Over the past 15 years, a spectacular decrease in mother-to-child transmission (MTCT) of HIV-1 has been obtained in industrialized countries leading to transmission rates on the order of 1–2% [1–5], largely as a result of antiretroviral therapies (ARTs). The first antiretroviral (ARV) prevention was zidovudine (ZDV) monotherapy, which was progressively replaced by dual therapy with nucleoside analogs and then triple combination therapies known as HAART, which is now recommended for the prevention of transmission, even in women without an indication for themselves .
The adverse effects of ART use in pregnancy are an important topic for concern. There is ongoing debate about a relationship between HAART and preterm delivery. HAART was found to be associated with prematurity in some surveys [7–10] but not in others [11–15]. Lower birth weight adjusted for gestational age was found to be associated with in-utero exposure to HAART, compared with mono or dual therapy, in the United Kingdom and Ireland National Study of HIV and Pregnancy and Childhood . In Cote d'Ivoire, lower birth weight (<2500 g) was recently reported in infants exposed to HAART compared with mono or dual therapy of nucleosidic reverse transcriptase inhibitors (NRTIs), not taking into account gestational age . Other surveys did not find any relation between low birth weight and in-utero HAART [10–13,17]. The proportion of low birth weight decreased between 1989 and 2004 in the US longitudinal Pediatric Spectrum of HIV disease, whereas HAART use during pregnancy increased .
Some discrepancies may be related to three kinds of methodological issues. First, all studies except one  included both HIV-infected and noninfected children, though in-utero HIV infection per se may be associated with intrauterine growth retardation [19–21]. Second, with the usual definition of low birth weight as less than 2500 g, preterm and small-for-gestational age (SGA) children are not distinguished. The association between birth weight and ARV exposure was not adjusted for gestational age in most of surveys, except in two studies, using logistic regression  or birth weight Z-score . Third, lower birth weight observed in neonates exposed to in-utero HAART, compared with ZDV monotherapy, may be partly due to indication bias. HAART became available in 1996 and progressively replaced mono and dual therapy of NRTI. However, it was prescribed initially to mothers who had lower virological and immunological status before becoming the standard of care for prevention of MTCT.
We aimed to study here whether ART administered during pregnancy may have an effect on anthropometric parameters at birth, independently of gestational age at delivery in children noninfected by HIV, and whether it increased risk of SGA birth. The large number of mother–child pairs included in the Agence Nationale de Recherche sur le SIDA (ANRS) French Perinatal Cohort provided us the opportunity to address methodological issues.
The ANRS French perinatal cohort
Since 1986, the ANRS French Perinatal Cohort (EPF-CO-01) has prospectively enrolled HIV-infected women who delivered in 90 centers throughout France . Informed consent was obtained from all mothers. No specific recommendation for HIV treatment and obstetric care was made for women included in the cohort, though French national guidelines for prevention of mother-to-child HIV transmission were regularly published and updated . The national policy since 1993 is to offer universal voluntary HIV testing as a part of prenatal care. Antenatal prophylaxis was based on ZDV monotherapy since 1994 or, since 1997 on dual nucleosidic therapy, with elective caesarean section according to risk/benefit evaluation. HAART was recommended to mothers with viral load above 10 000 copies/ml in 2002 and to all mothers in 2004. Since 2002, elective caesarean section was not recommended for those who delivered under HAART with viral load below 400 copies/ml. In all cases, intrapartum ZDV infusion and neonatal prophylaxis were recommended. This cohort study was approved by the Hôpital Cochin IRB and the French computer database watchdog commission (Commission Nationale de l'Informatique et des Libertés).
All live-born neonates born to HIV-infected mothers between 1/1/1990 and 31/12/2006 enrolled in the ANRS French Perinatal Cohort (EPF CO-01) were included in the present analysis, if they did not present obvious obstetrical risk factors of low birth weight—illicit drug use during pregnancy (n = 317) or twin pregnancies (n = 396). We also excluded HIV-infected neonates diagnosed by virologic tests done on site on two separate samples or if anti-HIV 1 antibodies detected by enzyme-linked immunosorbent assay and western blot persisted after 18 months of age (n = 439). We also excluded mothers who booked at maternity after 28 weeks gestation to avoid selecting children whose mothers had inadequate prevention strategies (no or short ART) because they booked too late or at delivery (n = 1321). Overall, 8192 neonates were included in the analysis.
We recorded maternal, obstetrical and HIV care informations—maternal age, geographical origin (categorized as Sub-Saharan African countries, Metropolitan France or other origins), parity, time at booking at obstetrical center (before or after than 14 gestational weeks), time at starting and ending ART, levels of CD4 cell count nearest to the time of delivery (categorized as less than 200, 200–349, at least 350 cells/μl), mode of delivery (vaginal, emergency caesarean section or elective caesarean section), and gestational age at delivery. Gestational age was recorded by the last menstrual period, corrected when appropriate by the date of conception determined by early ultrasound.
Weight, height and head circumference were measured at birth.
Birth weight, height and head circumference Z-scores, adjusted for gestational age at delivery and sex, were established using French standards, calculated from AUDIPOG (French Association of Users of Computerized Medical Records in Paediatrics, Obstetrics and Gynaecology Sentinel Network ), concerning 211 337 infants born in 209 French maternities between 1999 and 2005, close to our study period. In a normally grown cohort, the expected mean value for the Z-score is zero, and approximately 95% of observations are comprised in ±2 standard deviations (SD) range. An infant was considered to be SGA if birth weight Z-score was inferior to −2SD, following the international recommendations .
ARV exposure was categorized into four groups: no ART during pregnancy; NRTI monotherapy exclusively; dual NRTI therapy; HAART defined as more than three drugs prescribed simultaneously.
We first described changes in characteristics of the study population, strategies of prevention of MTCT, gestational age at delivery, anthropometric parameters and proportion of neonates SGA. We considered five periods: 1990–1993 (no ART during pregnancy), 1994–1996 (ZDV monotherapy as standard); 1997–1998 (dual nucleoside therapy trial and first availability of HAART); 1999–2004 (HAART widespread); 2005–2006 (HAART as standard for all). Categorical variables were compared using χ2 tests or Fisher's exact tests, and means using Student tests.
We then studied statistical association between ART exposure and anthropometric outcomes. Association with SGA birth was studied using univariate and multivariate logistic regressions. Association with birth weight Z-scores was studied using univariate and multivariate linear regression models fitted to obtain regression coefficients (differences of mean Z-scores) with 95% confidence interval (CI). Models were all adjusted for maternal geographical origin, maternal age, parity and gestational age at booking. Similar analyses were performed for height and head circumference. We did not adjust for year of birth as it was collinear with the type of ART exposure and for mode of delivery as elective cesarean can be a consequence of intrauterine growth retardation.
Analyses were conducted using the SAS statistical software (version 9.1; SAS, Institute, Inc., Cary, North Carolina, USA). A P value of less than 0.05 was used to determine statistical significance.
Description of study population
Overall, 8192 singleton neonates, non-HIV-infected, born to HIV-infected non drug-user mothers between 1990 and 2006 were included. Over this period, maternal age and proportion of women originating from sub-Saharan African countries increased. The proportion of elective caesarean started to increase in 1997–1998 to reach 50% in 1999–2004 and decreased subsequently to 33% in 2005–2006 (Table 1). The proportion of genital tract infections decreased between 1990 and 2006, from 39 to 18% (data not shown). The proportion of gestational diabetes increased between 1990 and 2006, from 2.3 to 5.3%, and the proportion of preeclampsia remained stable between 1997 and 2006 around 2% (Table 1).
The proportion of mothers who received monotherapy exclusively decreased from 80% in 1994–1996 to 19% between 1999 and 2004 and 2% in 2005–2006. Conversely, the proportion of women who received HAART increased from 14% in 1997–1998 to 59% between 1999 and 2004 and 90% in 2005–2006. Combinations based on protease inhibitor and NRTIs [with no non-nucleosidic reverse transcriptase inhibitor (NNRTI)] accounted for 73% of last HAART regimen during pregnancy between 1999 and 2004 and 86% during 2005–2006 (Table 1).
Changes over time of birth anthropometric parameters
The mean birth weight and gestational age at delivery slightly decreased from 3150 g and 39 weeks before 1996 to 3050 g and 38 weeks subsequently (Table 1). Figure 1 shows that curves of birth weight means over time, stratified for each week of gestational age, were parallel. Birth weight Z-score adjusted for gestational age significantly increased between 1990 and 1997 from −0.28 to −0.15 and remained stable subsequently (−0.14 in 2005–2006) (Table 1). The proportion of SGA (birth weight Z-score adjusted for gestational age and sex lower than −2 SD) was stable over the whole period around 4–5% (Table 1).
The proportion of low head circumference for gestational age tended to decrease over time (P = 0.07) (Table 1).
Relation between birth anthropometric parameters and in-utero exposure to ART
The risk of being born SGA was not associated with the type of ART exposure in both univariate and multivariate logistic regression (Table 2). It was similar in neonates exposed exclusively to HAART (3.9%) and exposed to monotherapy (4.0%), with an adjusted odds ratio (OR) of 1.04 and 95% CI of 0.77–1.42. These results did not change when adjusting for preeclampsia, also independently associated with being born SGA [adjusted OR 2.16; 95% CI 1.03–4.52 (data not shown)].
Neither genital tract infections during pregnancy nor gestational diabetes were associated with the risk of being born SGA (data not shown).
Birth weight Z-score adjusted for gestational age and sex was independently associated with type of ART exposure, geographical origin, maternal age, primiparity and gestational age at booking (Table 3). Compared with neonates exposed to ZDV monotherapy, mean Z-score was similar for neonates exposed to dual NRTI but was lower for neonates not exposed to ART during pregnancy (adjusted mean difference −0.09, 95% CI −0.17 to −0.01) and for neonates exposed to HAART (adjusted mean difference −0.09, 95% CI −0.15 to −0.02). However, adjusted Z-scores did not differ significantly when comparing neonates exposed to monotherapy in 1994–1996 and those exposed to HAART in 2005–2006, which corresponded respectively to standard care of each period (−0.06, 95% CI −0.17 to 0.04).
Among neonates exposed to HAART, neither time at first-line initiation and duration of ART during pregnancy, nor type of last HAART regimen was associated with SGA birth and with birth weight Z-scores (Tables 2 and 3).
Height or head circumference Z-scores did not differ in neonates exposed to HAART and to monotherapy (data not shown).
Our primary objective was to compare, according to the type of maternal therapy, the incidence of SGA, defined as a birth weight Z-score lower than −2 SD, which corresponds to a birth weight below the third centile adjusted for gestational age and sex. There was no relation between maternal HAART and SGA. Similarly, there was no relation with the incidence of Z-scores lower than −2 SD for height or head circumference. Furthermore, the incidence of SGA, as well as the mean birth weight Z-scores, did neither differ according to the type of HAART (protease inhibitor-based or NNRTI-based), nor according to the specific protease inhibitor used. These results suggest that the HAART regimens used to date are not responsible for any type of intrauterine growth retardation.
Our survey is the first to investigate in detail the potential role of multitherapy on birth weight and other anthropometric parameters, independently of its potential effect on gestational age, using Z-score adjusted for sex and gestational age as categorical (<−2 SD) and continuous dependent variables. We also tried to avoid some other potential methodological limitations of previous surveys by excluding illicit drug users, twin pregnancies and HIV-infected children and taking into account year of delivery, and type and duration of ART exposure during pregnancies. Only one previous study was performed in uninfected neonates . The outcome reported in most of the published studies was low birth weight, defined as lower than 2500 g [10–13,16,17]. Ekouevi et al.  found that low birth weight was more frequent in neonates exposed to HAART, compared with exposure to short course of NRTI. However, it was not possible to distinguish whether it was due to a direct effect on growth retardation or a higher prematurity rate. No association with ART exposure was found in the other studies, including that by Cotter et al. , which was the only one to adjust for gestational age in logistic regression.
One other study used Z-score to investigate gestational age-adjusted birth weight . The authors reported a significantly lower Z-score in HAART-exposed infants (−0.06) than in those exposed to mono or dual therapy (0.06) (P = 0.002). In our study, the mean birth weight Z-score was also lower in infants exposed to HAART than to ZDV monotherapy. However, a direct comparison between outcomes according to maternal ART can be misleading because there were changes in management of HIV-affected pregnancies over time. In the more recent period, monotherapy was administered to mothers with the best immuno-virological status. We, therefore, compared neonates exposed to standard-of-care strategy of each period: HAART in 2005–2006 and ZDV monotherapy in 1994–1996. Anthropometric Z-scores did not differ between these two groups. Furthermore, birth weight Z-scores remained stable between 1997 and 2006, despite a strong increase in HAART use during this period.
In the previous reported studies, the proportions of low birth weight infants ranged from 12 to 28%, with most studies finding a higher incidence than in the ANRS-EPF cohort, in which it was 9% before 1997 and 13% thereafter. Although no direct comparison can be made, the proportions of low birth weight neonates in this cohort are about twice that of the general population in France. In a French population-based survey (Enquête nationale périnatale Inserm U149 ), the proportion of low birth weight (<2500 g) live-born singletons was 4.6% in 1995, 5.0% in 1998 and 5.5% in 2003; the increasing trend over time was statistically significant. In another French population-based survey, the proportion of low birth weight in live-born singletons was 5.3% in 2002 and 5.8% in 2003 .
We adjusted for primiparity and maternal origin, which were associated with birth weight. However, a limitation to our study, as well as previously published reports, is the lack of data on other potential risk factors for intrauterine growth retardation, such as socio-economic status, smoking and alcohol use, not collected before 2005 in EPF.
In conclusion, our results suggest that the ARTs used on a large scale over the past 15 years do not have an impact on fetal growth. These issues should continue to be monitored in ongoing cohort studies such as the ANRS-EPF cohort, because there continue to be changes in guidelines and clinical practice concerning the indications for time to begin and the types of ARTs used in pregnant women.
Data have been previously presented at the World Aids Conference 2008 (Mexico). The present work was supported by the Agence Nationale de Recherches sur le SIDA et les Hépatites virales (ANRS). Sidaction offered a scholarship to Nelly Briand. All authors contributed significantly to this work. N.B. realized the statistical analysis and contributed to conception, interpretation of data and drafting the article. L.M. contributed to conception, design, interpretation and drafting the article. J.L.C. and J.-P.T. contributed to acquisition of data, analysis and interpretation. R.T., A.F., C.D., C.R. and S.B. contributed to conception, design and interpretation. J.W. is the principal investigator of the EPF and was responsible for the whole scientific process of this study. All authors revised the article and approved the final version.
We thank Dr Françoise Vendittelli and Olivier Riviere from AUDIPOG for providing us the formula to calculate the Z-scores.
We thank all families who agreed to participate in this study. We thank Valérie Benhammou, Yassine Benmebarek, Naïma Bouallag, Leila Boufassa, Nacima Chernai, Karima Hamrène, Paulette Huynh, Carine Jasseron, Corinne Laurent, Marlène Peres, Elisa Ramos, Thierry Wack.
There was no conflict of interest.
The following persons and institutions participated in the ANRS French Perinatal Cohort (EPF) (* indicates sites currently closed):
Hôpital d'Aix en Provence* (B. Tadrist); Hôpital Nord, Amiens (J.L. Schmit, B. Horlé ); Hôpital d'Angers (A. Fournié); Hôpital Victor Dupouy, Argenteuil (D. Brault); Hôpital Paris La Roseraie*, Aubervilliers (M.A. Rozan); Hôpital Robert Ballanger, Aulnay (A. Zakaria); Hôpital Saint Claude, Basse-Terre* (G. Sibille); Hôpital de Bastia (O. Pincemaille); Hôpital de la Côte Basque, Bayonne (C. Cayla); Clinique du Blanc Mesnil* (P. Balde); Hôpital Saint Jacques, Besançon (J.M. Estavoyer); Hôpital Avicenne, Bobigny (M. Bentata); Hôpital Jean Verdier, Bondy (E. Lachassine, A. Rodrigues); Hôpital Pellegrin, Bordeaux (D. Roux, D. Douard); Hôpital Ambroise Paré*, Boulogne Billancourt (D. Zenaty); Hôpital Clémenceau, Caen (J. Brouard); Hôpital André Rosemon, Cayenne (N. Elenga); Hôpital Beaujon*, Clichy (A. De Curtis); Hôpital de Creil (C. Kingue-Ekollo); Hôpital Intercommunal, Créteil (V. Garrait, S. Lemerle, C. Pichon); Hôpital Béclère, Clamart (V. Chambrin, P. Labrune, L. Clech); Hôpital Louis Mourier, Colombes (C. Crenn-Hebert, C. Floch-Tudal); Hôpital de Compiègne* (A. Lagrue); Hôpital d'enfants, Dijon (I. Reynaud; S. Martha); Hôpital de Dourdan* (V. Ercoli); Hôpital de Dreux* (M.F. Denavit); Hôpital des Feugrais*, Elbeuf (K. Lahsinat); Hôpital Intercommunal, Evreux (K. Touré); Hôpital Francilien Sud, Evry-Corbeil (A. Devidas, A. May, M. Granier); Hôpital de Fontainebleau (C. Routier); Hôpital Victor Fouche, Fort de France (Y. Hatchuel); Hôpital de Gonesse* (P. Balde); Hôpital Jean Rostand, Ivry (T. Jault); Hôpital de Lagny (A. Chalvon Demersay); Hôpital du Lamentin* (M. Monlouis); Hôpital Les Oudairies, La Roche sur Yon (P. Perré); Hôpital de La Seyne sur Mer (J.M. Chamouilli); Hôpital Louis Domergue, La Trinité* (N. Hugon); Hôpital André Mignot, Le Chesnay (V. Hentgen, F. Messaoudi); Hôpital de Bicêtre, Le Kremlin-Bicêtre (D. Peretti, S. Fridman); Hôpital Jeanne de Flandres, Lille (F. Mazingue, Y. Hammou); Hôpital Dupuytren*, Limoges (L. De lumley); Hôpital de Longjumeau (H. Seaume); Hôpital Hôtel Dieu-Hôpital Debrousse, Lyon (L. Cotte, K. Kebaïli); Hôpital François Quesnay, Mantes La Jolie (A. Doumet); Hôpital la Conception, Marseille (L. Cravello, I. Thuret); Hôpital de Meaux (L. Karaoui); Hôpital de Meulan* (D. Seguy); Hôpital Marc Jacquet, Melun (B. Le Lorier); Hôpital Intercommunal, Montfermeil (P. Talon); Hôpital Arnaud de Villeneuve, Montpellier (P. Benos, M. Lalande); Hôpital Intercommunal, Montreuil (B. Heller-Roussin); Maternité Régionale A. Pinard, Nancy (C. Hubert); Hôpital de Nanterre* (P. Karoubi); Hôpital de Nantes (V. Reliquet, C. Brunet-François); Hôpital de Neuilly sur Seine* (D. Berterottiere); Hôpital l'Archet-Fondation Lenval, Nice (F. Monpoux, A. Bongain, A. Deville); Hôpital Caremeau, Nîmes (J. Dendale); Hôpital Orléans (P. Arsac); Hôpital d'Orsay (C. De Gennes); Hôpital Bichat, Paris (S. Matheron, A. Batallan); Hôpital Boucicaut*, Paris (M.C. Lafay Pillet); Hôpital Cochin-Port Royal, Paris (G. Firtion, A. Pannier); Hôpital Lariboisière, Paris (N. Ciraru-Vigneron); Hôpital des Métallurgistes*, Paris (M. Rami); Institut Mutualiste Montsouris*, Paris (C. Carlus Moncomble); Hôpital Necker, Paris (S. Parat, S. Blanche, C. Rouzioux); Hôpital Notre Dame du Bon Secours, Paris (D. Ayral); Hôpital Pitié Salpêtrière, Paris (R. Tubiana); Hôpital Robert Debré, Paris (M. Levine, A. Faye, A. Ottenwalter); Hôpital Rothschild, Paris (A. Wallet ); Hôpital Saint-Antoine, Paris (B. Carbonne); Hôpital Hôpital Saint Michel, Paris (C. Aufrant); Hôpital Tenon, Paris (M.G. Lebrette); Hôpital Trousseau, Paris (C. Dollfus); Hôpital Marechal Joffre, Perpignan (M. Medus); Hôpital Les Abymes, Pointe-à-Pitre (H. Bataille); Hôpital de Poissy-Saint-Germain en Laye* (M.C. Rousset); Hôpital René Dubos, Pontoise (G. Mouchnino); Hôpital Américain, Reims (M. Munzer); Hôpital Charles Nicolle, Rouen (V. Brossard); Hôpital de Saint-Denis (M.C. Allemon, D. Ekoukou, M.A. Khuong); Hôpital Nord, Saint Etienne (K. Billiemaz); Hôpital de Saint Martin (F. Bissuel); Hôpital Esquirol*, Saint-Maurice (M. Robin); Hôpital de Sèvres* (L. Segard); Hôpital de Haute Pierre-Hôpital Civil, Strasbourg (M. Partisani, J.J. Favreau, N. Entz-Werle); C.M.C. Foch, Suresnes* (C. Botto); Hôpital Chalucet,Toulon (G. Hittinger); Hôpital La Grave, Toulouse (A. Berrebi, J. Tricoire); Hôpital Bretonneau, Tours (J.M. Besnier); Hôpital Brabois, Vandoeuvre les Nancy (L. Neimann); Hôpital Paul Brousse*,Villejuif (E. Dussaix); Hôpital de Villeneuve Saint Georges (F. Guillot, A. Chacé)
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