- Email: [email protected]
Hidden in plain sight: HIV, antiretrovirals, and stillbirths
Correspondence
Association of Blood Banks), Zika virus should be classified as a high-risk agent that threatens the safety of blood recipients.2 Measures to prevent transfusiontransmitted Zika virus include temporary deferral of blood donors in epidemic locations, donor self-reporting of Zika virus symptoms after donation with or without quarantine of blood components, supply by blood collected from non-endemic areas to epidemic regions, NAT of blood donations, and pathogen inactivation of blood products.4,5 In endemic areas, all blood donors are at risk of infection, so importation of blood from low-risk regions to supply most endemic areas is not practical, because of the high volume of blood needed and difficulties in blood transportation to remote areas. The sensitivity of donor deferral and post-donation information reporting are limited by the high rate of asymptomatic infections. No commercially available, sensitive NAT assays exist at present. Pathogen-inactivation methods capable of adequate levels of flavivirus reduction are only available for plasma and platelets, whereas red blood cells constitute the major part of transfused blood components.1,4 Zika virus-endemic areas that do not have the capacity to provide Zika virus-safe blood to all patient groups should focus on at-risk recipients (pregnant women and patients undergoing intrauterine transfusions), especially highly transfused women (eg, patients with sickle cell disease or thalassaemia). Development of NAT assays to screen all blood donations (optimally multiplexed assays that simultaneously detect Zika virus and distinguish Zika virus from dengue virus, chikungunya virus, and, ideally, West Nile virus) and pathogen-inactivation systems suitable for whole blood and red blood cells are urgently needed. Epidemiologically, Zika virus is following the path of dengue and chikungunya viruses, 1 and if the potential for Zika virus transfusion transmission is not addressed, Zika 1994
virus is highly likely to follow the path of West Nile viruses with a significant number of infections and serious outcomes attributable to blood transfusion. We declare no competing interests.
*Didier Musso, Susan L Stramer (on behalf of the AABB TransfusionTransmitted Diseases Committee), Michael P Busch (on behalf of the International Society of Blood Transfusion Working Party on Transfusion-Transmitted Infectious Diseases) [email protected] Unit of Emerging Infectious Diseases, Institut Louis Malardé, Tahiti, French Polynesia (DM); American Red Cross, Gaithersburg, MD, USA (SLS); and International Society of Blood Transfusions, Blood Systems Research Institute, San Francisco, CA, USA (MPB) 1 2
3
4
5
Musso D, Gubler DJ. Zika virus. Clin Microbiol Rev 2016; 29: 487–524. Stramer SL, Hollinger FB, Katz LM, et al. Emerging infectious disease agents and their potential threat to transfusion safety. Transfusion 2009; 49 (suppl 2): S1–29. Dodd RY, Foster GA, Stramer SL. Keeping blood transfusion safe from West Nile virus: American Red Cross Experience, 2003 to 2012. Transfus Med Rev 2015; 29: 153–61. US Food and Drug Administration. Recommendations for donor screening, deferral, and product management to reduce the risk of transfusion-transmission of Zika virus guidance for industry. February, 2016. http://www.fda.gov/downloads/ BiologicsBloodVaccines/ GuidanceComplianceRegulatoryInformation/ Guidances/Blood/UCM486360.pdf (accessed April 25, 2016) WHO. Maintaining a safe and adequate blood supply during Zika virus outbreaks. Interim guidance. February, 2016. http://apps.who.int/ iris/bitstream/10665/204436/1/WHO_ZIKV_ HS_16.1_eng.pdf?ua=1 (accessed April 25, 2016).
Hidden in plain sight: HIV, antiretrovirals, and stillbirths We read with interest The Lancet Series on stillbirths, and The Lancet Global Health report highlighting increased stillbirths in 55 countries since 2000, and goals for future stillbirth reduction.1,2 We would like to add a missing component to the discussion: the HIV pandemic. Both maternal HIV
infection and the use of three-drug antiretroviral treatment (ART) might be associated with increased risk of stillbirth. Nearly a million African women who are infected with HIV now receive ART during pregnancy, as compared with almost no three-drug ART use in pregnancy in the year 2000.3 Although untreated HIV infection itself can increase the risk of stillbirth by about 1·7 times,4 the stillbirth rate in the setting of ART seems to be even higher, especially for patients receiving ART from conception, and is caused by a currently unexplained mechanism. In the largest African series so far, which included more than 33 000 women between 2009 and 2011, 6·3% of women in Botswana who conceived while receiving nevirapine-based ART had a stillbirth, compared with 4·1% of all other women who were infected with HIV, and 2·5% of uninfected women.5 This is an estimated 20% population attributable fraction of stillbirths related to HIV or ART, or both. The study of new ART regimens and the investigation of immune-mediated mechanisms are promising areas of research, but the relation between HIV, ART, and stillbirth is complex and will continue to require scientific effort to be untangled. Interventions to mitigate risk of stillbirth are greatly needed, as is collaboration between currently distinct research areas to identify all preventable causes of stillbirth. We declare no competing interests.
*Roger Shapiro, Scott Dryden-Peterson, Kate Powis, Rebecca Zash, Shahin Lockman [email protected] Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA 02115, USA (RS, SD-P, KP, RZ, SL); Brigham and Women’s Hospital, Boston, MA, USA (SL); Massachusetts General Hospital, Boston, MA, USA (KP); and Botswana Harvard AIDS Institute Partnership, Princess Marina Hospital, Bontleng, Gaborone, Botswana (RS, SD-P, KP, RZ, SL) 1
Blencowe H, Cousens S, Jassir FB, et al. National, regional, and worldwide estimates of stillbirth rates in 2015, with trends from 2000: a systematic analysis. Lancet Glob Health 2016; 4: e98–108.
www.thelancet.com Vol 387 May 14, 2016
Correspondence
3
4
5
Lawn JE, Blencowe H, Waiswa P, et al. Stillbirths: rates, risk factors, and acceleration towards 2030. Lancet 2016; 387: 587–603. UNAIDS. UNAIDS global factsheets 2014. 2014. http://www.unaids.org/sites/default/ files/en/media/unaids/contentassets/ documents/factsheet/2014/20140716_ FactSheet_en.pdf (accessed March 17, 2016). Wedi CO, Kirtley S, Hopewell S, Corrigan R, Kennedy SH, Hemelaar J. Perinatal outcomes associated with maternal HIV infection: a systematic review and meta-analysis. Lancet HIV 2016; 3: e33–48. Chen JY, Ribaudo HJ, Souda S, et al. Highly active antiretroviral therapy and adverse birth outcomes among HIV-infected women in Botswana. J Infect Dis 2012; 206: 1695–705.
Mitigating the stillbirth challenge in India India, with 592 100 stillbirths, accounted for 22·6% of the global burden of stillbirths in 2015.1 The country has a ground-level health workforce of 1 million accredited social health activists (ASHA) and is pushing hard to ensure the survival of future generations. However, initiatives taken to safeguard pregnancy outcomes— such as the distribution of safe delivery kits, conditional cash transfers to increase the number of institutional deliveries, efforts to track pregnancies, and free transportation for antenatal mothers—have not been as successful as they could have been because of the inadequate monitoring system used to document the time and cause of death of unborn infants. A major reason that stillbirth has gone unnoticed as a public health issue in India is its lack of recognition at a policy or community level.2 The difficulty in differentiating stillbirth and neonatal death and the societal lack of acceptance and possible stigma towards miscarriage can prevent parents from mourning the end of an unsuccessful pregnancy. As a result, many pregnancies and stillbirths are not tracked or recorded, making the numbers seem lower than they should be. To end the mystery of missing stillbirths in the community, media needs to be used to encourage the population and health workers to report such events and to destigmatise the topic. www.thelancet.com Vol 387 May 14, 2016
The India Newborn Action Plan, launched in 2014, contains six interventions that aim to reduce the number of stillbirths by a third by 2025, and also help to decrease maternal and neonatal deaths. The plan emphasises the tracking of stillbirths and aims to strengthen the tracking mechanisim by 2018–19. With its ambitious vision to overcome the suboptimum antenatal care that is prevalent in India, the plan is expected to succeed in its goal to reduce the preventable stillbirth rate within the stipulated time period. Studies in India have already identified specific pregnancy-related disorders as risk factors for stillbirth. 3 However, knowledge about distal factors would also enhance understanding about stillbirth. Although clinical studies tend to overlook factors such as poverty and inequity, the triad of low socioeconomic status, illiteracy, and inadequate antenatal care is what contributes most to the likelihood of stillbirth. 1,3,4 As shown for high-income countries, adverse socioeconomic status could also increase risk for stillbirth, particularly in a nation with an uneven economic distribution like India. More than 40% of pregnant women in India are illiterate. Only 37% of pregnant Indian women have four or more antenatal visits. 5 Until India takes a holistic approach to addressing these issues, the country will have difficulty reducing mortality in isolation. I declare no competing interests.
Manas Pratim Roy [email protected] Department of Pediatrics, Safdarjung Hospital, New Delhi 110029, India 1
2
Blencowe H, Cousens S, Bianchi Jassir F, et al. National, regional, and worldwide estimates of stillbirth rates in 2015, with trends from 2000: a systematic analysis. Lancet Glob Health 2016; 4: e98–108. Lawn JE, Yakoob MY, Haws RA, Soomro T, Darmstadt GL, Bhutta ZA. 3·2 million stillbirths: epidemiology and overview of the evidence flow. BMC Pregnancy Childbirth 2009; 9: S2.
3
4
5
Korde-Nayak VN, Gaikwad PR. Causes of stillbirth. J Obstet Gynecol India 2008; 58: 314–18. Lawn JE, Blencowe H, Waiswa P, et al, for The Lancet Ending Preventable Stillbirths Series study group with The Lancet Stillbirth Epidemiology investigator group. Stillbirths: rates, risk factors, and acceleration towards 2030. Lancet 2016; 387: 587–603. IIPS and Macro International. National family health survey (NFHS-3), 2005–06. Mumbai, India: International Institute for Population Sciences, 2007.
Stillbirth in China The global stillbirth rate is estimated to be 18·4 per 1000 total births. A goal of reaching a rate of 12 per 1000 total births by 2030 has been proposed by Joy Lawn and colleagues1 in the Lancet Series Ending preventable stillbirths. The stillbirth rate in China has reduced by 4–6% in the past 15 years (2000–15). However, the number of stillbirths in China in 2015 remains high and ranked in the top fifth of the world.1,2 The mean stillbirth rate analysed from six tertiary hospitals in our network3 is even higher than the global rate and has increased from 3·11% in 2010 to 3·55% in 2015 (table). This increase is also much higher than the increase in preterm births we reported previously.4 Within these six hospitals, the mean maternal mortality rate has decreased from 17·53 per 100 000 people in 2010 to 9·95 per 100 000 people in 2015, and the mortality of children younger than 5 years has decreased from 10·51 per 1000 children in 2010 to 6·15 per 1000 children in 2015. Our analyses (unpublished) have determined the top ten risk factors causing stillbirth: fetal intrauterine malformation, pre-eclampsia, preterm premature rupture of membrane, placenta praevia, twin p r e g n a n c y, o l i g o h y d r a m n i o s , twin–twin transfusion syndrome, cervical incompetence, placental abruption, and complications of pregnancy. The opposite trends for stillbirth and mortality rates and the preventable
Abdelhak Senna/Staff
2
This online publication has been corrected. The corrected version first appeared at thelancet.com on May 23, 2015
1995
Association of Blood Banks), Zika virus should be classified as a high-risk agent that threatens the safety of blood recipients.2 Measures to prevent transfusiontransmitted Zika virus include temporary deferral of blood donors in epidemic locations, donor self-reporting of Zika virus symptoms after donation with or without quarantine of blood components, supply by blood collected from non-endemic areas to epidemic regions, NAT of blood donations, and pathogen inactivation of blood products.4,5 In endemic areas, all blood donors are at risk of infection, so importation of blood from low-risk regions to supply most endemic areas is not practical, because of the high volume of blood needed and difficulties in blood transportation to remote areas. The sensitivity of donor deferral and post-donation information reporting are limited by the high rate of asymptomatic infections. No commercially available, sensitive NAT assays exist at present. Pathogen-inactivation methods capable of adequate levels of flavivirus reduction are only available for plasma and platelets, whereas red blood cells constitute the major part of transfused blood components.1,4 Zika virus-endemic areas that do not have the capacity to provide Zika virus-safe blood to all patient groups should focus on at-risk recipients (pregnant women and patients undergoing intrauterine transfusions), especially highly transfused women (eg, patients with sickle cell disease or thalassaemia). Development of NAT assays to screen all blood donations (optimally multiplexed assays that simultaneously detect Zika virus and distinguish Zika virus from dengue virus, chikungunya virus, and, ideally, West Nile virus) and pathogen-inactivation systems suitable for whole blood and red blood cells are urgently needed. Epidemiologically, Zika virus is following the path of dengue and chikungunya viruses, 1 and if the potential for Zika virus transfusion transmission is not addressed, Zika 1994
virus is highly likely to follow the path of West Nile viruses with a significant number of infections and serious outcomes attributable to blood transfusion. We declare no competing interests.
*Didier Musso, Susan L Stramer (on behalf of the AABB TransfusionTransmitted Diseases Committee), Michael P Busch (on behalf of the International Society of Blood Transfusion Working Party on Transfusion-Transmitted Infectious Diseases) [email protected] Unit of Emerging Infectious Diseases, Institut Louis Malardé, Tahiti, French Polynesia (DM); American Red Cross, Gaithersburg, MD, USA (SLS); and International Society of Blood Transfusions, Blood Systems Research Institute, San Francisco, CA, USA (MPB) 1 2
3
4
5
Musso D, Gubler DJ. Zika virus. Clin Microbiol Rev 2016; 29: 487–524. Stramer SL, Hollinger FB, Katz LM, et al. Emerging infectious disease agents and their potential threat to transfusion safety. Transfusion 2009; 49 (suppl 2): S1–29. Dodd RY, Foster GA, Stramer SL. Keeping blood transfusion safe from West Nile virus: American Red Cross Experience, 2003 to 2012. Transfus Med Rev 2015; 29: 153–61. US Food and Drug Administration. Recommendations for donor screening, deferral, and product management to reduce the risk of transfusion-transmission of Zika virus guidance for industry. February, 2016. http://www.fda.gov/downloads/ BiologicsBloodVaccines/ GuidanceComplianceRegulatoryInformation/ Guidances/Blood/UCM486360.pdf (accessed April 25, 2016) WHO. Maintaining a safe and adequate blood supply during Zika virus outbreaks. Interim guidance. February, 2016. http://apps.who.int/ iris/bitstream/10665/204436/1/WHO_ZIKV_ HS_16.1_eng.pdf?ua=1 (accessed April 25, 2016).
Hidden in plain sight: HIV, antiretrovirals, and stillbirths We read with interest The Lancet Series on stillbirths, and The Lancet Global Health report highlighting increased stillbirths in 55 countries since 2000, and goals for future stillbirth reduction.1,2 We would like to add a missing component to the discussion: the HIV pandemic. Both maternal HIV
infection and the use of three-drug antiretroviral treatment (ART) might be associated with increased risk of stillbirth. Nearly a million African women who are infected with HIV now receive ART during pregnancy, as compared with almost no three-drug ART use in pregnancy in the year 2000.3 Although untreated HIV infection itself can increase the risk of stillbirth by about 1·7 times,4 the stillbirth rate in the setting of ART seems to be even higher, especially for patients receiving ART from conception, and is caused by a currently unexplained mechanism. In the largest African series so far, which included more than 33 000 women between 2009 and 2011, 6·3% of women in Botswana who conceived while receiving nevirapine-based ART had a stillbirth, compared with 4·1% of all other women who were infected with HIV, and 2·5% of uninfected women.5 This is an estimated 20% population attributable fraction of stillbirths related to HIV or ART, or both. The study of new ART regimens and the investigation of immune-mediated mechanisms are promising areas of research, but the relation between HIV, ART, and stillbirth is complex and will continue to require scientific effort to be untangled. Interventions to mitigate risk of stillbirth are greatly needed, as is collaboration between currently distinct research areas to identify all preventable causes of stillbirth. We declare no competing interests.
*Roger Shapiro, Scott Dryden-Peterson, Kate Powis, Rebecca Zash, Shahin Lockman [email protected] Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA 02115, USA (RS, SD-P, KP, RZ, SL); Brigham and Women’s Hospital, Boston, MA, USA (SL); Massachusetts General Hospital, Boston, MA, USA (KP); and Botswana Harvard AIDS Institute Partnership, Princess Marina Hospital, Bontleng, Gaborone, Botswana (RS, SD-P, KP, RZ, SL) 1
Blencowe H, Cousens S, Jassir FB, et al. National, regional, and worldwide estimates of stillbirth rates in 2015, with trends from 2000: a systematic analysis. Lancet Glob Health 2016; 4: e98–108.
www.thelancet.com Vol 387 May 14, 2016
Correspondence
3
4
5
Lawn JE, Blencowe H, Waiswa P, et al. Stillbirths: rates, risk factors, and acceleration towards 2030. Lancet 2016; 387: 587–603. UNAIDS. UNAIDS global factsheets 2014. 2014. http://www.unaids.org/sites/default/ files/en/media/unaids/contentassets/ documents/factsheet/2014/20140716_ FactSheet_en.pdf (accessed March 17, 2016). Wedi CO, Kirtley S, Hopewell S, Corrigan R, Kennedy SH, Hemelaar J. Perinatal outcomes associated with maternal HIV infection: a systematic review and meta-analysis. Lancet HIV 2016; 3: e33–48. Chen JY, Ribaudo HJ, Souda S, et al. Highly active antiretroviral therapy and adverse birth outcomes among HIV-infected women in Botswana. J Infect Dis 2012; 206: 1695–705.
Mitigating the stillbirth challenge in India India, with 592 100 stillbirths, accounted for 22·6% of the global burden of stillbirths in 2015.1 The country has a ground-level health workforce of 1 million accredited social health activists (ASHA) and is pushing hard to ensure the survival of future generations. However, initiatives taken to safeguard pregnancy outcomes— such as the distribution of safe delivery kits, conditional cash transfers to increase the number of institutional deliveries, efforts to track pregnancies, and free transportation for antenatal mothers—have not been as successful as they could have been because of the inadequate monitoring system used to document the time and cause of death of unborn infants. A major reason that stillbirth has gone unnoticed as a public health issue in India is its lack of recognition at a policy or community level.2 The difficulty in differentiating stillbirth and neonatal death and the societal lack of acceptance and possible stigma towards miscarriage can prevent parents from mourning the end of an unsuccessful pregnancy. As a result, many pregnancies and stillbirths are not tracked or recorded, making the numbers seem lower than they should be. To end the mystery of missing stillbirths in the community, media needs to be used to encourage the population and health workers to report such events and to destigmatise the topic. www.thelancet.com Vol 387 May 14, 2016
The India Newborn Action Plan, launched in 2014, contains six interventions that aim to reduce the number of stillbirths by a third by 2025, and also help to decrease maternal and neonatal deaths. The plan emphasises the tracking of stillbirths and aims to strengthen the tracking mechanisim by 2018–19. With its ambitious vision to overcome the suboptimum antenatal care that is prevalent in India, the plan is expected to succeed in its goal to reduce the preventable stillbirth rate within the stipulated time period. Studies in India have already identified specific pregnancy-related disorders as risk factors for stillbirth. 3 However, knowledge about distal factors would also enhance understanding about stillbirth. Although clinical studies tend to overlook factors such as poverty and inequity, the triad of low socioeconomic status, illiteracy, and inadequate antenatal care is what contributes most to the likelihood of stillbirth. 1,3,4 As shown for high-income countries, adverse socioeconomic status could also increase risk for stillbirth, particularly in a nation with an uneven economic distribution like India. More than 40% of pregnant women in India are illiterate. Only 37% of pregnant Indian women have four or more antenatal visits. 5 Until India takes a holistic approach to addressing these issues, the country will have difficulty reducing mortality in isolation. I declare no competing interests.
Manas Pratim Roy [email protected] Department of Pediatrics, Safdarjung Hospital, New Delhi 110029, India 1
2
Blencowe H, Cousens S, Bianchi Jassir F, et al. National, regional, and worldwide estimates of stillbirth rates in 2015, with trends from 2000: a systematic analysis. Lancet Glob Health 2016; 4: e98–108. Lawn JE, Yakoob MY, Haws RA, Soomro T, Darmstadt GL, Bhutta ZA. 3·2 million stillbirths: epidemiology and overview of the evidence flow. BMC Pregnancy Childbirth 2009; 9: S2.
3
4
5
Korde-Nayak VN, Gaikwad PR. Causes of stillbirth. J Obstet Gynecol India 2008; 58: 314–18. Lawn JE, Blencowe H, Waiswa P, et al, for The Lancet Ending Preventable Stillbirths Series study group with The Lancet Stillbirth Epidemiology investigator group. Stillbirths: rates, risk factors, and acceleration towards 2030. Lancet 2016; 387: 587–603. IIPS and Macro International. National family health survey (NFHS-3), 2005–06. Mumbai, India: International Institute for Population Sciences, 2007.
Stillbirth in China The global stillbirth rate is estimated to be 18·4 per 1000 total births. A goal of reaching a rate of 12 per 1000 total births by 2030 has been proposed by Joy Lawn and colleagues1 in the Lancet Series Ending preventable stillbirths. The stillbirth rate in China has reduced by 4–6% in the past 15 years (2000–15). However, the number of stillbirths in China in 2015 remains high and ranked in the top fifth of the world.1,2 The mean stillbirth rate analysed from six tertiary hospitals in our network3 is even higher than the global rate and has increased from 3·11% in 2010 to 3·55% in 2015 (table). This increase is also much higher than the increase in preterm births we reported previously.4 Within these six hospitals, the mean maternal mortality rate has decreased from 17·53 per 100 000 people in 2010 to 9·95 per 100 000 people in 2015, and the mortality of children younger than 5 years has decreased from 10·51 per 1000 children in 2010 to 6·15 per 1000 children in 2015. Our analyses (unpublished) have determined the top ten risk factors causing stillbirth: fetal intrauterine malformation, pre-eclampsia, preterm premature rupture of membrane, placenta praevia, twin p r e g n a n c y, o l i g o h y d r a m n i o s , twin–twin transfusion syndrome, cervical incompetence, placental abruption, and complications of pregnancy. The opposite trends for stillbirth and mortality rates and the preventable
Abdelhak Senna/Staff
2
This online publication has been corrected. The corrected version first appeared at thelancet.com on May 23, 2015
1995