although maternal infection was associated with low birth weight, prematurity, or other adverse birth outcomes in some cohorts (primarily from nonindustrialized countries), the outcome by infant infection status was often not delineated. Most cohorts from industrialized countries have not observed differences related to infection status in anthropomorphic parameters at birth. However, several reports suggest that intrauterine growth retardation may be confined to a small subset of infected infants, those born prematurely. It is possible that infected infants born prematurely are more likely to have acquired HIV-1 infection in utero than those born full-term. The timing and pattern of virologic parameters in infected infants may be useful to evaluate transmission. Dunn and colleagues29performed a meta-analysis of 13 studies that evaluated the use of HIV-1 DNA polymerase chain reaction for early diagnosis of infection. Data were available on the age of the subject at the time of the first positive test for 271 infected children. HIV-1 infection was detected in 38% 190% confidence interval (CI), 29% to 46%] of children at birth to 1 day of age, in 93% (90% CI, 76% to 97%) by 14 days of age, and in nearly 100% by 28 days of age (Fig. 2). If HIV-1 detection at birth represents transmission in utero, at least 60% of transmission may be intraparturn.

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28 days

Age at Time of Test

Figure 2. Detection of HIV-1 by DNA polymerase chain reaction assay in 271 HIV-1infected children, by age at time of first positive test. (Data from Dunn DT, Brandt CD, Krivine A, et at: The sensitivity of HIV-1 DNA polymerase chain reaction in the neonatal period and the relative contributions of intrauterine and intraparturn transmission. AIDS 9:F9-F11, 1995.)

MOTHER-CHILD HIV-1 TRANSMISSION

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Serologic data are also consistent with late transmission. In an evaluation of the timing and pattern of antibody production to viral proteins in infected infants, new antibody to HIV-1-specific proteins was observed to develop at a mean of 54 days of age in almost 70% of infected infants, consistent with the time to seroconversion following acute infection in Combining virologic and serologic data, the French Collaborative Study used mathematical modeling to estimate the timing of transmission in a non-breast-feeding population. It was estimated that 92% of all transmission occurred during the last 2 months before or during delivery, and that 65% (95% CI, 22% to 92%) occurred during the intraparturn period.” A study in a breast-feeding Zairian population used virologic data to define the timing of infection. The proportion of transmission estimated to occur in utero was 26% (95%CI, 14% to 35%); the proportion intrapartum/early postpartum was 65% (95%CI, 53% to 76%); and the proportion occurring late postpartum via breast milk was 12% (95% CI, 5% to 22%).7 In an analysis using data from the International Registry of HIVExposed Twins, the first-born twin had more than a twofold greater risk of infection in comparison with the second (26% versus 13%, respectively).28These data suggest that the greater risk of infection in the firstborn may be related to more prolonged exposure of the presenting twin to infectious secretions in the genital tract during the later stages of pregnancy and delivery. In a comparison of the transmission rate in firstborn vaginally delivered twins (%%),who have the greatest exposure to vaginal fluids and, presumably, both in utero and intraparturn exposure, with the rate in second-born surgically delivered twins (8%), who have the least exposure to vaginal fluids and, presumably, only intrapartum exposure, it was estimated that almost 80% of transmission occurred during the intraparturn period. Taken together, the accumulated clinical, serologic, and virologic data suggest that at least 40%, and perhaps as much as 8O%, of transmission may be occurring during or close to birth. Transmission via breast milk is supported by known transmission of other retroviruses by milk, the detection of HIV-1 in the cellular and acellular compartments of breast milk, and reports of transmission from mothers infected during the postpartum period.6s In these cases, the infant is exposed to high viral levels in the presence of minimal to no maternal HIV-1-specific humoral or cellular immune response. Studies of mothers infected prior to pregnancy have given conflicting results. The finding that transmission rates are higher in developing countries where most women breast-feed has been cited as indirect evidence of breast milk transmission. A 1994 study in Nairobi found that the risk of transmission via breast milk was 32% if an infected mother breast-fed her infant for more than 15 months.21However, the transmission rate in where breast-feeding is universal, is similar to that in the United States, where formula-feeding is the norm. In a meta-analysis of studies published before 1992, the attributable risk of transmission through breast milk was estimated to be 29% (95%CI, 16% to 42%) if the breast-

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feeding mother became infected postpartum and 14% (95% CI, 7% to 22%)if the mother had been infected prior to pregnancy.3o RISK FACTORS ASSOCIATED WITH TRANSMISSION

The risk for perinatal HIV-1 transmission is likely to be multifactorial. The identification of risk factors associated with transmission during these different time periods has great importance for the development of preventive interventions (Table 3). Maternal and Virologic Factors

Unprotected sexual intercourse with multiple sexual partners before and during pregnancy was associated with increased perinatal transmission in a Rwandan cohort; women with more than one sexual partner during the first trimester had an especially high risk of transmission, even after adjustment for maternal immune status and the presence of genital infections during pregnancy.12In two US cohorts, a high frequency of unprotected sexual intercourse during pregnancy was associated with an increased risk of transmission even after adjustment for multiple potential confounding variable^.'^, 55 Although the mechanism for this association is not known, possible factors may include multiple exposures to semen and sperm associated with increased immune activation leading to increased HIV-1 replication and high maternal viral load; exposure or superinfection or both to different HIV-1 strains leading to maternal acquisition of a more virulent or fetotropic viral strain or increased viral replication; and physical trauma or inflammation leading to disruption of placental membranes facilitating access of virus to the fetus. Several recent studies have demonstrated that the maternal CD4 + lymphocyte count is an independent predictor of transmission risk (see Table 2). In multivariate analyses of data from the European Collaborative Study involving more than 1800 mother-infant pairs, a linear relationship of transmission was observed with decreasing CD4+ C O U ~ Interestingly, women with a CD4+ count below 200/mm3 were more likely to deliver at an earlier gestational age when compared with those with higher CD4 + counts. A similar linear relationship between CD4 + count and transmission was reported in the French Cohort Study of 848 mother-infant pairs? No threshold was observed beyond which no transmission occurred; the rate of perinatal transmission was 11%for women with CD4+ counts above 800/mm3 in the European Collaborative Study, with a similar rate of 15% for women with CD4+ counts above 600/mm3 in the French Cohort Study. The level and specificity of maternal HN-1-specific antibody may be important. However, in the numerous published studies since 1990, decreased, increased, and no differences in the rate of perinatal transmis-

~ . ~ ~

MOTHER-CHILD HI!-1 TRANSMISSION

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Table 3. POTENTIAL MEDIATING FACTORS FOR PERINATAL HJV TRANSMISSJON AND POTENTIAL STRATEGIES FOR INTERVENTION Potential Mediating Factors Maternal factors Advanced disease stage Low CD4 + count or percent Elevated CD8 count Low titers or avidity/affinity HIV-specific antibody Low HIV-specific cellular immunity? High viral load Viral genotype: selection of neutralization escape mutant? Viral phenotype: non-syncytiainducing; slow/low; macrophage tropic? Placental factors Differing CD4+ expression by placental cells Placental cell susceptibility to HIV infection Fc-mediated transfer of HIV-associated immune complexes? Breaks in placental barrier Chorioamnionitis Syphilis and other sexually transmitted diseases Other etiologies (smoking, cocaine) Fetal factors Reduced functional immune competence Fetal cell susceptibility to HIV infection Genetic aspects (HLA haplotype) Laborhirth canal factors Cervicovaginal viral load Local HIV-specific immune response Maternal-fetal micro/macrotransfusion of blood

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Obstetric factors Duration of membrane rupture Mode of delivery lnvasive obstetric procedures/fetal monitoring Newborn factors Skin integrity Gastric acid secretion low Decreased functional immune responsiveness Breast milk factors Cell-associated viral load Cell-free viral load Viral load in colostrum/early milk? HIV-specific antibody Nonspecific protection (e.g., glycosaminoglycan content)

Potential Intervention Strategies Lower maternal viral load Antiretroviral Boost maternal immune response Passive immunization Polyclonal (HIVIG) Monoclonal Active immunization Passive-active immunization

Prevent viral attachment Passive immunization Other blockers (e.g., CDCIgG) Restrict viral replication Antiretroviral Prevention and treatment of cofactors Chorioamnionitis Sexually transmitted diseases Smoking Illicit drug use Prevent viral replication Antiretroviral Boost immune response Passive immunization Lower viral load Antiretroviral Vaginal viricide Boost immune response Local passive or active immunization? Role of elective cesarean section Avoid invasive procedures

Avoid invasive procedures Lower viral load Antiretroviral Boost immune response Passive immunization Active immunization Passive-active immunization Avoid breast-feeding if safe infant formula available Avoid breast-feeding only of early breast milk? Lower viral load Antiretroviral Boost immune response? Active immunization

From Mofenson LM; Epidemiology and determinants of vertical HIV transmission. Semin Pediatr Infect Dis 5:252265.1994.

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sion in the presence of antibody have been reported.63It is unclear whether the conflicting results are due to differences in technique, the use of linear synthetic peptides to viral proteins to detect antibody when conformational or other nonenvelope epitopes may be more important, or the use of laboratory rather than primary patient-derived viral sequences as antigens. Maternal neutralizing antibody may need to be evaluated in the context of viral isolates from the individual mother and her infant. This type of evaluation has been carried out in several small mother-child cohorts; transmitting mothers less frequently had antibody to their own virus in comparison with nontransmitting mothers.44,82 Additionally, transmitting mothers only rarely had neutralizing antibody against their child’s viral isolate, and, in one case, maternal antibody enhanced infectivity of infant virus in vitro. However, in another small study that adjusted for maternal CD4 lymphocyte count, no differences were seen in titers of autologous HIV-1 antibody, viral load, and syncytiuminducing phenotype between transmitting and nontransmitting mothers.40Studies in larger populations are needed to elucidate the role of HIV-l-specific antibody in transmission. It is possible that neutralizing antibody may be important in protection against infection from cellfree virus but not cell-associated virus. In an in vitro infection system, monoclonal HIV-1 V3 antibody completely prevented infection with cellfree virus, but when cell-to-cell transfer of virions was the primary mechanism of infection, inhibition was not Few studies have focused on the role of maternal cellular immune response to HIV-1. The presence of maternal HIV-1-specific antibodydependent cellular cytotoxicity has not been associated with protection from transmission, although, in infected children, it has correlated with a more favorable clinical stage.4l’53 Low maternal vitamin A levels during pregnancy were associated with increased transmission in a cohort of infected women in Malawi; a 4.4-fold increased risk of transmission was observed for women with vitamin A levels less than 0.7 p,mol/L in comparison with those with . ~ ~ relationship was independent of normal levels (>1.4 p , m ~ l / L ) This maternal CD4+ count. Vitamin A has a general stirnulatory effect on the immune system and helps to maintain the integrity of mucosal surfaces.84Low levels could be associated with increased immune dysfunction leading to increased viral burden, and mucosal breaks could increase viral shedding into genital secretions. Additionally, low maternal vitamin A levels have been associated with increased viral load in breast milk, possibly leading to an increased risk of transmission via brea~t-feeding.~~ Vitamin A deficiency (<0.7 p,mol/L) was also associated with perinatal transmission risk in one US cohort independent of CD4+ count and the duration of membrane rupture.36However, these data need to be confirmed in other cohorts. The vast majority of pregnant women in the United States already receive prenatal vitamin supplementation that includes vitamin A. Because of concern regarding the potential teratogenicity of vitamin A when administered early in gestation;8

+

MOTHER-CHILD HIV-1 TRANSMISSION

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vitamin A supplementation over and above that given in prenatal vitamin supplements is not recommended at this time. In several small studies, high maternal viral burden as measured by quantitative cell or plasma culture or plasma RNA copy number has been associated with increased transmission risk.'O, 25, 34, 96 These findings have led some researchers to propose the existence of a virologic threshold below which transmission would not occur. However, data accumulating from larger cohorts of mother-infant pairs indicate that, although an association between high HIV-1 RNA copy number and transmission risk exists among women not receiving antiretroviral therapy, an absolute threshold does not exist, and transmission may be observed across the full range of viral levels, including at undetectable RNA level^.^^,^^^ 58,89 Thus, although viral load may be an important determinant of transmission risk, it is not the sole determinant. On the basis of the limited data available for women receiving antiretroviral therapy [zidovudine (ZDV) in ACTG 0761, the predictive value of RNA copy number for transmission is attenuated and relatively poor.89Only a small portion of the protective effect of ZDV in reducing transmission was explained by the lowering of maternal HIV-1 RNA levels, and ZDV efficacy was observed at all RNA levels. These data suggest that an important component of protection may be preexposure and postexposure prophylaxis of the infant, and that ZDV should be offered to all infected pregnant women regardless of their HIV-1 RNA levels. Other characteristics of maternal virus may be important. Multiple heterogeneous strains of HIV-1 (quasispecies) exist in an infected individual, which may vary in replicative rate, cellular tropism, syncytiuminducing capacity, and the ability to be recognized by the host immune system, which could, in turn, cause variation in transmissibility between these strains. Genotypic sequences of virus isolated from infected neonates are more homogeneous than those of virus isolated from their mothers. In addition, a minor subset of maternal viral variants is transmitted in the majority of cases, although transmission of major or multiple viral variants has also been reported.2, 98 These data suggest that transmission is not a random event but may be selective, either of a viral variant with specific cellular tropism or growth properties or of an immune-escapable maternal viral variant. Some studies have suggested that viral biologic phenotype may influence transmission risk. Monocyte-macrophagetropic (M-tropic)maternal viral isolates have been reported to be more likely to be transmitted than maternal isolates with T-cell tropic phenotype. Isolates obtained from infected infants during the first few days of life are predominantly M-tropic, suggesting selective transmission or replication of M-tropic virus.7o,95 In support of this hypothesis, neonatal macrophages have been found to be more susceptible than adult macrophages to HIV-1 infection in vitro and are preferentially infected by non-syncytium-inducing, Mtropic viral isolates.75,88 HIV-1 can be classified into at least nine different genotype subtypes (clades) based on variation in the envelope region of the viral genome.

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The global distribution of these subtypes varies, with subtype B predominating in the United States and Europe; cocirculation of multiple subtypes has been observed in some areas of the world, such as Africa (subtypes A, C, and D) and Thailand (subtypes B and E). Possible differences in cell tropism and transmissibility between subtypes have been suggested by the in vitro finding that HIV-1 subtype E may grow more efficiently in Langerhans cells from the genital tract mucosa in comparison with subtype B. Some epidemiologic findings suggest more 87 It is possible that efficient sexual transmission of subtype E than B.47, subtype could influence perinatal transmission risk and could account, in part, for the differential transmission rates observed between nonindustrialized and industrialized countries. Relevance to Prevention

Data suggest that therapy capable of reducing maternal viral burden may reduce transmission risk. Additionally, enhancement of the maternal humoral or cellular HIV-1 immune response through passive or active immunization or both could be an important preventive intervention. In the developing world where severe vitamin A deficiency is common, vitamin A supplementation may be an effective intervention. Promotion of safer sexual practices, including condom use and limiting sexual partners, is an additional behavioral measure that may reduce perinatal transmission risk. Placental Factors Studies of placentas obtained from infected women have shown that HIV-1 can be isolated from the placenta, and that viral antigens or nucleic acids can be identified within placental cells, although this has not necessarily correlated with infection status of the ir~fant.2~ Infection of placental macrophages (Hofbauer cells) has been documented, but there is controversy regarding the infectibility of trophoblast cells.59If trophoblast cells are not infectable, the mechanism by which cell-free HJY-1 could gain entry to the villous stroma and placental macrophages might include passage through disruptions in the syncytiotrophoblast, endocytosis of the viral particle by the trophoblast cell with subsequent passage through the cell and exit at the villous basal membrane surface, or active transport of HIV-1 immune complexes via IgG Fc or complement receptors on the surface of the syncytiotr~phoblast.~~ h a placental perfusion model, passage of cell-free HIV-1 from maternal to fetal circulation was not ~bserved.~ Lymphocytic cells have been shown to adhere to cultured syncytiotrophoblast cells, and this adhesion is increased in the presence of cytokines such as tumor necrosis factor alpha (TNF-a), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin 1 (IL-1).26It is possible that adhesion of infected lymphocytes to the syncytiotrophoblast could result in highly

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efficient infection of the trophoblast cells themselves, particularly in the presence of cytokine activation. Alternatively, such adhesion could result in facilitated migration of the lymphocyte into the villous stroma where infection of placental macrophages can occur.73,83 Breaches in the placental barrier could lead to mixing of maternal and fetal cells. Several conditions known to be associated with placental disruption have been associated with increased transmission risk, including chorioamnionitis, cigarette smoking, and illicit drug use.16,76, 90 Relevance to Prevention

Provision of antiretroviral therapy during pregnancy could potentially prevent infection of placental cells or restrict HIV-1 replication within cells that have become infected. If passage of HIV-1 through an intact placental barrier requires an initial step of maternal lymphocyte adhesion to the trophoblast, administration of agents that block adhesion may prevent in utero transmission (e.g., administration of monoclonal antibodies against the receptor). Because disruption of the placental barrier permits direct access of HIV-1 to placental macrophages and fetal endothelial cells in the villous stroma, measures directed at identifying and treating causes of placental dysfunction may assist in reducing transmission. Prevention and treatment of sexually transmitted diseases and chorioamnionitis and discontinuation of cigarette smoking and illicit drug use during pregnancy could have important roles in reducing transmission risk.

Fetal Factors

Susceptibility of fetal cells to infection by maternal virus may be important. In a small study, peripheral bIood mononuclear cells obtained from uninfected children were found to be relatively resistant to infection with the viral isolate obtained from their mother.70The mechanism of such resistance is not known, but differences in host cell susceptibility to HIV-1 infection have been reported. Recent identification of a requirement for a coreceptor in addition to the CD4+ molecule for HIV-1 binding may provide an explanation for this phenomenon. The fusin receptor has been identified as the coreceptor required for infection of T lymphocytes by T-cell-tropic virus. The chemokine receptor CKR-5 is required for infection of macrophages/monocytes by M-tropic virus.z4,51 Homozygous mutations in the gene for the CKR-5 coreceptor have been associated with protection from HIV-1 infection in multiply exposed cohorts of hemophiliacs, homosexual men, and intravenous drug users.52,72 Evaluations for such mutations in mother-infant cohorts with regard to perinatal transmission risk are just beginning. However, a role for genetic susceptibility to HIV-1 has been suggested by some studies demonstrating an association of certain HLA haplotypes with transmis-

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sion4 Fetal cell susceptibility to infection could vary by gestational age, possibly because of developmental ontogeny of CD4 + expression. Relevance to Prevention

Prevention of infection once HIV-1 has entered the fetal circulation may prove difficult. Indirect therapy for the fetus could be provided by transplacental passage of antiretroviral therapy administered to the mother. The nucleoside analogue antiretroviral drugs ZDV and lamivudine (3TC) and the nonnucleoside reverse transcriptase inhibitor, nevirapine, have been shown to cross the human placenta and have cord/ maternal blood ratios near 1.O. Other nucleosides [zalcitabine (ddC), didanosine (ddI), stavudine (d4T)l have been shown to cross the placenta in primate models, but there is minimal information on placental passage in humans. There are no data currently available regarding the transplacental passage of the protease inhibitors. The potential for toxicity to the developing fetus must be taken into account when administering antiretroviral drugs, and the long-term outcome of in utero exposure to any of the antiretroviral drugs, including ZDV, is not known. Passive immunization of the fetus could be accomplished through transplacental active transport of neutralizing antibody administered to the mother following the second trimester of pregnancy or induced in the mother by active immunization. However, it is likely that once HIV-1 enters the fetus, the ability to prevent infection in the newborn may be lost. lntrapartum Factors

The presence and amount of virus in the genital tract may affect transmission risk. Free virus and infected cells have been identified in cervicovaginal secretions of HIV-1-infected women. In a study of pregnant women in Nairobi, HIV-1 DNA was detected in 32% of cervical and 10% of vaginal samplesa The presence of HIV-I-infected cells in genital secretions was associated with immunosuppression, anemia, abnormal cervical or vaginal discharge, and severe vitamin A deficiency. Local genital tract viral burden is not directly correlated with systemic viral load or CD4+ count. In one study, 17% of women with high plasma HIV-1 l7NA levels did not have detectable HIV-1 RNA in cervicovaginal secretions, and 26% of women without detectable plasma RNA had significant levels of cell-free virus in genital secretion^.^^ Intensive exposure of the infant’s thin skin or mucosal surfaces to maternal blood and secretions during the birth process could provide a significant route for viral transmission. Langerhans cells in the skin and gastrointestinal tract have been shown to express CD4+ and be infectable by HIV-1. Primate studies have demonstrated that fetal skin and mucous membranes may provide a route for HIV-1 infection. In a rhesus monkey model, SIV was injected into the amniotic fluid of uninfected mothers during late gestation; six of seven newborns were in-

MOTHER-CHILD HIV-1 TRANSMISSION

775

fe~ted.3~ Additionally, transmission via the oral route has been demonstrated in newborn animals; four of four monkeys who were born by cesarean section to uninfected mothers and administered SIV orally immediately after birth became infected? This indicates that swallowing of infectious maternal fluids during birth may be another mechanism of transmission. By 7 days after oral exposure, SIV was identified by in situ hybridization in lymphoid follicles in the ileum and mesenteric lymph nodes but not peripheral lymph nodes of these animals. This suggests that mucosal Langerhans cells within the small bowel may have a major role in initial infection by this route in newborn animals. Consistent with a possible route of HIV-1 transmission by oral exposure in humans, in one study, HIV-1 was detected in gastric aspirates from two of four newborns who were subsequently shown to be infe~ted.6~ The importance of mucosal HIV-1 antibody in genital secretions in reducing the infection risk during the birth process is unknown. In a mouse model of genital herpes simplex virus (HSV), vaginal application of HSV antibody protected mice against vaginal inoculation with HSV2?7 However, intermittent cervicovaginal shedding of HIV-1 occurs despite the presence of mucosal HIV-1-specific IgA antibodies, suggesting that the antibody is not neutralizing the virus.69In one study, anti-HIV1 secretory IgA in maternal genital secretions was associated with an increased risk of transmission61;however, increased local antibody may be a reflection of higher levels of local viral replication.6 Invasive procedures that breach the infant skin barrier could provide another mechanism for viral entry. In a large French cohort, invasive procedures (particularly,amniocentesis and arnnioscopy)were associated with increased transmission risk; other obstetric-related risk factors were premature membrane rupture, hemorrhage in labor, and bloody amniotic fluid.%Prolonged duration of membrane rupture could permit increased exposure to HIV-1 in secretions. Consistent with this hypothesis, several researchers have correlated the duration of mem6o These data suggest that cesarean brane rupture with transmis~ion.4~, delivery prior to the onset of labor might prevent transmission. Studies evaluating the influence of cesarean section on transmission have produced conflicting results (Fig. 3). Whereas a meta-analysis of 11 prospective studies suggested a protective effect, a recent study of more than 1600 mother-infant pairs from France showed no decrease in trans% None of the mission after emergency or elective cesarean de1ive1-y.~~. published studies have been able to control adequately for all important covariates.62Additionally, an increased risk of infectious complications following operative delivery in infected women has been reported in some studies.86In a study in Rwanda, an increased frequency of maternal deaths following cesarean delivery was observed in HIV-1-infected women when compared with uninfected women.I3It is therefore premature to draw definitive conclusions regarding the mode of delivery and transmission.

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40%

-c 0

............................................

30%

....................

01 01

Em

20%

C

R)

10%

0% 1 -

-

a

~ k g $ g g~w r6% 53, Number Cesarean Blrths

3zz

0% W

r

5% am

= r

ur

= a

-g

szm Z at r8 m

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Z % +% ZEZ 98

39

270

355

274

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48

Figure 3. Mode of delivery and HIV-1 perinatal transmission. Transmission rates in vaginal are compared with cesarean delivery in selected recent studies (1995-1996). WITS = Women and Infants TransmissionStudy; PACTS = Perinatal AIDS CollaborativeTransmission Study; ECS = European Collaborative Study; IRT = International Registry of HIVInfected Twins. Open bar = vaginal; solid bar = cesarean.

Relevance to Prevention

Diagnosis and treatment of genital infections during pregnancy are important to reduce the risk of premature membrane rupture associated with such infections, and avoidance of invasive procedures during pregnancy is advisable. Cesarean delivery is an expensive invasive intervention and is associated with higher maternal morbidity and mortality than vaginal deliveries even in uninfected women. It is not an intervention that could be easily implemented on a wide scale in the developed or developing world. If intrapartum transmission occurs primarily through exposure to virus in genital secretions, in addition to cesarean section, viricidal cleansing of the birth canal prior to vaginal delivery and immediate surface decontamination of the infant might provide a less costly strategy to reduce transmission, as used successfully to reduce perinatal group B streptococcal infection. However, a study in Malawi that evaluated chlorhexidine vaginal swabbing during labor did not find an overall beneficial effect on transmission.8 Data obtained from the herpes simplex animal model showing protection with vaginal antibody indicate that enhancement of the local mucosal immune response may be a potential intervention. If maternofetal blood exchange during delivery is the important source of virus, analogous to the transmission of hepatitis €3, such measures will be less

MOTHER-CHILD HIV-1 TRANSMISSION

777

beneficial. Transmission may also be decreased if antiviral therapy is provided to the infant prior to intense viral exposure during delivery. Transplacental passage of antiviral therapy given during late gestation or labor to the mother could supply systemic antiviral activity in the infant during delivery. Newborn Factors

Several reports of transient HIV-1 infection have suggested that the newborn immune response to HIV-1 exposure may have a role in averting transmission. These reports have described an apparent "clearing" of infection in infants who had several initially positive HIV1 virologic tests.*,11, 67, 77 In a study in rhesus monkeys, exposure to subinfectious doses of SIV provided protection on subsequent exposure to infectious doses of SIV.lSFollowing subinfectious exposure, a transient viremia was observed followed by a cell-mediated immune HIV-1specific immune response. Several researchers have reported finding a transient HIV-1-specific cellular immune response in uninfected infants born to infected women. An HIV-1-specific cellular immune response was observed in 18%to 40% of uninfected children, although only small 22, 8o These data suggest that cell-mediated numbers were eval~ated.'~, immunity in the fetus or newborn may have a crucial role in protection or clearance of infection. Relevance to Prevention

The strategy of passive/active immunization of the infant has been successfully employed to prevent hepatitis B transmission. If the intrapartum period is the predominant time of transmission, boosting the HIV-1 immune response of the newborn may reduce transmission. Even if such a strategy does not prevent transmission, it could modify the manifestations of HIV-1 disease in infected children. Breast Milk Factors

The risk of transmission via breast milk may be related to the amount of exposure, time of exposure, infectivity of milk, and specific susceptibility of the infant. In a cohort from Nairobi, prolonged duration of breast-feeding beyond 15 months was associated with a 1.9-fold increased risk of infection; 32% of HIV-1 infection was attributable to breast-feeding beyond 15 months.21Using mathematical modeling, it was estimated that the risk of HIV-1 transmission exceeded the potential benefits of breast-feeding after 3 to 7 months of age." Colostrum and early milk could constitute a greater risk than later milk because of their high cellular content and potential for elevated viral content. In some studies, viral detection is more common in early

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milk samples, whereas in others this is not observed. The Nairobi study discussed previously evaluated the prevalence and load of infected cells in breast milk. Fifty-one percent to 71% of cells were HIV-1 DNA PCR-positive through 9 months of age, declining to 20% after 9 months; quantitative viral load was lower after 9 months of age.65Severe maternal vitamin A deficiency was associated with a 20-fold increased risk of PCR-positivity in cells in the breast milk of the more severely immunosuppressed women. In another study, no significant association between the detection of cell-associated HIV-1 by DNA PCR in breast milk at 6 weeks' postpartum and perinatal transmission was observed.37Immune complex dissociated p24 antigen (presumably reflecting cell-free virus) was not detected in any of the milk samples, and it was hypothesized that there was little ongoing HIV-1 replication in breast milk, at least, at the single time point that was evaluated. Similarly, another study showed that while proviral HIV-1 DNA was detectable in breast milk for up to 1 year, p24 antigen was detected in milk obtained during the first week of life only, implying that infectivity may be greatest in early breast milk.8l IgG, IgA, and IgM antibodies to HIV-1 have been identified in the breast milk of a significant proportion of healthy HIV-1-infected women. In a study in Rwanda, the combination of positive HIV-1 DNA PCR in breast milk at 15 days' postpartum and a lack of persistent HIV-1 IgM response was found to be a strong predictor of transmi~sion.9~ Nonimmunologic components of breast milk have been identified that inhibit the binding of the glycoprotein viral envelope to the CD4 receptor; one substance, a glycosaminoglycan, has been identified in milk from infected as well as uninfected women.66Lactoferrins from breast milk have been shown to have a potent antiviral effect in vitro on both HIV-1 and cytomegalovims.39 The newborn's immature gastrointestinal tract may facilitate transmission; gastric acidity is diminished in the newborn, and the mucosa and microvilli are thin with a deficiency in IgA-secreting cells. However, an immature gastrointestinal tract is not a requirement, because transmission has been reported in infants beginning breast-feeding after the neonatal period. Relevance to Prevention Clearly, the way to avoid transmission by breast milk is to avoid breast-feeding. However, women in developing countries may not have a safe alternative to breast milk, and maternal antibodies to endemic pathogens that pass to the infant through breast milk may prevent significant infant mortality. Thus, recommendations must examine the risk-benefit ratio of breast-feeding for the specific population.68If early milk is most likely to transmit HIV,avoiding breast-feeding during the infectious period should be considered. The provision of an antiviral agent to the mother that passes to the milk or the provision of drug to the infant may be alternative methods of prevention.

MOTHER-CHILD HIV-1 TRANSMISSION

779

POTENTIAL PREVENTIVE AND THERAPEUTIC INTERVENTIONS

In 1994, ACTG Protocol 076 demonstrated that a regimen of ZDV given to the mother during pregnancy and labor, and to the newborn for 6 weeks could remarkably reduce the risk of perinatal HIV-1 transmission. Almost a 70% reduction in transmission risk was observed, ranging from 25% in the placebo group to 8% in the ZDV group.2O The ZDV regimen developed in ACTG 076 is being successfully integrated into clinical practice in the United States and Europe and has been accompanied by dramatic declines in perinatal transmission rates in these countries. However, the vast majority of perinatal HIV-1 infection occurs in the developing world. The ACTG 076 ZDV regimen is too costly and logistically complex for many nonindustrialized countries to implement on a widespread scale, and its efficacy in a breast-feeding

Table 4. CURRENT RESEARCH STRATEGIES TO REDUCE THE RISK OF PERINATAL HIV TRANSMISSION Type 0.f Intervention

Targeted Period

Antiretroviral therapy

IU (late), IP, NB'

Various modifications of the ACTG protocol 076 zidovudine regimen (including combination therapy regimens) Nevirapinet

Passive immunization

IU (multiple doses), NB IU (single dose), NB IU

Hyperimmune HIV immune globulin (HIVIG)

Active immunization

NB

Modified obstetric practices

IP IP

Infant feeding practices Micronutrient supplementation

NB IU

Agent Under Evaluation

Genentech MN rgp 120 vaccinet (to mothers) Genentech MN rgp 120 vaccine? and Biocene SF rgp 120 vaccine? (to newborns) Cesarean vs vaginal delivery Virucidal vaginal cleansing Chlorhexidine vaginal washing Benzalkoniurn chloride suppositories Breast-feeding vs bottlefeeding Vitamin A supplementation

Study Location Current or Planned Ivory Coast, Thailand, Haiti, Uganda, World Health Organization multisite collaboration, United States United States (Phase 1, ACTG protocol 250) United States (ACTG protocol 185) Uganda United States (Phase 1, ACTG protocol 235) United States (Phase 1, ACTG protocol 230) European Collaborative Group Malawi, Kenya Ivory Coast (Phase 1) Kenya Malawi, Tanzania, Zimbabwe, South Africa

ACTG = AIDS Clinical Trials Group; IU = intrauterine; IP = intrapartum;PP = postpartum; NB = newborn. 'Treatment regimens target all or combinations of these periods. tUse of trade names is for identificationonly and does not imply endorsement by the Public Health Service or the US Department of Health and Human Services. Modified from Rogers MF. Mofenson LM, Moseley RR: Reducing the risk of perinatal HIV transmission through zidovudine therapy: Treatment recommendations and implications. J Am Med Womens ASSOC50:78-93, 1995; with permission.

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population is unknown. An ideal preventive intervention would be cheap, nontoxic to mother and fetus, and easy to administer, and would need to be given only once or for a limited period of time and have utility in preventing postpartum transmission. The results of ACTG 076 have spurred the worldwide evaluation of other modalities to reduce transmission. Potential interventions to reduce transmission have focused on the reduction of maternal viral load, the enhancement of maternal and infant HIV-1-specific immune response, prophylaxis of the newborn, and attempts to reduce peripartum and postpartum exposure to the virus. Several different interventions are currently under evaluation, as shown in Table 4. The future challenge for researchers is to use the increasing understanding of the pathogenesis of perinatal HIV-1 transmission to design preventive regimens that will be applicable on a global basis.

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Address reprint requests to Lynne M. Mofenson, MD Pediatric, Adolescent & Maternal AIDS Branch Center for Research for Mothers and Children National Institute of Child Health & Human Development National Institutes of Health 6100 Executive Boulevard, Room 4811 Rockville, MD 20852