Risk factors of mother-to-child transmission in term births with virological failure
In the 364 women who term delivered with viral load ≥ 10 000 copies/ml, the MTCT rate was: 6.6% (95%CI, 4.3–9.7%). Intrapartum prophylaxis was strongly associated with a lower risk of transmission: 5.3% (18/339) versus 22.7% (5/22) without intrapartum prophylaxis (P = 0.009) (Table 2). Mothers who booked in the first trimester had a lower transmission risk (1.9%) than those booking in the second (9.9%) or third trimester (10.9%) (P = 0.03). These two factors remained associated with MTCT after adjustment in both initial and final stepwise logistic regression models (Table 3). The ORa associated with no intrapartum therapy was 4.72 (95%CI, 1.42–15.71; P = 0.011).
Risk factors of mother-to-child transmission in term births with virological success
In the 2856 mothers who term delivered with viral load below 400 copies/ml, the MTCT rate was 0.6% (95%CI, 0.3–1.0%). The rate was as low as 0.4% (5/1338; 95%CI, 0.1–0.9) in women who delivered with viral load below 50 copies/ml. Global duration of ART was the only significant risk factor which remained in the initial and final models issued from stepwise logistic regression. The OR for each increment week was: 0.94 (95%CI, 0.90–0.99; P = 0.031). Included in the model instead of global ART duration, time at initiation of ART or duration of last ART were also correlated with transmission (P = 0.011 and 0.013, respectively). Similar results were obtained when children with missing HIV status were included as uninfected. Among the more homogenous subgroup of 780 women who booked at first trimester and received HAART, the transmission rate was: none of 392 for women already treated at the onset of pregnancy; 1.0% (2/192) when ART was started in the first trimester; 0.9% (1/113) in the second trimester; and 3.6% (3/83) in the third trimester (P = 0.006). It is of interest to note that the five mothers who transmitted despite viral loads below 50 copies/ml started therapy relatively late, between 32 and 33 weeks. Among the infected children term born to mothers having less than 400 copies/ml at delivery, 43% had a positive HIV1 PCR in the first 3 days, suggesting in-utero transmission. This proportion was 21% at 10 000 copies/ml or more (Fig. 1).
The objective of this study, the largest to date of HIV-1 mother-to-child transmission in the HAART era, was to identify risk factors for persistent cases of transmission despite the use of antiretroviral therapy during pregnancy. During the period 1997–2004, the rate of HIV-1 transmission from mothers receiving any antiretroviral therapy during the pregnancy was 1.3% (95% CI, 1.0–1.6). Similar rates are reported during the same period in other studies from industrialized countries [2,4,26]. Three main factors were independently related to transmission: high maternal plasma viral load near delivery, short duration of antenatal antiretroviral therapy and very premature delivery. We also found an independent association with gender as previously reported [27–29].
Maternal viral load clearly stands out as the key determinant of MTCT risk, as has been consistently reported in all studies [2,6,30–37]. In term births, the MTCT rate was 10 times higher when last maternal plasma HIV1 RNA was above rather than below 10 000 copies/ml (7.2 versus 0.8%, P < 0.01). The rate was 0.5% below 400 copies/ml and as low as 0.4% below 50 copies/ml.
In French guidelines issued in the study period, zidovudine monotherapy was restricted to women who did not require therapy for their own health and had pretherapeutic plasma viral loads below 10 000 copies/ml . Thus monotherapy was indicated in women at lower risk of transmitting the virus, which was likely to explain that MTCT rate did not differ according to the antiretroviral regimen. Be that as it may, our data confirmed that good control of maternal viral load is a key method to prevent MTCT, whatever the type of antiretroviral strategy used to obtain it.
Maternal viral load above 10 000 copies/ml at term delivery should not occur according to accepted guidelines [6,38]. This situation concerned less than 10% of mothers, but contributed to half of the infected children. It occurred even though 45% delivered with HAART and 27% with dual-drug therapy, and may be due to poor adherence, multidrug resistance or treatment interruptions related to poor tolerance, or late access to adequate prenatal care, significantly associated with transmission. Intrapartum prophylaxis appeared to have a strong protective effect in the case of virological failure. In contrast, among women with viral loads below 10 000 copies/ml, there was no case of transmission among the 125 women who did not receive intrapartum prophylaxis.
MTCT rate was inversely related to duration of antenatal therapy. Relation with very short zidovudine monotherapy was previously demonstrated in Thailand . The nonlinear increasing risk in our survey reflected the high rate of transmission in very premature births with low duration: poorer control of HIV viral load due to an unexpectedly short time between the start of maternal therapy and delivery may partly explain the association between transmission and severe prematurity. Overall, the rate was six-fold higher when deliveries occurred before 33 weeks than at 37 weeks or more. Two results suggest that other factors, not collected in EPF during the study period, may increase perinatal exposure to HIV in severely preterm delivery, such as preterm premature rupture of the membranes, abruption, and chorio-amnionitis: the association remained significant after adjusting for duration of ART, maternal plasma viral load, mode of delivery and intrapartum prophylaxis; the transmission rate was not increased in cases of moderately premature deliveries.
In term births, the increasing risk of transmission with duration of therapy seemed more related to a very low transmission in women who were receiving ART since the first weeks of pregnancy. The time needed to achieve undetectable HIV RNA by the time of delivery may partly account for this finding, as it is generally obtained in non-pregnant adults by 10 to 16 weeks . In addition, in-utero transmission may occur before therapy is initiated or effective. Presumed in-utero transmission occurred in nearly one-half of the children term born with maternal HIV1 RNA level below 400 copies/ml.
Elective cesarean section tended to be associated with a lower risk of MTCT in the overall population; however, we observed no significant difference in transmission risk according to the mode of delivery among women who delivered with viral load below 400 copies/ml (crude OR, 0.83; 95% CI, 0.29–2.39; P = 0.37). A protective effect of elective cesarean section was established in our cohort  and others [17,18], in the absence of antiretroviral prevention and in a period when standard care was zidovudine monotherapy. It is unclear whether such a protective effect persists in women receiving ART with low viral load at delivery. Data from the PACTG [26,40] failed to show a difference in transmission rate according to mode of delivery in treated women with low viral loads. A recent study reported an association between the mode of delivery and mother-to-child HIV-1 transmission risk, although the association was not statistically significant in the subgroup of women receiving antenatal HAART . In our study, women who received HAART and delivered with viral load below 400 copies/ml had a transmission rate of 0.4% (3/747) with elective cesarean and 0.5% (3/574) with vaginal delivery (P = 0.35), but the power to show a two-fold decrease was only 18%. The potential benefit of systematic cesarean delivery would have to be balanced with the risks, in a scenario where at least several hundred operations would be required to avoid one case of transmission [11,41].
The methods available today are able to reduce MTCT to well below 1%. Our data confirm the major impact of achieving an undetectable maternal plasma viral load, with only 0.4% transmission among term-born children whose mothers had viral loads below 50 copies/ml at delivery. The most consistent means available to obtain such a control of viral replication is the use of triple combination therapy. Furthermore, our findings strongly suggest that antiretroviral therapy should be started relatively early, at the latest by 28 weeks, to obtain maximum efficacy. Any incremental benefit of more aggressive and/or longer antiretroviral exposure, however, has to be evaluated against the risks of toxicities, such as adverse events during pregnancy, prematurity, neonatal malformations or mitochondrial dysfunctions in uninfected infants [11,42,43]. The key challenge is to improve early access to specific care and treatment as well as adherence in pregnant women in order to achieve viral suppression during the last trimester of the pregnancy.
We thank Valerie Benhammou, Karima Hamrene, Yassine Benmebarek, Corinne Laurent, Elisa Ramos, Marlène Peres.
Josiane Warszawski declares herself to be independent of any commercial funder, to have performed the statistical analysis and have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
The persons and institutions who participated in the ANRS French Perinatal Cohort (EPF) are listed below (* indicates sites currently closed).
Hôpital d'Aix en Provence* (Tadrist B.); Hôpital Nord, Amiens (Schmit J.L., Horlé B.); Hôpital d'Angers (Fournié A.); Hôpital Victor Dupouy, Argenteuil (Brault D.); Hôpital Paris La Roseraie*, Aubervilliers (Rozan M.A.); Hôpital Robert Ballanger, Aulnay (Zakaria A.); Hôpital Saint Claude, Basse-Terre* (Sibille G.); Hôpital de Bastia (Pincemaille O.); Hôpital de la Côte Basque, Bayonne (Cayla C.); Clinique du Blanc Mesnil* (Balde P.); Hôpital Saint Jacques, Besançon (Estavoyer J.M.); Hôpital Avicenne, Bobigny (Bentata M.); Hôpital Jean Verdier, Bondy (Lachassine E., Rodrigues A.); Hôpital Pellegrin, Bordeaux (Roux D., Douard D.); Hôpital Ambroise Paré*, Boulogne Billancourt (Zenaty D.); Hôpital Clémenceau, Caen (Brouard J.); Hôpital André Rosemon, Cayenne (Elenga N.); Hôpital Beaujon*, Clichy (De Curtis A.); Hôpital de Creil (Kingue-Ekollo C.); Hôpital Intercommunal, Créteil (Garrait V., Lemerle S., Pichon C.); Hôpital Béclère, Clamart (Chambrin V., Labrune P., Clech L.); Hôpital Louis Mourier, Colombes (Crenn-Hebert C., Floch-Tudal C.); Hôpital de Compiègne* (Lagrue A.); Hôpital d'enfants, Dijon (Reynaud I.; Martha S.); Hôpital de Dourdan* (Ercoli V.); Hôpital de Dreux* (Denavit M.F.); Hôpital des Feugrais*, Elbeuf (Lahsinat K.); Hôpital Intercommunal, Evreux (Touré K.); Hôpital Francilien Sud, Evry-Corbeil (Devidas A., May A., Granier M.); Hôpital de Fontainebleau (Routier C.); Hôpital Victor Fouche, Fort de France (Hatchuel Y.); Hôpital de Gonesse* (Balde P.); Hôpital Jean Rostand, Ivry (Jault T.); Hôpital de Lagny (Chalvon Demersay A.); Hôpital du Lamentin* (Monlouis M.); Hôpital Les Oudairies, La Roche sur Yon (Perré P); Hôpital de La Seyne sur Mer (Chamouilli J.M.); Hôpital Louis Domergue, La Trinité* (Hugon N.); Hôpital André Mignot, Le Chesnay (Hentgen V., Messaoudi F.); Hôpital de Bicêtre, Le Kremlin-Bicêtre (Peretti D., Fridman S); Hôpital Jeanne de Flandres, Lille (Mazingue F., Hammou Y.); Hôpital Dupuytren*, Limoges (De lumley L.); Hôpital de Longjumeau (Seaume H.); Hôpital Hôtel Dieu-Hôpital Debrousse, Lyon (Cotte L., Kebaïli K.); Hôpital François Quesnay, Mantes La Jolie (Doumet A.); Hôpital la Conception, Marseille (Cravello L., Thuret I.); Hôpital de Meaux (Karaoui L.); Hôpital de Meulan* (Seguy D.); Hôpital Marc Jacquet, Melun (Le Lorier B.); Hôpital Intercommunal, Montfermeil (Talon P.); Hôpital Arnaud de Villeneuve, Montpellier (Benos P., Lalande M.); Hôpital Intercommunal, Montreuil (Heller-Roussin B.); Maternité Régionale A. Pinard, Nancy (Hubert C.); Hôpital de Nanterre* (Karoubi P.); Hôpital de Nantes (Reliquet, V., Brunet-François C.); Hôpital de Neuilly sur Seine* (Berterottiere D.); Hôpital l'Archet-Fondation Lenval, Nice (Monpoux F., Bongain A., Deville A.); Hôpital Caremeau, Nîmes (Dendale J.); Hôpital Orléans (Arsac P.); Hôpital d'Orsay (De Gennes C.); Hôpital Bichat, Paris (Matheron S., Batallan A.); Hôpital Boucicaut*, Paris (Lafay Pillet M.C.); Hôpital Cochin-Port Royal, Paris (Firtion G., Pannier A); Hôpital Lariboisière, Paris (Ciraru-Vigneron N.); Hôpital des Métallurgistes*, Paris (Rami M.); Institut Mutualiste Montsouris*, Paris (Carlus Moncomble C.); Hôpital Necker, Paris (Parat S., Blanche S., Rouzioux C.); Hôpital Notre Dame du Bon Secours, Paris (Ayral D.); Hôpital Pitié Salpêtrière, Paris (Tubiana R.); Hôpital Robert Debré, Paris (Levine M., Faye A., Ottenwalter A.); Hôpital Rothschild, Paris (Wallet A.); Hôpital Saint-Antoine, Paris (Carbonne B.); Hôpital Hôpital Saint Michel, Paris (Aufrant C.); Hôpital Tenon, Paris (Lebrette M.G.); Hôpital Trousseau, Paris (Dollfus C.); Hôpital Marechal Joffre, Perpignan (Medus M.); Hôpital Les Abymes, Pointe-à-Pitre (Bataille H.); Hôpital de Poissy-Saint-Germain en Laye* (Rousset M.C.); Hôpital René Dubos, Pontoise (Mouchnino G.); Hôpital Américain, Reims (Munzer M.); Hôpital Charles Nicolle, Rouen (Brossard V.); Hôpital de Saint-Denis (Allemon M.C., Ekoukou D., Khuong M.A.); Hôpital Nord, Saint Etienne (Billiemaz K.); Hôpital de Saint Martin (Bissuel F.); Hôpital Esquirol*, Saint-Maurice (Robin M.); Hôpital de Sèvres* (Segard L.); Hôpital de Haute Pierre-Hôpital Civil, Strasbourg (Partisani M., Favreau, J. J, Entz-Werle N.); C.M.C. Foch, Suresnes* (Botto C.); Hôpital Chalucet,Toulon (Hittinger G.); Hôpital La Grave, Toulouse (Berrebi A., Tricoire J.); Hôpital Bretonneau, Tours (Besnier J.M.); Hôpital Brabois, Vandoeuvre les Nancy (Neimann L.); Hôpital Paul Brousse*,Villejuif (Dussaix E.); Hôpital de Villeneuve Saint Georges (Guillot F., Chacé A.).
Sponsorship: this study was supported by the French National Agency for AIDS Research (ANRS), Paris, France.
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
cohort; epidemiology; HIV; prevention of mother-to-child transmission; public health