Are girls more at risk of intrauterine-acquired HIV infection than boys?

To investigate whether previously described sex differences in virological and immunological markers in vertically infected children are preceded by sex differences in the overall risk or timing of mother-to-child transmission (MTCT) we analysed 3231 mother–child pairs enrolled in the European Collaborative Study. Girls were at a 1.5 times increased risk of MTCT overall, but the sex effect was limited to elective caesarean section deliveries, suggesting that girls may have an increased risk of intrauterine transmission compared with boys. Sex differences in virological and immunological markers of disease progression have been described among HIV-infected adults and children [1–5], suggesting that men and women respond to infection in different ways. In a recent paper from the European Collaborative Study (ECS), the level and pattern of HIV-RNA viral load differed between infected girls and boys [1]. Girls were shown to have an earlier and substantially higher peak viral load compared with boys, and after 4 years of age, the viral load was consistently 0.25–0.5 log10 lower for girls than for boys. Similarly, girls in the ECS have consistently lower CD4 counts than boys at the same ages [2]. These findings suggest that girls may have a different reaction to primary infection compared with boys, but it is unclear whether these early findings indicate a difference in immune response or in the timing of infection. There is little evidence from either adult or paediatric populations to suggest that immunological or virological sex differences affect overall disease progression [2,3,5]. Whether the risk or timing of mother-to-child transmission (MTCT) differs by sex is unclear. Two early studies on a limited number of mother–child pairs suggested that girls may be at higher risk of acquiring infection than boys [6,7]. No studies have subsequently reported a sex difference in absolute MTCT risk, and none have addressed timing. Following our recent findings of immunological and virological differences between boys and girls, we investigate here whether these sex differences are preceded by sex differences in MTCT risk. The ECS is an ongoing cohort study in which infants of HIV-infected women identified during pregnancy are followed according to standard clinical and laboratory protocols. Full methods have been described elsewhere [1,8]. In this analysis, children with a positive virological or serological marker of infection or children aged more than 18 months with a persistence of antibody were included as infected. If a child was HIV antibody-negative and no virus or antigen had ever been detected, they were classified as uninfected. Data entry was carried out using MS Access 2000 and analyses were performed using SAS statistical software (v8.02; SAS Institute, Cary, NC, USA). This analysis includes 3231 mother–child pairs (1684 boys, 52.1%; and 1547 girls, 47.9%) enrolled between 1986 and end-May 2003. Overall, 1121 infants (35.4%) were exposed to antenatal antiretroviral therapy (ART), 1086 (33.8%) were delivered by elective caesarean section (CS) and none were breastfed. The overall MTCT rate was 10.6% [95% confidence interval (CI) 9.56–11.7%], declining from 14.4% (95% CI 12.0–17.1%) before ART prophylaxis was introduced [9], to 2.2% (95% CI 0.46–6.36%) in the last complete year of the study (2002), when the mothers of 92% of infants (226/246) took antenatal ART, of whom 202 (89%) received highly active antiretroviral therapy (HAART) and 58% (n = 143) were delivered by elective CS. There were 350 infected children (170 male, 48.6%; and 180 female, 51.4%) and 2881 uninfected children (1514 male, 52.6%; and 1367 female, 47.5%). In univariable logistic regression the association between sex and MTCT was of borderline statistical significance (Table 1). In multivariable analysis, allowing for antenatal ART, elective CS and maternal CD4 cell count, girls had a 1.5 times higher risk of infection compared with boys (Table 1).Table 1: Risk of vertical transmission (n = 1539).Further analyses to explore the timing of MTCT showed the sex effect to be limited to infants delivered by elective CS, and no statistically significant associations between sex and infection status were apparent for vaginal or emergency CS deliveries. Among all 1086 infants delivered by elective CS, 6.23% of girls (32/514) were infected versus 2.80% of boys (16/572; χ2 = 6.74, P = 0.0094). Adjusting for antenatal ART (no/yes) and time period (pre-1995, 1995–1997, 1998–2003) to control for intervention and population changes over time [8], girls were twice as likely to be infected as boys (adjusted odds ratio 2.14, 95% CI 1.14–4.00, P = 0.017). Allowing for the type of antenatal ART was not possible because of the small numbers. However, univariably antenatal ART classified as none, mono/dual therapy and HAART showed significant sex differences; within the no treatment and mono/dual therapy groups more girls than boys were infected [11.73% (23/196) versus 6.53% (13/199); 4.05% (6/148) versus 0.52% (1/193), respectively], but in the HAART group there was no evidence of a sex effect [1.36% of girls (2/147) versus 1.25% of boys (2/160) infected], possibly because of the small number of infections. Despite substantial advances in the prevention of MTCT, the complex, multifactorial mechanisms and timing of transmission remain poorly understood. In this non-breastfeeding cohort, all infections resulted from intrauterine or intrapartum acquisition. On the crude assumption that infections among infants delivered by elective CS without labour and before membrane rupture are a proxy for intrauterine transmission, our findings would suggest that transmission before 36–38 weeks (when elective CS is performed) may be more common for girls than for boys. The possible reasons why girls may be more susceptible to the acquisition of HIV infection in utero are unclear, but may reflect underlying genetic or immunological differences between the sexes. Compared with those born by elective CS, infants born vaginally or by emergency CS would have had on average one additional week of intrauterine exposure (data not shown), as well as intrapartum exposure to infective maternal blood and genital secretions, ascending infection after rupture of the membranes and maternal–fetal microtransfusions during uterine contractions. However, in this ECS analysis the risk of MTCT did not differ by sex for infants with intrapartum exposure. In a recent meta-analysis of the postnatal transmission of HIV through breastfeeding (after the age of 4 weeks), boys were at significantly greater risk of acquisition than girls, which could not be explained by differences in modes of feeding [10]. It could thus be hypothesized on the basis of all available evidence that although there is no significant absolute difference between the sexes in the overall risk of MTCT if one considers all three routes, there may be a sex difference in the timing of acquisition, with susceptible girls acquiring infection earlier than boys. This hypothesis is consistent with, and could help to explain, our finding of a higher and earlier viral load peak in infected girls compared with boys in the ECS cohort. ECS collaborators C. Giaquinto, O. Rampon, and A. De Rossi (Universita degli Studi di Padova, Padua, Italy); I. Grosch-Wörner (Charite Virchow-Klinikum, Berlin, Germany); J. Mok (Royal Hospital for Sick Children, Edinburgh, UK), F. Johnstone (Department of Obstetrics, University of Edinburgh, UK); I. de José, I. Bates, F. Hawkins, C. Ladrón de Guevara, J.M. Peña, J. Gonzalez Garcia, J.R. Arribas Lopez, Dr M.C. Garcia-Rodriguez (Hospital Infantil La Paz, Madrid, Spain); F. Asensi-Botet, M.C. Otero, D. Pérez-Tamarit, G. Suarez, R. de la Torre (Hospital La Fe, Valencia, Spain); H. Scherpbier, M. Kreyenbroek, M.H.Godfried, F.J. Nellen, K. Boer (Academisch Medisch Centrum, Amsterdam, the Netherlands); A.B. Bohlin, S. Lindgren, E. Belfrage, L. Naver (Huddinge and Karolinska University Hospitals, Huddinge, Sweden); J. Levy, P. Barlow, M. Hainaut, A. Peltier (Hospital St Pierre, Brussels, Belgium); A. Ferrazin, D. Bassetti, (Department of Infectious Diseases, University of Genoa, Genoa, Italy); A. De Maria (Department of Internal Medicine, University of Genoa, Genoa, Italy); C. Gotta (Obstetrics and Gynecology-Neonatology Unit, University of Genoa, Genoa, Italy); A. Mûr, A. Payà, M. Viñolas, M.A. López-Vilchez, M. Rovira, R. Carreras, E. Esteban Tores, S. Herrero Perez (Hospital del Mar, Universidad Autonoma, Barcelona, Spain); N.H. Valerius (Hvidovre Hospital, Hvidovre, Denmark); J. Jimenez (Hospital 12 De Octubre, Madrid, Spain); O. Coll, S. Pisa, C. Fortuny (Hospital Clinic, Barcelona, Spain); J. Boguña (Hospital Sant Joan de Deu, Barcelona, Spain); M. Casellas Caro (Hospital Vall D'Hebron, Barcelona, Spain); Y. Canet (Hospital Parc Tauli de Sabadell, Barcelona, Spain); G. Pardi, M. Ravizza (Ospedale San Paolo, Milan, Italy); B. Guerra, M. Lanari, S. Bianchi, L. Bovicelli (Policlinico S Orsola, Bologna, Italy); E. Prati, M. Duse (Universita di Brescia, Brescia, Italy); G. Scaravelli, M. Stegagno (Universita La Sapienza, Rome, Italy); M. De Santis (Universita Cattolica, Rome, Italy); E. Ferrazzi, V. Savasi, A. Viganò (Ospedale L. Sacco, Milan, Italy); F. Ravagni Probizer, Prof A. Maccabruni (Policlinico S Matteo, Pavia, Italy); A. Bucceri, L. Rancilio (Clinica Mangiagalli and Clinica De Marchi, Milan, Italy); G.P. Taylor, E.G.H. Lyall (St Mary's Hospital, London, UK); Z. Penn (Chelsea and Westminster Hospital, London, UK); W. Buffolano, R. Tiseo (Pediatric Department, Federico II University, Naples, Italy); P. Martinelli, M. Sansone (Obstetric Department, Federico II University, Naples, Italy); C. Tibaldi, N. Ziarati, C. Benedetto (University di Torino, Turin, Italy); T. Niemieç (National Research Institute of Mother and Child, Warsaw, Poland); M. Marczynska, A. Horban (Medical University of Warsaw, Warsaw, Poland).