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A link between antiretrovirals and perinatal outcomes?
 
 
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Perinatal genotoxicity and carcinogenicity of
anti-retroviral nucleoside analog drugs
http://www.natap.org/2012/HIV/081012_02.htm

 
Mitochondrial disturbances in HIV pregnancies
http://www.natap.org/2014/HIV/013015_03.htm

findings of the present study demonstrate a significantly lower birth weight and genetic and functional maternofoetal mitochondrial toxicity in HIV-infected mothers and their infants
 
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"Very few data were available for comparison of pregnancy outcomes between women initiating ART before conception and those beginning ART after conception......ART started before conception and continued throughout pregnancy is associated with extremely low rates of mother-to-child transmission of HIV. In a report5 from the UK and Ireland on 5652 deliveries between 2007 and 2011, only four (0⋅19%) of 2105 women on ART before conception transmitted HIV to their infant. In the French Perinatal Cohort,6 no cases of mother-to-child transmission were noted among 2651 women who started ART before conception and had achieved viral suppression at delivery."
 
"Prematurity was reported in ten studies.9, 10, 16, 21, 23, 24, 25, 26, 27, 28 ART initiation before conception was associated with significantly higher risk of prematurity than ART initiation after conception (pooled RR 1⋅20, 95% CI 1⋅01-1⋅44; figure 2)....In our systematic review and meta-analysis, preterm delivery, very preterm delivery, and low birthweight were significantly more common in pregnant women with HIV who initiated ART before conception than in women who first initiated ART after conception. On subgroup analysis, the magnitude of these associations was highest in studies done in low-income and middle-income countries (data not shown), where background rates of preterm delivery and low birthweight are higher than in high-income countries. Before the ART era, studies of the association between HIV infection and adverse pregnancy outcomes showed that HIV infection was significantly associated with adverse outcomes in low-income but not high-income countries.29"
 
"A systematic review and meta-analysis1 by Olalekan A Uthman and colleagues in The Lancet HIV shows a significant increase in preterm births associated with ART started before conception compared with ART started after conception. ......Another cause for caution is the potential for toxicities in the developing fetus and the resulting short-term and long-term risks, including mitochondrial diseases, cardiac dysfunction, genotoxicity, and cancer, which were not topics of Uthman and colleagues' review but are of crucial importance when assessing risks related to use of ART in pregnancy. The next step in research should be to analyse outcomes according to the individual antiretrovirals used and the causes of adverse perinatal outcomes.....The association between ART and preterm birth is intriguing and elusive. Multicentre observational cohorts are a good way to study outcomes in large populations, but are not designed to inform whether starting ART before pregnancy has an effect on outcomes. An important treatment bias to remember is that, until recently, ART used to be reserved for people with advanced immune deficiency. The timing of initiation of ART could be important for interactions between HIV and the immune system. HIV infection is a state of chronic inflammation. The effect of ART on this inflammatory state is complex: it depends on immune deficiency and the viral reservoir at the time of treatment initiation. Inflammation is also a major factor in preterm birth, intrauterine growth restriction, and pre-eclampsia. Concentrations of inflammatory markers related to microbial translocation were higher in pregnant women with HIV than in HIV-negative pregnant women,8 and were associated with preterm delivery."
 
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Comment
 
A link between antiretrovirals and perinatal outcomes?
 
*Laurent Mandelbrot, Jeanne Sibiude
 
Assistance Publique-H.pitaux de Paris, H.pital Louis Mourier, Service de Gyn.cologie-Obst.trique, H.pitaux Universitaires Paris-Nord Val de Seine, 178 rue des Renouillers, 92700 Colombes, France (LM); Universit. Paris-Diderot, Universit. Sorbonne Paris-Cit., Paris, France (LM); D.partement Hospitalier Universitaire Risques et Grossesse, Paris, France (LM, JS); INSERM U1018, Kremlin-Bic.tre, France (LM, JS); and Assistance Publique- H.pitaux de Paris, Maternit. Port Royal, H.pital Cochin, Paris, France (JS)
 
Because starting combination antiretroviral therapy (ART) as early as possible is now the norm, all women with HIV should be on treatment before becoming pregnant (although some women might not be diagnosed until they are pregnant). The benefits of ART are overwhelming, but the risks include adverse pregnancy outcomes, which encompass a wide range of birth defects and maternal, obstetric, and perinatal complications. A systematic review and meta-analysis1 by Olalekan A Uthman and colleagues in The Lancet HIV shows a significant increase in preterm births associated with ART started before conception compared with ART started after conception. Many, though not all, studies have shown a strong association between ART and preterm births.2 This review is the first in which adverse pregnancy outcomes by timing of ART are specifically assessed. The risk ratios are quite coherent among studies from low-income and high-income countries, although background risks differ. The increased risk concerns not only moderate preterm birth (ie, delivery between 34 and 37 weeks' gestation) but also deliveries at less than 34 weeks' gestation, which can lead to death or permanent disabilities.
 
The relation between timing of ART initiation and other outcomes is less clear. Low birthweight was significantly more frequent when ART was started before pregnancy than after pregnancy, but the frequency of small for gestational age did not differ significantly between groups. Low birthweight can be a proxy for preterm birth. By contrast, small for gestational age is, by definition, adjusted for gestational age. It is also an important indication for preterm induction or caesarean section. In the French Perinatal Cohort,3 ART was mostly associated with induced preterm birth for complications. Uthman and colleagues report that the incidence of pre-eclampsia was independently associated with starting ART before conception (rather than after conception). Small for gestational age and pre-eclampsia are both related to placental dysfunction, which is a consequence of faulty trophoblast invasion in early pregnancy. However, other studies showed no association between ART and pre-eclampsia.4
 
There was a non-significant risk of stillbirth, which is less frequent than preterm birth and small for gestational age, when ART was started before conception compared with after conception. The risk of congenital anomalies is a major outcome. Congenital anomalies were an outcome in only one study5 included in Uthman and colleagues' analysis because preconception initiation of ART was not distinguished from initiation after conception in other studies. The teratogenic potential of efavirenz in first-trimester ART exposures is controversial.6 In the French Perinatal Cohort,7 CNS malformations were increased after first-trimester exposure to efavirenz, but that study was not included in the systematic review because the publication did not specify that all these exposures had begun before conception (unpublished).
 
The association between ART and preterm birth is intriguing and elusive. Multicentre observational cohorts are a good way to study outcomes in large populations, but are not designed to inform whether starting ART before pregnancy has an effect on outcomes. An important treatment bias to remember is that, until recently, ART used to be reserved for people with advanced immune deficiency. The timing of initiation of ART could be important for interactions between HIV and the immune system. HIV infection is a state of chronic inflammation. The effect of ART on this inflammatory state is complex: it depends on immune deficiency and the viral reservoir at the time of treatment initiation.
 
Inflammation is also a major factor in preterm birth, intrauterine growth restriction, and pre-eclampsia. Concentrations of inflammatory markers related to microbial translocation were higher in pregnant women with HIV than in HIV-negative pregnant women,8 and were associated with preterm delivery.
 
One might thus assume that treating HIV infection improves pregnancy outcomes, but the opposite has been described.9 The effects could differ regarding spontaneous and induced prematurity, with HIV infection increasing the frequency of spontaneous preterm birth and boosted protease-inhibitor-based ART possibly increasing the frequency of induced preterm birth.10 Other researchers suggest that ART favours spontaneous preterm birth and adverse outcomes via the T helper cell 1 and T helper cell 2 shift or via decreased progesterone concentrations.11 Whether the adverse effects of ART on pregnancy will be increased or decreased by starting treatment earlier in the course of HIV infection—ie, before immune dysregulation occurs—is unknown, Another cause for caution is the potential for toxicities in the developing fetus and the resulting short-term and long-term risks, including mitochondrial diseases, cardiac dysfunction, genotoxicity, and cancer, which were not topics of Uthman and colleagues' review but are of crucial importance when assessing risks related to use of ART in pregnancy. The next step in research should be to analyse outcomes according to the individual antiretrovirals used and the causes of adverse perinatal outcomes.
 
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ART started before conception and continued throughout pregnancy is associated with extremely low rates of mother-to-child transmission of HIV. In a report5from the UK and Ireland on 5652 deliveries between 2007 and 2011, only four (0⋅19%) of 2105 women on ART before conception transmitted HIV to their infant. In the French Perinatal Cohort,6 no cases of mother-to-child transmission were noted among 2651 women who started ART before conception and had achieved viral suppression at delivery.
 
Timing of initiation of antiretroviral therapy and adverse pregnancy outcomes: a systematic review and meta-analysis
 
Summary
 
Background

 
Although lifelong combination antiretroviral therapy (ART) is recommended for all individuals with HIV, few data exist for pregnancy outcomes associated with ART initiation before conception. We assessed adverse pregnancy outcomes associated with ART initiated before conception compared with that of ART started after conception.
 
Methods
 
We did a systematic review of studies from low-income, middle-income, and high-income countries by searching the Cochrane Central Register of Controlled Trials, Embase, LILACS, MEDLINE, Toxline, Web of Knowledge, and WHO Global Index Medicus and trials in progress (International Clinical Trials Registry Platform) for randomised trials, quasi-randomised trials, and prospective cohort studies done between Jan 1, 1980, and June 1, 2016, in which timing of ART initiation in pregnant women living with HIV was reported. We used the risk ratio (RR) and corresponding 95% CIs as the primary measure to assess the association between the selected outcomes and ART initiation before conception versus after conception. We used a random-effects model to pool risk ratios.
 
Findings
 
We included 11 studies with 19 189 mother-infant pairs. Women who started ART before conception were significantly more likely to deliver preterm (pooled RR 1⋅20, 95% CI 1⋅01-1⋅44) or very preterm (1⋅53, 1⋅22-1⋅92), or to have low-birthweight infants (1⋅30, 1⋅04-1⋅62) than were those who began ART after conception. Few data exist for neonatal mortality. The risk of very low birthweight, small for gestational age, severe small for gestational age, stillbirth, and congenital anomalies did not differ significantly between women who were taking ART before conception and those who began ART after conception.
 
Interpretation
 
The benefits of ART for maternal health and prevention of perinatal transmission outweigh risks, but data for the extent and severity of these risks are scarce and of low quality. As use of ART before conception rapidly increases globally, monitoring for potential adverse pregnancy outcomes will be crucial.
 
Funding
 
WHO.
 
Introduction
 
In 2013, WHO recommended that all pregnant and breastfeeding women with HIV infection should initiate combination antiretroviral therapy (ART) irrespective of clinical or immune status, and that ART be continued at least for the duration of mother-to-child transmission risk, with the option of continuing lifelong ART—an approach adopted by many low-income countries as a result of its programmatic and clinical benefits.1 After the results of the TEMPRANO2 and START3 trials showed that beginning ART at higher CD4 cell counts (>500 cells per μL) was associated with significant clinical benefits, in 2015, WHO recommended immediate initiation of lifelong ART for all HIV-infected individuals, including pregnant women.4 Thus, an increasing proportion of HIV-infected women will become pregnant while receiving ART.
 
ART started before conception and continued throughout pregnancy is associated with extremely low rates of mother-to-child transmission of HIV. In a report5from the UK and Ireland on 5652 deliveries between 2007 and 2011, only four (0⋅19%) of 2105 women on ART before conception transmitted HIV to their infant. In the French Perinatal Cohort,6 no cases of mother-to-child transmission were noted among 2651 women who started ART before conception and had achieved viral suppression at delivery.
 
Lifelong ART for all HIV-infected pregnant women will not only contribute substantially to the global elimination of new paediatric HIV infections and improve maternal health and survival, but will also lead to a rapid rise in fetal exposure to antiretrovirals as pregnant and breastfeeding women started on ART have subsequent pregnancies. Despite nearly two decades of ART use during pregnancy, evidence for safety is scarce and conflicting.7 ART use during pregnancy has been associated with increased risk of adverse birth outcomes, such as preterm delivery and low birthweight, in reports from both high-income and low-income countries.8, 9, 10, 11 Some data suggest that adverse pregnancy outcomes could be specifically associated with use of protease inhibitors during pregnancy;12, 13, 14, 15 other data, including the results of a large population-based study in Botswana9 and a study in Tanzania,16 suggest that such outcomes might also be associated with nevirapine-based or efavirenz-based ART. We did a systematic review to summarise the data about safety of, and adverse pregnancy outcomes associated with, ART initiated before conception compared with those of ART started after conception to inform the upcoming WHO 2015 consolidated ART guidelines. We did not address potential longer-term effects of in-utero ART exposure in HIV-exposed but uninfected children.
 
Research in context
 
Evidence before this study

 
We did a systematic literature review of the Cochrane Central Register of Controlled Trials, Embase, LILACS, MEDLINE, Toxline, Web of Knowledge, and WHO Global Index Medicus and trials in progress (International Clinical Trials Registry Platform) to identify studies published between Jan 1, 1980, and June 1, 2016, in which pregnancy outcomes in pregnant women with HIV initiating antiretroviral therapy (ART) before conception were compared with those in women beginning ART after conception. We found 11 studies including 19 189 women with HIV, 10 232 of whom started ART before conception and 8957 of whom started ART after conception. ART use during pregnancy has been associated with increased risk of adverse birth outcomes, such as preterm delivery and low birthweight, when compared with use of less complex regimens such as zidovudine prophylaxis in some studies in both low-income and high-income countries. The results of some studies have suggested that adverse pregnancy outcomes could be specifically associated with protease inhibitor use during pregnancy, but data from large studies in Botswana and Tanzania suggest such outcomes could also be linked to nevirapine-based or efavirenz-based ART. Very few data are available to allow comparison of pregnancy outcomes in women initiating ART before conception with outcomes in those beginning ART after conception. Until 2013, in low-income settings, where the largest proportion of women living with HIV are, WHO guidelines recommended use of lifelong ART during pregnancy only for pregnant women with low CD4 cell counts or advanced disease. Thus, the number of women who conceived while taking ART was low. In high-income settings, ART was recommended for all pregnant women, but until 2015, many women with high CD4 cell counts (>500 cells per μL) stopped ART after delivery. In some studies, use of ART before conception was compared with use of any regimen during pregnancy, including zidovudine alone, whereas in other studies ART use before conception was combined with first trimester use, without accounting for timing of first trimester initiation.
 
Added value of this study
 
To our knowledge, ours is the first systematic review that has specifically assessed adverse pregnancy outcome risks by timing of initiation of ART (ie, before conception vs after conception). Although, reassuringly, many adverse outcomes, such as stillbirth, small for gestational age, and congenital abnormalities did not seem to differ by timing of ART initiation, we found that preterm delivery and low birthweight were significantly more likely in women who began ART before conception than in those who began ART after conception. However, data are sparse and of low to very low quality, and correlation with infant mortality or morbidity was not shown.
 
Implications of all available evidence
 
Although the clear benefits of ART for maternal health and prevention of perinatal transmission outweigh potential risks, data for the extent or severity of these risks remain few and of poor quality. We showed an increased risk of preterm delivery and low birthweight associated with pre-conception initiation of ART, but there are potential confounders, because ART was used before conception primarily by women with low CD4 cell counts who were felt to require treatment for their health. In view of new guidelines for immediate ART in all individuals with HIV, use of ART before conception can be expected to increase rapidly worldwide, and will be crucial to monitor for potential adverse pregnancy outcomes.
 
Discussion
 
In our systematic review and meta-analysis, preterm delivery, very preterm delivery, and low birthweight were significantly more common in pregnant women with HIV who initiated ART before conception than in women who first initiated ART after conception. On subgroup analysis, the magnitude of these associations was highest in studies done in low-income and middle-income countries (data not shown), where background rates of preterm delivery and low birthweight are higher than in high-income countries. Before the ART era, studies of the association between HIV infection and adverse pregnancy outcomes showed that HIV infection was significantly associated with adverse outcomes in low-income but not high-income countries.29
 
Although the results of some studies have suggested that increased risk of preterm delivery is confined to protease-inhibitor-based ART,12, 13, 14, 15 a range of regimens were used in the studies included in our review. For example, in Chen and colleagues' study,9 which included 3290 pregnant women with HIV receiving ART (2189 started before conception and 1101 started after conception), 2851 (87%) women were receiving nevirapine-based ART and only 312 (9%) were receiving protease-inhibitor-based ART (24 initiated before conception, 278 initiated after conception). Similarly, in the study16 by Li and colleagues, 91% of women were receiving nevirapine-based ART, and 3% efavirenz-based ART.
 
Very few data were available for comparison of pregnancy outcomes between women initiating ART before conception and those beginning ART after conception. Until 2013, in low-income settings, where the largest proportion of women with HIV reside, WHO guidelines recommended use of ART during pregnancy only for pregnant women with low CD4 cell counts (<350 cells per μL) or advanced disease. Thus, the number of women who conceived while taking ART was low. In high-income settings, where ART was recommended for all pregnant women living with HIV, until 2015 many women with high CD4 cell counts (>500 cells per μL) stopped ART after delivery.
 
A potentially important source of bias is that women initiating ART before conception could have risk factors for adverse pregnancy outcomes not present in women first initiating ART after conception. For example, women initiating ART before conception might be older, more likely to be multigravidae, and more likely to have been initiated on ART because they were sick than women who start ART after conception, who might be more likely to be younger, healthier primigravidae who do not require ART for their own health. In Chen and colleagues' Botswanan study,9 compared with those who initiated ART after conception, women on ART before conception were more likely to be older (32 years vs 29 years, respectively), to be multigravidae (67% vs 47%), and to have a history of adverse pregnancy outcome (18% vs 13%). However, CD4 cell counts in the women starting ART before conception were higher than were those in women starting ART after conception (384 cells per μL vs 225 cells per μL; proportion with <200 CD4 cells per μL 2% vs 28%), and difference between the two groups in other risk factors for adverse pregnancy outcomes (such as rates of syphilis or smoking) were not noted. Additionally, multivariate analyses that controlled for risk factors such as maternal age, parity, illicit drug use, and CD4 cell count were done in several of the larger studies,9, 16, 21, 24 and associations were still significant. However, residual unmeasured confounding could still exist.
 
Another potential bias is that women who start ART very late in pregnancy (eg, after 36 weeks' gestation) do not have the same opportunity for a preterm delivery as those starting earlier or before conception. However, in most studies, pre-conception and post-conception initiation of ART were compared without taking into account the gestational week that ART was begun, and median gestational age for those starting ART during pregnancy was not provided.
 
Strengths of our meta-analysis include the use of a predefined protocol, a comprehensive search strategy, and involvement of two independent reviewers in all stages of the review process. To our knowledge, ours is the first systematic review in which measures of adverse pregnancy outcomes in women with HIV were pooled to address specifically associations with initiation of ART before conception.
 
Our study also has some limitations. The review was limited by the scarcity of studies reporting most of the outcomes of interest. Although we examined for publication bias, we recognise that publication bias is always present when investigating routine outcomes from interventions widely provided in non-research settings. Also, all studies included were observational, which could lead to bias as a result of unmeasured confounding.
 
Several published studies did not differentiate women initiating ART before conception from those initiating ART during the first trimester, and hence could not be included in our analysis. For example, a previous meta-analysis30 published in 2007 showed that ART use after conception did not increase pre-term delivery overall, but initiation of combination ART before pregnancy or in the first trimester resulted in an increased risk of preterm delivery (odds ratio 1⋅71, 95% CI 1⋅09-2⋅67) compared with initiation in the second or third trimester. The authors noted that increased surveillance is needed to quantify this risk accurately.
 
Additionally, in some studies, pre-conception initiation of ART was compared with initiation of various regimens during pregnancy, including zidovudine single-drug prophylaxis, and thus could not be included in our analysis. For example, in their large French study,11 Sibiude and colleagues reported increased rates of preterm delivery in women who began ART before conception compared with women starting antiretroviral regimens during pregnancy. However, this study included use of zidovudine alone or dual antiretroviral prophylaxis.11 The Antiretroviral Pregnancy Registry compares use of different antiretroviral drugs in the first trimester with use in the second or third trimester, but does not provide data for pre-conception use or by type of regimen.31
 
Few investigators differentiated between very preterm delivery (<34 weeks' gestation) and preterm delivery (34-37 weeks' gestation),16, 27 or between very low birthweight (<1500 g) and low birthweight.16 Severe prematurity and low birthweight are associated with significantly more infant morbidity and mortality than are more moderate prematurity and birthweight. Additionally, reports of neonatal and infant mortality were lacking from all but one study. In Chen and colleagues' report,9 ART initiation before conception was not associated with increased neonatal mortality compared with ART initiation after conception, despite being associated with higher risks of prematurity and low birthweight. Finally, spontaneous preterm delivery was not differentiated from induced prematurity (induction of labour or caesarean section for complications) in any of the included studies.
 
The benefits of ART for prevention of mother-to-child transmission of HIV and for maternal health clearly outweigh any risks identified so far, and there is no question that ART should be initiated in all pregnant women and continued thereafter. Nevertheless, further research is needed to define these risks better and to determine how to optimise ART to allow safe, healthy pregnancies for women with HIV and good health outcomes for both mother and child. With recom-mendations for immediate initiation of ART after HIV diagnosis and 1⋅5 million pregnancies annually in women with HIV, fetal exposure to ART begun before conception will increase. Therefore, better monitoring of adverse pregnancy outcomes is essential to determine whether these outcomes are more common in people with HIV than in those without HIV. More research is needed to investigate causal mechanisms for adverse pregnancy outcomes with ART use to establish if modifiable factors could be exploited to reduce or prevent such outcomes.32, 33 Differences in pregnancy outcomes between ART regimens need to be established, and a better understanding is needed of the ultimate effect of such outcomes on maternal, neonatal, and infant morbidity and mortality.

 
 
 
 
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