A link between antiretrovirals and perinatal outcomes?
Authors: Laurent Mandelbrot, Jeanne Sibiude
Journal: The Lancet HIV (2016)

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-analysis1Uthman OA Nachega JB Anderson J et al.Timing of initiation of antiretroviral therapy and adverse pregnancy outcomes: a systematic review and meta-analysis.Lancet HIV. 2016; (published online Nov 15.)http://dx.doi.org/10.1016/S2352-3018(16)30195-3Google Scholar 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.2Townsend C Schulte J Thorne C et al.Antiretroviral therapy and preterm delivery—a pooled analysis of data from the United States and Europe.BJOG. 2010; 117: 1399-1410Crossref PubMed Scopus (79) Google Scholar 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,3Sibiude J Warszawski J Tubiana R et al.Premature delivery in HIV-infected women starting protease inhibitor therapy during pregnancy: role of the ritonavir boost?.Clin infect Dis. 2012; 54: 1348-1360Crossref PubMed Scopus (127) Google Scholar 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.4Canlorbe G Matheron S Mandelbrot L Oudet B Luton D Azria E Vasculoplacental complications in pregnant women with HIV infection: a case-control study.Am J Obstet Gynecol. 2015; 213 (e1–9.): 241Summary Full Text Full Text PDF Scopus (8) Google Scholar 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 study5Patel D Thorne C Fiore S Newell ML European Collaborative SDoes highly active antiretroviral therapy increase the risk of congenital abnormalities in HIV-infected women?.J Acquir Immune Defic Syndr. 2005; 40: 116-118Crossref PubMed Scopus (67) Google Scholar 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.6Ford N Mofenson L Shubber Z et al.Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis.AIDS. 2014; 28: S123-S131Crossref PubMed Scopus (95) Google Scholar In the French Perinatal Cohort,7Sibiude J Mandelbrot L Blanche S et al.Association between prenatal exposure to antiretroviral therapy and birth defects: an analysis of the French Perinatal Cohort Study.PLoS Med. 2014; 11: e1001635Crossref PubMed Scopus (73) Google Scholar 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,8Lopez M Figueras F Coll O et al.Inflammatory markers related to microbial translocation among HIV-infected pregnant women: a risk factor of preterm delivery.J Infect Dis. 2016; 213: 343-350Crossref Scopus (27) Google Scholar and were associated with preterm delivery. One might thus assume that treating HIV infection improves pregnancy outcomes, but the opposite has been described.9Bagkeris E Malyuta R Volokha A et al.for the Ukraine European Collaborative Study in EuroCoordPregnancy outcomes in HIV-positive women in Ukraine, 2000–12 (European Collaborative Study in EuroCoord): an observational cohort study.Lancet HIV. 2015; 2: e385-e392Summary Full Text Full Text PDF Scopus (12) Google Scholar 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.10Lopez M Figueras F Hernandez S et al.Association of HIV infection with spontaneous and iatrogenic preterm delivery: effect of HAART.AIDS. 2012; 26: 37-43Crossref PubMed Scopus (65) Google Scholar 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.11Papp E Mohammadi H Loutfy MR et al.HIV protease inhibitor use during pregnancy is associated with decreased progesterone levels, suggesting a potential mechanism contributing to fetal growth restriction.J Infect Dis. 2015; 211: 10-18Crossref PubMed Scopus (78) Google Scholar 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. LM has received lecturing fees from Abbott Diagnostics. JS declares no competing interests. Timing of initiation of antiretroviral therapy and adverse pregnancy outcomes: a systematic review and meta-analysisThe 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. Full-Text PDF Open Access