The median duration of antiretroviral treatment during pregnancy was 11 [interquartile range (IQR): 7–18] weeks for mothers who received only zidovudine monotherapy (n = 2115) and 20 (IQR: 11–37) weeks for mothers who received combinations of drugs (n = 6644). Treatment began before or during the first trimester of pregnancy (before 14 weeks of amenorrhea) in 31.5% of mothers, during the second or third trimester (14 weeks of amenorrhea) and later) for 64.5% and was solely perpartum and postnatal for 3.0% of mother–child pairs (Fig. 2). The timing of treatment initiation during pregnancy was unknown (missing data) for 1.0% of the mother–child pairs. Among children exposed during pregnancy, 98% received postnatal prophylaxis consisting mostly (82%) of zidovudine monotherapy for 4 or 6 weeks, and of zidovudine–lamivudine for most other children.
Cancers detected and circumstances of their detection
By 1 May 2007, 10 cases of cancer had been identified in the cohort: three cases of acute lymphoblastic leukemia, two cases of retinoblastoma (one bilateral, one unilateral), two cases of pineoblastoma, three cases of glioma (one cerebellar pilocytic astrocytoma, one biopsied chiasmatic tumor and one intraventricular fibrillary astrocytoma) (Table 1). Diagnostic procedures and treatment were administered in specialized pediatric oncology centers for all children. The mean age at onset of cancer was 54 months (range: 10–132), with six boys and four girls affected. The child with the chiasma tumor suffered from familial neurofibromatosis type 1 (NF1 or von Recklinghausen's disease) which predisposes to this type of cancer. A constitutional mutation in the RB1 gene was identified in the child presenting with bilateral retinoblastoma. The two tumors in children under the age of 2 years were both declared as part of the active follow-up of the cohort. The spontaneous notification system notified the coordinating center about the other eight. No additional cases were identified by crosschecking with the national register after having checked the identifiers of 618 children with concordant date and place of birth and sex. Conversely, all cases of hematopoietic malignancy from 1990 and all solid tumors from 2000 notified directly to the EPF cohort were also notified by the national registries. No case was observed in the 1852 uninfected children included in the EPF cohort not exposed to perinatal antiretroviral therapy.
All the children with tumors were exposed to nucleoside analogues during pregnancy: four were exposed to zidovudine monotherapy, three to a combination of zidovudine and lamivudine, two to a combination of zidovudine, didanosine and lamivudine and one to a combination of didanosine and lamivudine. Concerning the other classes of antiretroviral treatments, two mothers received nelfinavir and one ritonavir. Two children received two doses each of nevirapine.
Comparison of cancer incidence among exposed children included in Enquête Périnatale Française cohort with that in the general population
The present analysis was based on all 9127 children exposed at any time (prepartum, intrapartum, postpartum) to at least one NRTI between September 1984 and May 2007 (Acknowledgements); this represents 53 052 exposed person-years for ages 0–15 years old, and 10 746 for the period 2000–2004 when the national registries RNHE and RNTSE were both exhaustive.
The number of cancer cases observed in the cohort (10 cases) did not differ significantly from the expected numbers based on regional (8.9 cases; SIR = 1.1 [0.5–2.1]) or national (9.6 cases; SIR = 1.0 [0.5–1.9]) reference rates (Table 2). The result was similar when the analysis was restricted to children born and followed up during the period 2000–2004 with three cases of cancer observed for 2.1 or 2.3 expected. However, five of the tumors involved the central nervous system (CNS), whereas only 1.6 or 2.1 would be expected using the 1990–1999 regional and 2000–2004 national references [SIR = 3.1 (1.0–7.2), P = 0.05 and 2.4 (0.8–5.6), P = 0.12, respectively] (Table 2). Similar estimates were obtained for the period 2000–2004 when crosschecking with national registries became possible. Two of the five tumors of the CNS were pinealoblastomas. A third tumor was unusual: an intraventricular fibrillary astrocytoma. Conversely, 4.1 cases of other cancers (sympathetic nervous system tumors, renal tumors or other tumors) were expected over the study period and none was observed.
Factors associated with risk of cancer among children exposed to prenatal antiretroviral treatment
Among the 8853 children exposed to NRTIs during the prepartum phase, cancer was not associated with maternal geographical origin, drug addiction, last viral load before delivery or sex of the child. Prematurity was associated with cancer (P-logrank = 0.0018), with a hazard ratio (HR) of 10.0 (95% CI 2.1–48.5) for severe prematurity (<33 weeks) compared with full-term delivery. Combinations including both zidovudine and lamivudine, with or without other molecules except didanosine, were not associated with a higher risk of cancer than zidovudine monotherapy. The risk of cancer was significantly higher [HR: 12.5 (2.4–66.1)] in the 365 children exposed simultaneously to NRTI combinations including at least both lamivudine and didanosine, than the 2147 children exposed only to zidovudine monotherapy (Table 3 and Fig. 4). In utero exposure to the protease inhibitors nelfinavir or lopinavir was not significantly associated with a higher risk of cancer. Prematurity and lamivudine–didanosine combinations remained independently associated with cancer in a multivariate Cox model (Table 3). Adjustments for maternal CD4 cell count as a continuous variable did not change the results.
The long-term tolerance of anti-HIV perinatal prophylaxis should be evaluated, but there are several obstacles to the implementation of an epidemiological surveillance system able to detect potential adverse events among uninfected children. After the first 2 years of life (standardized follow-up), the children diagnosed as HIV-uninfected are generally no longer followed by the medical team that managed the perinatal period. For understandable reasons, the parents do not necessarily reveal the history of this perinatal exposure, or do not see the utility of doing so. Crossmatching of children included in HIV perinatal cohorts with children notified to national specific registries, as proposed recently by UK team for cancer screening , may be an appropriate approach to detecting such events without an active follow-up.
With 10 cases of cancer observed to date in our cohort, the overall risk of cancer was not greater than that for the general population [25,28], as previously suggested on two smaller cohorts [21–23].
In the EPF cohort, cancer cases were actively detected through the 2-year standardized follow-up, spontaneous declarations and crossmatching with national registries. Despite the large number of children included, the statistical power of the study was limited. With a power of 80%, and an α risk at 5%, the size of the present study allowed detection of SIR higher than two for all cancers, three for leukemia and four for CNS tumors. The median age of exposed children was only 5.4 years old (IQR: 2.9–8.3); a longer follow-up is warranted.
Five CNS tumors were observed, whereas only 1.6–2.1 (according to the reference rate used) were expected, and the difference was close to statistical significance (P = 0.05 to 0.12). The analysis restricted to the period 2000–2004 for which the French register of childhood cancers was exhaustive gave similar results with two observed tumors versus 0.3–0.4 expected. We used the two different reference rates that were available in France. For CNS tumors, the national rates produced by the national registries in the recent period 2000–2004 are higher than those of the previous regional registries, which covered around 30% of the French territory in 1990–1999. This is probably due to the increase in quality of notification and registration that came with the development of computerized hospital files, but an increase in incidence cannot be ruled out. Both incidence rates are consistent with those published at the same period in other western countries. The annual age-standardized incidence rate estimated in the 1990s by the French regional registries was 29.1 cases per million  and 29.9 per million in Europe over the 1988–1997 period . The rates estimated by the French national registries for 2000–2004 (36.1 per million; unpublished data) were also close to the figures reported in the United States (http://apps.nccd.cdc.gov/uscs/ChildhoodCancerData.aspx) and Germany (http://info.imsd.uni-mainz.de/K_Krebsregister/english/) (32.9 and 31 per million, respectively) for the same period.
The observation of two cases of pineoblastoma among the five CNS tumors, together with two cases of retinoblastoma, is worrying. Pineoblastoma is a rare tumor in children, with a mean of only three cases per year reported in the French national registry of solid tumors. It is also one of the secondary tumors that may affect children with hereditary retinoblastoma . Another tumor observed in this cohort, an intraventricular fibrillar astrocytoma or ‘holoventricular low-grade glioma’, is extremely rare .
Unexpectedly higher risk of cancer was observed for children who were exposed to combinations including didanosine–lamivudine than for those exposed to zidovudine monotherapy (adjusted HR = 13.6 [2.5–73.9]). Didanosine–lamivudine was given to less than 4% of treated women of the cohort and is associated with one-third of tumors. Given the small number of cancer events seen, interpretation of this difference must be cautious. We used a global logrank test with a single P-value to study the association between cancer incidence and the type of NRTI combinations ever administered during pregnancy, and not multiple tests to compare each of the five combination to the reference category (exclusive monotherapy). This P-value was very low (<0.0001) and remained lower than the Bonferroni corrected P-value threshold (0.05/8 = 0.006) taking into account eight statistical tests as we also tested separately the association between cancer incidence and seven molecules. Moreover, the hazard ratio associated with ‘didanosine and lamivudine’ was very high (12.5) and the lower bound of 95% CI strongly higher than the unity: 95% CI 2.4–66.1. Interestingly, a rare neuroectormic tumor (melanotic progonoma tumor) was recently diagnosed in a child exposed to a didanosine–lamivudine combination but not included in the EPF cohort (D. Plantaz, MD, Grenoble, France, personal communication).
A scale of genotoxicity for several NRTI combinations has been recently suggested on the basis of data from in-vitro mutagenesis assays for hypoxanthine–guanine phosphoribosyl transferase (HPRT) and thymidine kinase. The combinations were ranked as follows in decreasing order: zidovudine–didanosine > didanosine–lamivudine > zidovudine–lamivudine , but no comparative assay of these combinations in animal models of in utero exposure for tumor induction has been published. The combination of didanosine and lamivudine has been rarely prescribed for pregnant women. However, didanosine is now sometimes used as secondary or subsequent treatment and an increasing number of exposed children might be expected. In chronically HIV-1 infected adults and children, there is no evidence that zidovudine or other NRTIs alone or in combination contribute to the development of cancers despite 20 years of use. However, fetal and neonatal exposure may be a particular situation. Fetal and neonatal life is characterized by intense DNA replication activity and the activation of many oncogenes and tumor suppressor genes. Exposure to a genotoxic agent during this period may, therefore, have consequences different from those observed in adults . In newborn and infants, exposure to zidovudine in utero leads to biological abnormalities, reflecting this genotoxicity. Thus, the integration of zidovudine into the DNA of neonates exposed to the drug in utero  may lead to mutagenesis  or other abnormalities, such as an increase in the frequency of micronuclei in erythrocytes  or an increase in heterochromatin dispersion . The effects of other NRTIs alone or in combination have been less studied experimentally; nevertheless, some of them show effects in vitro similar to those of zidovudine and/or induce an additive or synergistic effect in combination. Our findings certainly highlight the need for further data concerning the genotoxicity of the various NRTI combinations.
Antiretroviral combinations are extremely powerful prophylaxis for HIV mother-to-child transmission but an effort to select genotoxicity-free combinations is justified.
All authors contributed significantly to this work. V.B. was the project coordinator. J.W. was the leader of EPF cohort, assisted by R.T., L.M. and S.B. for clinical aspects. J.C. and B.L. were the leaders of cancer registries, assisted by F.D., N.A. and M.L. for cases review. F.B. transmitted data from pharmacovigilance network. J.W., J.C., B.L. and S.Be. performed the statistical analysis. S.B. and J.W. initiated the project. Main writing process was done by V.B., J.W., J.C. and S.B. All authors reviewed and approved the papers before final submission.
We thank all families who agreed to participate in this study. We thank also Dr B. Pautard (Amiens), J. Tricoire (Toulouse), J.L. Stephan (Saint Etienne), S. Marthas (Dijon) and J. Grill (Villejuif), M. Zerah (Paris), I. Thuret (Marseille) for collaboration and data transmission.
The present work was supported by the Agence Nationale de Recherche sur le SIDA (ANRS) and the Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS). French childhood cancer registries are supported by Institut de Veille Sanitaire (InVS) and Institut National pour la Santé et la Recherche Medicale (INSERM).
The authors have no conflicts of interest.
The following persons and institutions participated in the ANRS French Perinatal Cohort (EPF).
Aix-en-Provence: Brusquet Y., Opimel P., Tadrist B., Thevenieau D., Tramier D.; Amiens: Boulanger J.C., Douadi Y., Gondry J., Horle B., Pautard B., Roussel C., Schmidt J.L., Smail A., Vergne C.; Angers: Achard, Binelli C., Chennebault J.M., Fournie A., Grosieux P., Rialland X.; Argenteuil: Allizy C., Brault D., Genet P., Piquet, Rischebe, Tordjeman N.; Aubervilliers: Rozan M.A.; Basse-Terre: Couchy B., Sibille G., Sid Elmrabt S.; Bastia: Bastien, Belgodere, Colombani D., Lonrenzi, Pincemaille O., Salvetti A., Turquini; Bayonne: Bonnal F., Cayla C., Chabanier C., Guerre P., Hernandorena X.; Besançon: Bassignot A., Bettinger Lab M., Chirouze C., Estavoyer J.M., Leroy J., Maillet R., Schaal J.P.; Blanc Mesnil: Bajer A., Balde P.; Bobigny: Deny P.; Bondy: Benoist L., Carbillon, François F., Jeantils V., Lachassinne E., Rodriguez A., Uzan-Cohen M.; Bordeaux: Beylot J., Brun J.L., Douard D., Elleau C., Fleury H., Guyon F., Horovitz J., Lacoste, Leng J.J., Masquelier B., Morlat P., Pontgahet M., Ragnaud, Roux D., Schaeffer V.; Boulogne Billancourt: Gilles I., Zenaty D.; Bourg La Reine: Gantzer A.; Bullion: Colin-Gorki A.M.; Caen: Barjot P., Brouard J., Freymuth F., Goubin P., Muller G., Petit J., Six M.; Cayenne: Delattre P., Elenga N., Magnien C., Patient G.; Clamart: Bornarel D., Chambrin V., Clech L, Dehan M., Dommergues, Foix L., Frydman R., Keros L., Vial M.; Clichy: De Curtis A., Levardon M., Mazy F.; Colombes: Crenn-Hebert C., Engelmann P., Ferreira C, Floch-Tudal C., Gaba S., Joras M., Mandelbrot L., Marty L, Mazy F., Meier F.; Compiègne: Coicaud M., Lagrue A., Meriem D.; Corbeil Essonnes: Blasquez, Daveau C., Devidas A., Lotfy N.; Courbevoie: Botto, Bourdon P.; Creil: Cesbron P., Cordier F., Devulder G., Duval-Arnould M., Kingue-Ekollo C.; Creteil: Cortey A., Delacroix I., Elharrar B., Garrait V., Huraux-Rendu C., Paniel J.B., Touboul C.; Dijon: Buisson M., Guerin M.N., Kohli, Martha S., Reynaud I., Rousseau T., Sagot P.; Dourdan: Guth, Ercoli V.; Drancy: Boddaert M.; Dreux: Denavit M.F., Garnier J., Roudiere, Tribalat S.; Elbeuf: Lahsinat K., Paquet M., Pia P.; Evreux: Allouche C., Elhaik, Pascal C., Toure K.; Evry: Farvacque R., Grall F., Khanfar, May A., N'guyen R.; Fontainebleau: All-Issa K., Cosnefroy, Cote, Dallot M.C., Fillipini, Kalengi, Lhuillier P., Routier C.; Fort de France: Cabie A., Cecile W., Hatchuel Y., Mezin R., Ouka M., Sainte-Rose D.; Gonesse: Balde P., Dauptain G., Lobut J.B. Paindaveine; Ivry: Gervais A., Jault T., Jrad I., Pathier D., Lagny sur Marne, Agbo P., Algava G., Chalvon Dermesay A., David Ouaknine F., Gourdel B., Lanty C., Lerudulier C., Pfeiffer F.; Le Chesnay: Beal G., carre N, Harzic M., Hentgen,Jacquemot M.C., Lasfargues P., Messaoudi F., Teboul; Le Kremlin Bicêtre: Bader-Meunier B., Desfraissy J.F., Goujard C., Fridmann S., Peretti D.,; Le Lamentin: Chout, Monlouis M.; Lille: Bocket L., Codaccioni X., D'Angelo S., Delmas S., Hammou Y., Mazingue F., Vanderstichele S.; Limoges: Alain J., Denis F., Rogez S., Tabaste J.L., Venot C.; Longjumeau: Abbara A., Bailly Salin P., Blanchard I., Bronstein R., Dalvilic S., De San Pedro, Lemercier Y., Seaume H.; Lyon: Andre, Bertrand Y., Brochier C., Communal P.H., Cotte L., Kebaili K., Raudrant D., Ritter J., Roussouly M.J., Tardy, Thouarain V.; Mantes La Jolie: Berardi J.C., Botto C., DeLanete A., Doumet A., Furioli J., Granier F.,Grise, Salomon J.L., Wipff P.; Marseille: Blanc B., Cravello L., Deboisse P., Gallais H., Michel G., Pelloux, Tamalet C., Thuret I.; Meaux: Crumiere C., Demachy M.C., Karaoui L., Lefevre V., Michel F., Morel B.; Melun: Kleitz, Le Lorier B., Pauly-Ravelly I., Ponge B.; Meulan: Robichez, Seguy D.; Montfermeil: Camus M., Dehlinger M., Echard M., Mullard C., Rideau F., Ropert, Talon P.; Montpellier: Benos P., Boulot P., Bouzinger, Dechaud H., Guigue N., Laffargue F., Lalande M., Nicolas J., Reynes J., Segondy B., Sobierajski J., Vendrel; Montreuil: Heller-Roussin B., Saint-Leger S., Winter C.; Nancy: Delaporte M.O., Hubert C., May T., Neimann L., Schweitzer M.; Nanterre: Karoubi P., De Sarcus B.; Nantes: Auger M., Billaudel S., Brunet-François C., Boog G., Ferre V., Mechinaud F., Reliquet V., Winer N.; Neuilly sur Seine: Berterottiere D., Boto; Nice: Allione J., Bongain A., Cottalorda J., Couderc A., Deville A., Durant J., Galiba E, Gillet J.Y., Monpoux F.; Nîmes: Arnaut A., Barbuat C., Carles M.J., Dendale J., Ferrer C., Rouannet I., Sotto A.; Orléans: Arsac P., Barthez, Bondeux D., Mesnard L., Tescher M., Werner E.; Orsay: De Gennes C., Devianne, Drisset, Isart V., Razon; Perpignan: Bachelard G., Bachelard B., Medus M., Roudil; Pointe-à-Pitre: Bardinet F., Bataille, Duffilot D., Samar K, Sow M.T., Strobel M.; Poissy: Nisand I., Pavard, Rousset M.C.; Pontoise: Blum L., Danne O., Hervio P., Mouchnino G., Muray; Reims: Beguinot I., Graesslin O., Ingrand D., Munzer M., Quereux C., Remy G., Rouger C., Saniez D.; Rouen: Borsa-Lebas F., Brossard V., Buffet-Janvresse C., Clavier B., Debab Y., Marpeau L., Vannier J.P.; Saint-Etienne: Berger C., Billiemaz K., Fresard A., Pozzetto B., Stephan J.L., Varlet M.N.; Saint-Denis: Allemon M.C., Ekoukou D., Ghibaudo N., Khuong M.A., Luzolo A., Mechali D., Normand V., Poupard M.P., Retbi J, Retbi J.M., Rotten D., Seffert; Saint-Germain en Laye: Guyot B., Michelon, Narcy P.; Saint-Martin: Bissuel F., De Caunes F., Elouedghiri, Laborde O., Walter V.; Saint-Maurice: Jeny R., Robin; Sèvres: Belaisch-Allart J., Segard L.; Strasbourg: Brettes, Cheneau C., David, Dreyfus M., Entz-Werle N., Favreau J.J., Fischer P., Lang J.M., Langer B., Lutz P., Nisand I., Partisani M., Ritter, Treisser A., Vayssiere C., Weill M.; Suresnes: Clement, Colau J. C.; Toulouse: Armand, Berrebi A., Cohen M., De Coster P., Lecuyer I., Massip P., Perez-Baronne, Puel J., Reme J. M., Tricoire J.; Tours: Bansard H, Bastides F., Besnier J.M., Borderon J.C., Barin F., Lansac, Lionnet C., Marchand S Nau P, Pascale, Perrotin F., Potin J., Sigogneau H; La Trinité: Hugon N.; Vandoeuvre Les Nancy: Finance, Le Faou; Villejuif: Dussaix E.; Villeneuve Saint Georges: Bantsimba J., Bonnard C, Camuss A, Chace A., Guillot F., Jubin C., Maria B., Montaland F, Patey O., Richier L, Stampf F., Tran Van P.; Villepinte: Boulanger M.C., Broyard A., Caruge, Caubel P., Chitrit Y., Delassus J.L., Goldenstein, Le Pennec M., Poulen, Scart G., Zakaria A.; Vitry sur Seine: Lacroix-Coutry A., Sturbois G. Paris: ASE St Vincent de Paul, Commeau A.; Centre d'Hémobiologie Périnatale: Parnet Mathieu F.; Clinique Notre Dame de Bon Secours: Ayral D., De Kermadec S.; Groupe Hospitalier Cochin Tarnier Port-Royal: Brival, Cabrol D., Clement D., Compagnucci A., Desfeux P., Fikenstein, Firtion G., Goupil I., Henrion R., Launay O., Mandelbrot L., Pannier E., Pons J.C., Taulera; Hôpital Boucicaut: Bardin C., De Bievre P., Gras V., Labussiere E., Lafay Pillet M.C., Parat S., Taurelle R.; Hôpital Robert Debré: Bensaid Ph., Blot P., Boissinot Ch., Cotten G., Faye A., Levine M., Ottenwalter A., Oury J.F., Schaller F., Vilmer E.; Hôpital Trousseau: Chenon, Dollfus C., Gabarg-Chenon A., Tabone, Vaudre G., Institut de Puériculture Brune, Dubois M., Hôpital Lariboisière, Brunner C., Ciraru-Vigneron N., Peynet J., Colonna R., Sanson-Lepors, Truc; Hôpital des Métallurgistes: Cheynier J.M., Hatem-Gantzer G., Heller-Roussin B., Rami M.; Hôpital Rothschild: Fritel, Lebrette M.G., Nicolas J.C., Uzan M., Wallet A.; Hôpital Saint-Antoine: Bouillie J., Bui E., Carbonne B., Meyohas M.C., Milliez J., Rodriguez J., Schrub S.; Centre Hospitalier Pitié Salpetrière: Agut H., Bricaire F., Daher S., Diop A., Darbois Y., De Montgolfier, Dermer E., Deville-Chabrol A., Dommergues M., Huraux J.M., Noseda G., Pauchard M., Tubiana R., Hôpital Saint-Vincent de Paul, Boccara J.F., Francoual C., Krivine A., Lebon P.; Institut Mutualiste Montsouris: Carlus Moncomble C., Cohen H., Groupe Hospitalier Necker, Benachi A., Blanche S., Burgard M., Diop A. Parat S., Rouzioux C., Viard J.P.; Hôpital Saint-Michel: Aufrant C.; Hôpital Bichat-Claude Bernard: Allal, Bastian H., Batallan A., Brun-Vezinet F., Bernard, Damond F., Darai E., Faucher Ph., Longuet P., Madelenat P, Matheron S., Mazy F, Moreau G., Proust A., Rajguru M, Simon F.; Hôpital Tenon: Berkane N., Chaux M.C., Herve F., Lebrette M.G., Uzan S.
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
cancer; didanosine; HIV-1; lamivudine; nucleoside reverse transcriptase inhibitor; pregnancy; prophylaxis; zidovudine