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Association between Prenatal Exposure to Antiretroviral Therapy and Birth Defects: An Analysis of the French Perinatal Cohort Study (ANRS CO1/CO11) AND COMMENTARY follows below by Lynne M. Mofenson, D. Heather Watts
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Published: April 29, 2014
Jeanne Sibiude1,2*, Laurent Mandelbrot1,2,3, Stephane Blanche4,5, Jerome Le Chenadec2,6, Naima Boullag-Bonnet2, Albert Faye3,7, Catherine Dollfus8, Roland Tubiana9,10, Damien Bonnet11, Nathalie Lelong12, Babak Khoshnood12, Josiane Warszawski2,6,13 1 Hospital Louis Mourier, Assistance Publique-Hospitaux de Paris, Colombes, France, 2 Centre de Recherche en Epidemiologie et Sante des Populations, INSERM U1018, Le Kremlin-Bice tre, France, 3 Universite Paris Diderot-Paris 7, Paris, France, 4 Hospital Necker, Assistance Publique-Ho pitaux de Paris, Paris, France, 5 EA 3620, Universite Paris Descartes 5, Paris, France, 6 Institut National d'Etudes Demographiques, Paris, France, 7 Hospital Robert Debre , Assistance Publique-Hospitaux de Paris, Paris, France, 8 Hospital Trousseau, Assistance Publique-Hospitaux de Paris, Paris, France, 9 Hospital Pitie Salpetriere, Assistance Publique-Hospitaux de Paris, Paris, France, 10 INSERM U943, Paris, France, 11 Pediatric Cardiology, M3C Necker-Enfants Malades, Assistance Publique-Ho pitaux de Paris, Universite Paris Descartes, Paris, France, 12 INSERM UMR S953, Universite Paris 6, Paris, France, 13 Universite Paris Sud, Le Kremlin-Bicetre, France
These are EXCERPTS from the full article, I suggest reading the entire report to put it all in context.
In conclusion, we found a higher rate of CHDs in children exposed in utero to zidovudine, which should be taken into consideration, given the large number of children exposed to perinatal zidovudine in the world. Potential mechanisms underlying this association must be investigated. This alert reinforces recent recommendations for PMTCT, which no longer consider zidovudine to be the first-line ART during pregnancy [39]. Though the higher rate of neurological birth defects observed in infants exposed to efavirenz in the first trimester must be interpreted with caution, as discussed previously, our results reinforce the importance of careful clinical follow-up of children in case of perinatal exposure to efavirenz, as recommended in the WHO guidelines [39]. In our study, ventricular dilatation, partial agenesis of the corpus callosum with an interhemispheric cyst, pachygyria, and subependymal cyst, detected by routine prenatal ultrasound screening and/or clinical postnatal follow-up, may have been missed by neonatal examination only. The absence of association between birth defects and several ARV drugs that are increasingly prescribed during pregnancy, such as tenofovir, which is the first-line WHO recommendation for PMTCT, is reassuring and may encourage us to explore various zidovudine-sparing regimens. Nonetheless, whatever the impact some ARV drugs may have on birth defects, it is largely surpassed by the major role of ART in successful PMTCT, leading to the decrease of transmission rates from 20% without ART to the current rate of less than 1%.
The analysis was conducted in 13,124 live-born children, born between 1 January 1994 and 31 December 2010, among whom 42% (n = 5,388) were exposed to ART in the first trimester of pregnancy. PMTCT strategies varied over time, and the proportion of infants exposed to ART in the first trimester increased from 19% in 1994-1996 to 52% in 2005-2010. The evolution in time of types of treatment and trimesters of exposure are presented in Table 3. The median maternal age was 31 y, most women were from sub-Saharan Africa (61%) and parous (62%), and very few were intravenous drug users (2%). Most women had a good immunovirological status (CD4≥350 cells/ml and viral load <400 copies/ml; Table 4). Data at birth was collected for the newborns of all women enrolled. Median follow-up of children was 19 mo (interquartile range 12-24 mo).
The prevalence of birth defects in our study population was 4.4% as assessed using the EUROCAT guidelines and 7% using the MACDP classification. This is higher than the rates reported in most large studies including patients exposed to ARV drugs, which were 1.5% in the European Collaborative Study, published in 2005 and thus including different drugs than those used in more recent studies [18], 2.8% in a recent study in the United Kingdom [17], and 2.9% in the APR [13]. The prevalence in our cohort is, however, consistent with that observed in smaller prospective studies, which all report higher rates, from 5.3% to 8.3% [11],[12],[16],[27]. We hypothesize that studies involving few centers may have a higher level of reporting because of greater motivation of clinicians for the specific research program and more intensive data monitoring than in large multicenter cohort studies and registries. In this sense, the higher prevalence in EPF despite the large number of pregnancies and study sites may result from the high level of completeness of our data collection, which is sustained through regular monitoring at study sites and motivated clinicians uniting in an active national network, but may also result from easier referral for free further investigations, facilitated by the French health insurance system.
The presence of a birth defect was significantly associated with male gender and higher maternal age. Neonates with birth defects were more frequently born by cesarean section, preterm, and with low birth weight (Table 4).
An important result is that no association was found between birth defects and lopinavir or ritonavir with a power >80% for an OR of 1.5, and for tenofovir, nevirapine, and abacavir with a power >70%. For all these drugs, the power was >95% for an OR of 2. This result is very reassuring in view of the fact that several of these ARV drugs are currently being increasingly used.
Overall Birth Defects
The overall birth defect rate was 4.4% (95% CI 4.0%-4.7%) (n = 575/13,124), according to the EUROCAT classification and 7.0% (95% CI 6.5%-7.4%) (n = 914/13,124) according to the MACDP classification. The rate increased from 1994-1996 to 1997-1999 and then decreased slightly afterwards. The presence of a birth defect was significantly associated with male gender and higher maternal age. Neonates with birth defects were more frequently born by cesarean section, preterm, and with low birth weight (Table 4).
Associations with ARV drugs are presented using the EUROCAT classification, and studied in sensitivity analyses for the MACDP classification. Using the EUROCAT classification, overall birth defects were significantly associated with zidovudine in the first trimester, compared with no zidovudine during pregnancy (5.1% for n = 3,267 children exposed in the first trimester versus 4.0% for n = 2,152 children not exposed to zidovudine, AOR = 1.39 [95% CI 1.06-1.83], p<0.05), as well as with didanosine (6.3%, n = 927, for first-trimester exposure versus 4.3%, n = 11,651, for unexposed, AOR = 1.44 [95% CI 1.08-1.92], p = 0.02), lamivudine (5.0%, n = 3,772, for first-trimester exposure versus 4.0%, n = 3,734, for unexposed, AOR = 1.37 [95% CI 1.06-1.76], p = 0.02) and indinavir (7.7%, n = 350, for first-trimester exposure versus 4.3, n = 12,492, for unexposed, AOR = 1.66 [95% CI 1.09-2.53], p = 0.03) (Figure 2; Table 2). Defects according to the MACDP classification were associated with the same four drugs, as well as with zalcitabine (AOR = 2.16 [95% CI 1.17-4.00], p = 0.01) and any kind of NNRTI (AOR = 1.33 [95% CI 1.07-1.66], p = 0.03) (Table 5). These associations were independent of IDU, geographical origin, maternal age, and maternity center.
Birth Defects by Organ System
Exposure to efavirenz during the first trimester was not found to be associated with birth defects overall in the EUROCAT classification (5.4%, n = 20/372, AOR = 1.16 [95% CI 0.73-1.85], p = 0.70) (Figure 2; Table 2). However, there was a statistically significant association between neurological birth defects and efavirenz in the first trimester in the secondary analysis using the modified MACDP classification (1.1% among 372 children exposed to efavirenz in the first trimester versus 0.4% among 12,729 children unexposed, AOR = 3.0 [95% CI 1.1-8.5], p = 0.04, absolute risk difference +0.7% [95% CI +0.07%; +1.3%]) (Table 6). This association did not reach significance in the primary analysis using the EUROCAT classification (AOR = 2.1 [95% CI 0.7-5.9], p = 0.16). The four neurological defects, according to MACDP, reported in children exposed to efavirenz in the first trimester were ventricular dilatation with anomalies of the white substance, partial agenesis of the corpus callosum, subependymal cyst, and pachygyria. Congenital infection or associated non-neurological defects were not reported for these four children. Efavirenz was not associated with other birth defects.
Exposure to zidovudine during the first trimester was associated with CHDs according to the EUROCAT classification (2.3% among the 3,267 children exposed to zidovudine in the first trimester versus 1.1% among the 2,152 children unexposed to zidovudine, AOR = 2.2 [95% CI 1.3-3.7], p = 0.003) (Table 6). The absolute risk difference attributed to zidovudine was therefore +1.2% (95% CI +0.5; +1.9%). CHDs according to EUROCAT classification were also associated with zalcitabine, lamivudine, and indinavir in the univariate analysis, but after adjustment for other concomitant ARV drugs, the association did not reach significance. Six children exposed to emtricitabine during the second or third trimester were diagnosed with a CHD (5.1%, n = 6/118, versus 1.4% among the 12,420 children unexposed to emtricitabine, AOR = 4.5 [95% CI 1.9-10.9], p = 0.001), but four of them were also exposed to zidovudine during the first trimester. The association between zidovudine and heart defects remained the same when (1) limited to diagnoses made in the first 6 mo or in the first week of life, or to infants exposed to only one combination of ART during pregnancy, (2) adjusted for prematurity, parity, CD4 count, year of birth, and gender (AOR for zidovudine = 2.2 [95% CI 1.3-3.6], p = 0.003), (3) using alternate categorization for zidovudine exposure (AOR = 2.1 [95% CI 1.3-3.6], p = 0.003, for zidovudine in the first trimester versus no treatment at all during the first trimester), (4) using the MACDP classification (Table 6), and (5) including TOPs and stillbirths. Zidovudine was not found to be associated with other types of birth defects. In the largest multivariate model cited above, the other variables significantly associated with CHDs were maternal age >35 y, prematurity (AOR = 2.5 [95% CI 1.7-3.6]), female gender (AOR = 1.4 [95% CI 1.0-2.0]), and CD4 count <200 cells/ml (AOR = 1.7 [95% CI 1.1-2.7] versus CD4>350 cells/ml). Time period was not independently associated with heart defects (p = 0.23). Among the 74 children with a diagnosis of CHD and exposed to zidovudine during the first trimester, the most frequent heart defects were ventricular septal defects (n = 43), atrial septal defects (n = 13), and persistence of the ductus arteriosus (n = 9). We found no significant association between heart defects and any of the other ARV drugs included in the multivariate model, which were lamivudine, zalcitabine, emtricitabine, and indinavir. No interaction was found between zidovudine and lamivudine. Head and neck defects, as described in the EUROCAT guidelines [22],[23], were associated with didanosine (0.5%, n = 5/927, for first-trimester exposure versus 0.2%, n = 18/11,651, in the unexposed group, AOR = 3.4 [95% CI 1.1-10.4], p = 0.04) and with indinavir (0.9%, n = 3/350, in the exposed versus 0.2%, n = 22/12,470, in the unexposed group, AOR = 3.8 [95% CI 1.1-13.8], p = 0.04) (Table 6). Didanosine and indinavir were prescribed to 6.9% and 3% of the women in the study in the last 6 y, respectively.
The association between birth defect by organ system and each ARV drug is described in Table 7. All birth defects among live births are listed Table 8, and birth defects among TOP are listed in Table 9. We found no association between exposure to other ARV drugs and overall birth defects or specific birth defects, including for tenofovir, with 823 children exposed in the first trimester: AOR = 0.75 (95% CI 0.51-1.10), with a power of 72% for an OR of 1.5 (Table 2).
COMMENTARY - Safety of Pediatric HIV Elimination: The Growing Population of HIV- and Antiretroviral-Exposed but Uninfected Infants
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Lynne M. Mofenson, D. Heather Watts
1 Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America, 2 Office of the Global AIDS Coordinator, US Department of State, Washington (D.C.), United States of America Published: April 29, 2014
This Perspective discusses the following new study published in PLOS Medicine: Sibiude J, Mandelbrot L, Blanche S, Le Chenadec J, Boullag-Bonnet N, et al. (2014) Association between Prenatal Exposure to Antiretroviral Therapy and Birth Defects: An Analysis of the French Perinatal Cohort Study (ANRS CO1/CO11). PLoS Med 11(4): e1001635.
Jeanne Sibiude and colleagues use the French Perinatal Cohort to estimate the prevalence of birth defects in children born to HIV-infected women receiving antiretroviral therapy during pregnancy.
One of the greatest public health successes has been the development and implementation of antiretroviral interventions to prevent mother-to-child HIV transmission (MTCT). The landmark 1994 Pediatric AIDS Clinical Trials Group (PACTG) 076 results, demonstrating zidovudine given to HIV-infected pregnant women and their infants reduced MTCT by nearly 70%, led to rapid implementation in the Unites States, with subsequent decline in MTCT from 25% to 4%-5% within two years [1]. Pregnant HIV-infected women in the United States and other high-resource countries now receive combination antiretroviral therapy (cART) including three or more drugs, which has led to further reductions in MTCT; in the United States, MTCT has been nearly eliminated, with rates currently <2% [2].
Additionally, there has been striking progress in reducing MTCT in resource-constrained countries, with 1 million children prevented from acquiring HIV between 2003 and 2013 because of maternal and infant antiretroviral prophylaxis [3]. The 2013 WHO consolidated guidelines recommend that all HIV-infected pregnant women initiate cART, and if breastfeeding, continue cART throughout breastfeeding [4]. After the MTCT risk period has ended, women may either continue life-long treatment regardless of clinical status or stop if they do not meet treatment eligibility criteria for non-pregnant individuals. However, accompanying this success is a rapidly expanding population of HIV-exposed but uninfected children with substantial exposure to antiretroviral drugs, both in utero and, in resource-constrained countries, while breastfeeding. There is an urgent need to better understand the consequences of antiretroviral drug exposure on HIV-uninfected children and to improve monitoring and management of any potential adverse effects in this burgeoning population. Sibiude and colleagues in this week's issue of PLOS Medicine provide a detailed analysis related to birth defects in infants with in utero antiretroviral drug exposure in the French Perinatal Cohort [5].
Given the emphasis on early treatment of HIV in adults and the move toward initiation of life-long therapy in all pregnant women in many resource-constrained countries, it can be anticipated that there will be a dramatic increase over time in women who conceive while receiving antiretroviral drugs, with fetal exposure from conception onward. Data from epidemiologic studies suggest MTCT may be lowest in infants born to mothers receiving cART prior to conception and continued during pregnancy [6]. However, there are only limited data on potential toxicities of fetal/infant antiretroviral drug exposure.
Birth Defects and Drug Exposures
A critical factor in the risk of drug-related birth defects is fetal developmental stage at the time of exposure. During the first two weeks after conception, exposures are unlikely to cause malformations, as immediately after conception the embryo has not yet formed, and after its formation, an additional period of time intervenes before its cells become committed to specific developmental paths [7]. The time of greatest sensitivity to teratogenic exposures is the stage of organogenesis (18-60 days after conception or 4-13 weeks after the beginning of the last menstrual period), before many pregnancies are recognized, particularly in resource-constrained settings. Exposures later in gestation are less likely to produce gross structural abnormalities of the fetus. However, because this period is a time of active cell growth, differentiation, maturation, and migration, particularly in the central nervous system (CNS), teratogenic exposures may cause growth retardation or functional CNS disorders that may not be apparent until much later in life and would be missed by examination confined to the neonatal period.
Animal studies have been used to evaluate whether drug exposures may be associated with teratogenic potential prior to use in humans. However, it is difficult to extrapolate animal findings because of species differences in placentation, embryonic development, innate predisposition to fetal abnormalities, and drug pharmacokinetics/dynamics [7]. Thus, identification of human teratogenic exposures relies on epidemiologic studies, but such studies require careful interpretation. Ascertainment and recall biases can result in erroneous associations. Additionally, the maternal disease that created the need for administration of the drug rather than the drug itself could be responsible for an observed association. Teratogenic exposures most often produce distinct or characteristic patterns of congenital abnormalities as opposed to a single malformation in an otherwise normal child [7]. Importantly, a statistically significant association in an epidemiologic study does not necessarily indicate causality.
Birth Defects with Antiretroviral Drug Exposure: French Perinatal Cohort
The French Perinatal Cohort study reports on birth defect surveillance in 13,124 live-births to HIV-infected pregnant women delivering in 90 clinical centers in France between 1994 and 2010; 5,388 (42%) of infants had first trimester exposure to one or more antiretroviral drugs [5]. There are a number of important differences between the French Perinatal Cohort and most other reports on birth defects, including the Antiretroviral Pregnancy Registry [8]. In France, fetal ultrasounds in each trimester are standard-of-care for all pregnant women, and the identification of birth defects in the children in their cohort extended through age two years. In contrast, the Antiretroviral Pregnancy Registry and many published studies report on defects detected at birth or within a few days of birth, without extended follow-up for later detection of birth defects, and active fetal ultrasound surveillance was not conducted. The primary finding in the the French Perinatal Cohort study was a significant association of first-trimester zidovudine exposure with congenital heart defects, which persisted after adjustment for a number of potential confounders. Most were ventricular or atrial septal defects (58% and 18%, respectively) and persistent ductus arteriosus, and were not associated with other malformations. The clinical significance of these defects or whether these were primarily detected through active fetal ultrasound surveillance was not described. Spontaneous closure of ventricular septal defects (VSDs) is frequent; in a study of 249 fetuses with VSDs detected by fetal ultrasound, spontaneous closure of the VSD occurred in 5% of fetuses prenatally and 76% postnatally by age one year [9]. The association of heart defects with first trimester zidovudine exposure has been reported in two smaller studies but not in larger cohorts, including the Antiretroviral Pregnancy Registry [8],[10],[11].
The authors also report a significant association between first-trimester efavirenz exposure and neurologic defects in the MACDP classification system of birth defects, but not the EUROCAT classification, which excludes minor anomalies with no serious medical or functional consequences [12]. Efavirenz-based cART is the WHO recommended regimen for pregnant HIV-infected women; primate data have raised concerns regarding potential CNS teratogenicity although data in humans have been more reassuring [4],[13]. The MACDP association was based on only four CNS defects, two of which (subependymal cyst and partial agenesis of the corpus callosum) are asymptomatic findings likely detected on fetal ultrasound that may have no clinical significance. None were neural tube defects (a defect of concern from primate studies) and they do not have similar embryologic origins. Interestingly, the three neural tube defects (spina bifida) noted in live-births in the study were not in efavirenz-exposed infants. While drug exposure for the two neural tube defects observed in pregnancy terminations was not specified, since sensitivity analyses including these defects were performed, it is assumed these were also not in efavirenz-exposed infants. Thus, these data are actually reassuring regarding a lack of neural tube defects in infants with first-trimester efavirenz exposure [5].
Reassuringly, no association with birth defects were observed for other WHO-recommended first or second-line drugs, including tenofovir, lamivudine, and lopinavir/ritonavir [5].
Clinical Implications of the French Perinatal Cohort Data
The use of antiretroviral drugs by HIV-infected pregnant women has resulted in a paradigm shift in the maternal and pediatric HIV epidemics, with markedly improved maternal survival and dramatic reductions in MTCT. However, despite the widespread use of antiretroviral drugs by pregnant women, systematic evaluation of birth defects has been limited. The Antiretroviral Pregnancy Registry only enrolls ~15% of HIV-infected pregnant women giving birth annually in the United States and only about 200 pregnant women from other countries [8]; clinicians are urged to report exposures to the Registry.
The largest amount of data on birth defects and antiretroviral drug exposure comes from high-resource countries. However, the largest population of HIV-infected women of childbearing age resides in resource-constrained countries, where women are exposed to multiple factors that could increase risk of birth defects, such as under-nutrition, micronutrient deficiency, anemia, and co-infections. Additionally, in many resource-constrained countries, data on the background risk of birth defects in the general population are lacking. Determining the potential risk of birth defects due to antiretroviral drug exposure requires knowledge of the underlying risk of birth defects in the population being studied.
Given that the HIV burden in women is greatest in resource-constrained countries, where rapid expansion in antiretroviral drugs use in pregnancy (and increasingly at conception) is expected with implementation of WHO guidelines, there is an ethical imperative to systematically and critically evaluate the safety of these recommendations for the fetus/infant, both in terms of potential teratogenicity but also long-term outcomes. While the Sibiude study raises some important questions, given the enormous benefits of maternal antiretroviral drugs, the unclear clinical significance of the heart defects and the lack of a specific pattern of CNS defects with efavirenz, no change in prescribing practices is indicated, but continued surveillance is critical.
WHO has established a Pregnancy Registry protocol that is beginning to be implemented in several resource-constrained countries [14]. Additionally, the President's Emergency Plan for AIDS Relief (PEPFAR) is initiating active surveillance for birth defects in HIV-infected and -uninfected women at sentinel sites in Malawi and Uganda. These data will be critical in evaluating safety of cART regimens and determining the best regimens to ensure the greatest benefit to the health of both the mother and her child.

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