- Email: [email protected]
Antiretroviral therapy and perinatal outcomes
Comment
Combination antiretroviral therapy (ART) can virtually eliminate HIV transmission from mother to child, but a broader approach to perinatal health for HIV-positive women and their children is required. Preterm delivery, small size for gestational age, and birth defects are common adverse birth outcomes that can lead to perinatal death or lifelong disability. ART might be both part of the solution and part of the problem. In The Lancet HIV, Emmanouil Bagkeris and colleagues1 report findings from the continuing European Collaborative Study on pregnancy outcomes among 8884 HIV-positive women who delivered liveborn singletons from 2000 to 2012 in Ukraine. Although there was no reference group, the incidence of preterm delivery seemed to be higher than that reported in the Ukraine general population (780 [9%, 95% CI 8–9] of 8860 births overall vs 5%). Untreated HIV infection was an important risk factor for preterm delivery (adjusted incidence risk ratio for no ART 2·94, 95% CI 2·43–3·57 vs zidovudine monotherapy and WHO stage 4 HIV 2·42, 1·71–3·41 vs WHO stage 1). Bagkeris and colleagues also found that the use of ART, versus zidovudine monotherapy, was associated with increased risks of preterm delivery (1·40, 95% CI 1·14–1·73) and small size for gestational age (1·33, 1·12–1·60). Additionally, risk factors associated with preterm delivery in the general antenatal population were relevant in HIV-positive women, including substance use and social deprivation. The former Soviet region has the sad privilege of having an expanding HIV epidemic. For those who were involved in fighting AIDS in western Europe in the 1980s and early 1990s, the situation today in most ex-Soviet countries is completely different thanks to the introduction of ART, but at the same time is reminiscent. Antiretroviral drugs are provided free, yet the spread of HIV is fuelled by high frequencies of injecting drug use, sexual partners who are injecting drug users, abuse of women, social deprivation, and discrimination against people with HIV. Additionally, repression of illicit drug use without harm reduction drives users underground (often literally into basements) and excludes them from prenatal care. In view of these many risk factors, the 9% rate of preterm delivery in HIV-positive women in Ukraine is surprisingly low. The incidence of preterm delivery
in the general population ranges from around 5% in most European countries, to 12% in the USA, and up to 18% in some African countries.2 The rate of small size for gestational age was 10%, which, by definition, is the expected rate for the tenth percentile. In France, Sibiude and colleagues3 reported a preterm delivery rate of 14% in HIV-infected women for 2005–09, compared with a national average of 6% in liveborn singletons, despite generally good access to prenatal care and little consumption of tobacco or illicit drugs. However, the proportion of African migrants, who often live in conditions of social deprivation, was high. Before the introduction of ART in the early 1990s, when the characteristics of HIV-infected women in France and southern Europe resembled those in Ukraine today (European origin, marginalisation, and high rates of substance abuse by women, their partners, or both), the incidence of preterm delivery was, also similarly, 9%.3 Therefore, this cohort in Ukraine has the potential to enable study of the effects of ART on pregnancy outcomes with adjustment for other risk factors. Bagkeris and colleagues’ findings confirmed that untreated HIV infection with low CD4 cell counts has a negative effect on pregnancy outcomes. Adjustment for the fact that women who did not receive ART were more likely to have other risk factors for pregnancy complications did not alter this effect. Treatment of HIV infection, therefore, might be assumed to improve pregnancy outcomes. The worrying finding, though, was that both preterm delivery and small size for gestational age increased with the use of ART versus zidovudine monotherapy. Several previous studies, including the European Collaborative Study, have shown a strong relation between ART and preterm delivery,4 although others have not. Bagkeris and colleagues adjusted their analysis for calendar time to take into account changes in the use of ART. Previous cohort studies have shown some effect of ART on small size for gestational age, but most have not.5,6 The association between ART and preterm delivery is puzzling. Among the hypotheses are a shift from a T-helper-1 to a T-helper-2 immune response,7 ritonavir boosting of protease inhibitors,3,8 and an indirect effect of ART increasing pregnancy complications that lead to medically indicated preterm delivery as opposed to
www.thelancet.com/hiv Published online July 13, 2015 http://dx.doi.org/10.1016/S2352-3018(15)00131-9
Jim Varney/Science Photo Library
Antiretroviral therapy and perinatal outcomes
Lancet HIV 2015 Published Online July 13, 2015 http://dx.doi.org/10.1016/ S2352-3018(15)00131-9 See Online/Articles http://dx.doi.org/10.1016/ S2352-3018(15)00079-X
1
Comment
increasing spontaneous preterm delivery.3 One group suggested that ART might contribute to low birthweight by lowering progesterone concentrations,9 but most studies have found no increases in complications that commonly lead to medically indicated preterm delivery, such as small size for gestational age and pre-eclampsia.10 ART use is not the only risk factor for preterm delivery for which the causal mechanisms are poorly understood.11 Other examples include smoking and bacterial vaginosis. An important question related to ART prescription in pregnancy will be whether the effect on preterm delivery, if confirmed, can be reduced by starting treatment before pregnancy, by use of different drugs, or both. In the study by Bagkeris and colleagues,1 as in most previous studies, the ART was principally composed of nucleoside reverse transcriptase inhibitors and a ritonavir-boosted protease inhibitor. The findings of Bagkeris and colleagues reveal a clear need for further research on the maternal, perinatal, and long-term consequences of using various antiretroviral drugs during pregnancy. At the same time, clinicians must be aware that despite the tremendous progress of ART, pregnancies in HIV-positive women are still high risk and require personalised interdisciplinary attention.
I have received lecturing fees from Bristol-Myers Squibb, Gilead, and Merck Sharpe Dohme. 1
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11
Laurent Mandelbrot
Bagkeris E, Malyuta R, Volokha A, et al, for the Ukraine European Collaborative Study in EuroCoord. Pregnancy outcomes in HIV-positive women in Ukraine, 2000–12 (European Collaborative Study in EuroCoord): an observational cohort study. Lancet HIV 2015; published online July 13. http://dx.doi.org/10.1016/S2352-3018(15)00079-X. Blencowe H, Cousens S, Oestergaard MZ, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet 2012; 379: 2162–72. Sibiude 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: 1348–60. Townsend 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: 1399–410. Briand N, Mandelbrot L, Le Chenadec J, et al. No relation between in-utero exposure to HAART and intrauterine growth retardation. AIDS 2009; 23: 1235–43. Jao J, Abrams EJ. Metabolic complications of in utero maternal HIV and antiretroviral exposure in HIV-exposed infants. Pediatr Infect Dis J 2014; 33: 734–40. Fiore S, Newell ML, Trabattoni D, et al. Antiretroviral therapy-associated modulation of Th1 and Th2 immune responses in HIV-infected pregnant women. J Reprod Immunol 2006; 70: 143–50. Powis KM, Kitch D, Ogwu A, et al. Increased risk of preterm delivery among HIV-infected women randomized to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy. J Infect Dis 2011; 204: 506–14. Papp 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: 10–18. Canlorbe 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; published online March 19. DOI:10.1016/j.ajog.2015.03.035. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371: 75–84.
Department of Gynaecology and Obstetrics, Hôpital Louis Mourier, Hôpitaux Universitaires Paris Nord, Colombes 92700, and Université Paris-Diderot, Paris, France. [email protected]
2
www.thelancet.com/hiv Published online July 13, 2015 http://dx.doi.org/10.1016/S2352-3018(15)00131-9
Combination antiretroviral therapy (ART) can virtually eliminate HIV transmission from mother to child, but a broader approach to perinatal health for HIV-positive women and their children is required. Preterm delivery, small size for gestational age, and birth defects are common adverse birth outcomes that can lead to perinatal death or lifelong disability. ART might be both part of the solution and part of the problem. In The Lancet HIV, Emmanouil Bagkeris and colleagues1 report findings from the continuing European Collaborative Study on pregnancy outcomes among 8884 HIV-positive women who delivered liveborn singletons from 2000 to 2012 in Ukraine. Although there was no reference group, the incidence of preterm delivery seemed to be higher than that reported in the Ukraine general population (780 [9%, 95% CI 8–9] of 8860 births overall vs 5%). Untreated HIV infection was an important risk factor for preterm delivery (adjusted incidence risk ratio for no ART 2·94, 95% CI 2·43–3·57 vs zidovudine monotherapy and WHO stage 4 HIV 2·42, 1·71–3·41 vs WHO stage 1). Bagkeris and colleagues also found that the use of ART, versus zidovudine monotherapy, was associated with increased risks of preterm delivery (1·40, 95% CI 1·14–1·73) and small size for gestational age (1·33, 1·12–1·60). Additionally, risk factors associated with preterm delivery in the general antenatal population were relevant in HIV-positive women, including substance use and social deprivation. The former Soviet region has the sad privilege of having an expanding HIV epidemic. For those who were involved in fighting AIDS in western Europe in the 1980s and early 1990s, the situation today in most ex-Soviet countries is completely different thanks to the introduction of ART, but at the same time is reminiscent. Antiretroviral drugs are provided free, yet the spread of HIV is fuelled by high frequencies of injecting drug use, sexual partners who are injecting drug users, abuse of women, social deprivation, and discrimination against people with HIV. Additionally, repression of illicit drug use without harm reduction drives users underground (often literally into basements) and excludes them from prenatal care. In view of these many risk factors, the 9% rate of preterm delivery in HIV-positive women in Ukraine is surprisingly low. The incidence of preterm delivery
in the general population ranges from around 5% in most European countries, to 12% in the USA, and up to 18% in some African countries.2 The rate of small size for gestational age was 10%, which, by definition, is the expected rate for the tenth percentile. In France, Sibiude and colleagues3 reported a preterm delivery rate of 14% in HIV-infected women for 2005–09, compared with a national average of 6% in liveborn singletons, despite generally good access to prenatal care and little consumption of tobacco or illicit drugs. However, the proportion of African migrants, who often live in conditions of social deprivation, was high. Before the introduction of ART in the early 1990s, when the characteristics of HIV-infected women in France and southern Europe resembled those in Ukraine today (European origin, marginalisation, and high rates of substance abuse by women, their partners, or both), the incidence of preterm delivery was, also similarly, 9%.3 Therefore, this cohort in Ukraine has the potential to enable study of the effects of ART on pregnancy outcomes with adjustment for other risk factors. Bagkeris and colleagues’ findings confirmed that untreated HIV infection with low CD4 cell counts has a negative effect on pregnancy outcomes. Adjustment for the fact that women who did not receive ART were more likely to have other risk factors for pregnancy complications did not alter this effect. Treatment of HIV infection, therefore, might be assumed to improve pregnancy outcomes. The worrying finding, though, was that both preterm delivery and small size for gestational age increased with the use of ART versus zidovudine monotherapy. Several previous studies, including the European Collaborative Study, have shown a strong relation between ART and preterm delivery,4 although others have not. Bagkeris and colleagues adjusted their analysis for calendar time to take into account changes in the use of ART. Previous cohort studies have shown some effect of ART on small size for gestational age, but most have not.5,6 The association between ART and preterm delivery is puzzling. Among the hypotheses are a shift from a T-helper-1 to a T-helper-2 immune response,7 ritonavir boosting of protease inhibitors,3,8 and an indirect effect of ART increasing pregnancy complications that lead to medically indicated preterm delivery as opposed to
www.thelancet.com/hiv Published online July 13, 2015 http://dx.doi.org/10.1016/S2352-3018(15)00131-9
Jim Varney/Science Photo Library
Antiretroviral therapy and perinatal outcomes
Lancet HIV 2015 Published Online July 13, 2015 http://dx.doi.org/10.1016/ S2352-3018(15)00131-9 See Online/Articles http://dx.doi.org/10.1016/ S2352-3018(15)00079-X
1
Comment
increasing spontaneous preterm delivery.3 One group suggested that ART might contribute to low birthweight by lowering progesterone concentrations,9 but most studies have found no increases in complications that commonly lead to medically indicated preterm delivery, such as small size for gestational age and pre-eclampsia.10 ART use is not the only risk factor for preterm delivery for which the causal mechanisms are poorly understood.11 Other examples include smoking and bacterial vaginosis. An important question related to ART prescription in pregnancy will be whether the effect on preterm delivery, if confirmed, can be reduced by starting treatment before pregnancy, by use of different drugs, or both. In the study by Bagkeris and colleagues,1 as in most previous studies, the ART was principally composed of nucleoside reverse transcriptase inhibitors and a ritonavir-boosted protease inhibitor. The findings of Bagkeris and colleagues reveal a clear need for further research on the maternal, perinatal, and long-term consequences of using various antiretroviral drugs during pregnancy. At the same time, clinicians must be aware that despite the tremendous progress of ART, pregnancies in HIV-positive women are still high risk and require personalised interdisciplinary attention.
I have received lecturing fees from Bristol-Myers Squibb, Gilead, and Merck Sharpe Dohme. 1
2
3
4
5
6
7
8
9
10
11
Laurent Mandelbrot
Bagkeris E, Malyuta R, Volokha A, et al, for the Ukraine European Collaborative Study in EuroCoord. Pregnancy outcomes in HIV-positive women in Ukraine, 2000–12 (European Collaborative Study in EuroCoord): an observational cohort study. Lancet HIV 2015; published online July 13. http://dx.doi.org/10.1016/S2352-3018(15)00079-X. Blencowe H, Cousens S, Oestergaard MZ, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet 2012; 379: 2162–72. Sibiude 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: 1348–60. Townsend 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: 1399–410. Briand N, Mandelbrot L, Le Chenadec J, et al. No relation between in-utero exposure to HAART and intrauterine growth retardation. AIDS 2009; 23: 1235–43. Jao J, Abrams EJ. Metabolic complications of in utero maternal HIV and antiretroviral exposure in HIV-exposed infants. Pediatr Infect Dis J 2014; 33: 734–40. Fiore S, Newell ML, Trabattoni D, et al. Antiretroviral therapy-associated modulation of Th1 and Th2 immune responses in HIV-infected pregnant women. J Reprod Immunol 2006; 70: 143–50. Powis KM, Kitch D, Ogwu A, et al. Increased risk of preterm delivery among HIV-infected women randomized to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy. J Infect Dis 2011; 204: 506–14. Papp 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: 10–18. Canlorbe 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; published online March 19. DOI:10.1016/j.ajog.2015.03.035. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371: 75–84.
Department of Gynaecology and Obstetrics, Hôpital Louis Mourier, Hôpitaux Universitaires Paris Nord, Colombes 92700, and Université Paris-Diderot, Paris, France. [email protected]
2
www.thelancet.com/hiv Published online July 13, 2015 http://dx.doi.org/10.1016/S2352-3018(15)00131-9