- Email: [email protected]
HIV, hepatitis and pregnancy
OTHER PROBLEMS
HIV, hepatitis and pregnancy
Facts about HIV infection
Claire Thorne
• In January 2004, an estimated 38 million people were living with HIV/AIDS globally, including 17 million women.1 • During 2003, at least two million women became newly infected with HIV, mainly through heterosexual transmission, and 630,000 children acquired infection, mostly through mother-to-child transmission. • The estimated HIV seroprevalence in the UK antenatal population is 0.14% overall,2 but as high as 2% in women from subSaharan Africa living in London3 • There were an estimated 15,000 women with HIV infection living in the UK in 2002, around 4500 of whom were undiagnosed.4
Marie-Louise Newell
HIV HIV is an RNA virus, targeting the cell-associated immune system, particularly CD4+ cells. Once immunodeficiency is established, the risk of opportunistic infections and other serious clinical manifestations becomes great. AIDS is diagnosed according to specific clinical criteria.5 Without antiretroviral therapy, median time between primary infection and AIDS is about 10 years, and time from AIDS to death around 2 years. Use of highly active antiretroviral therapy (HAART) substantially delays disease progression and HIV infection has become a chronic infection in developed countries.6,7
for antiretroviral therapy in pregnant women in developed country settings (where HAART is the standard of care for adults requiring treatment) in addition to other management issues. An elective Caesarean section before labour and before membrane rupture substantially reduces mother-to-child transmission,18,19 even in settings where HAART is easily available. HIV-infected women are at increased risk of postpartum complications compared to uninfected women, especially those with severe immunosuppression, regardless of mode of delivery. However, such complications are predominantly minor and easily managed.20-22 In settings where formula-feeding is safe, affordable and feasible, HIV-infected women are advised to avoid breastfeeding. However, in many resource-poor settings, infants of HIV-infected mothers would be at a greater risk of illness and death if they were not breastfed.23 (If breastfeeding is chosen, it should be exclusive as bottle feeds increase the risk of gastroenteritis and penetration of the virus through the bowel wall.)
Mother-to-child transmission Mother-to-child transmission of HIV can occur: • during pregnancy • around delivery • through breastfeeding. Without specific interventions, the transmission rate ranges from 15 to 40% depending on the prevalence of risk factors, especially breastfeeding (Figure 1). However, with a combination of prophylactic measures, mother-to-child transmission rates of around 1–2% are achievable.10-13 Breastfeeding is associated with an approximate doubling of overall transmission risk (from about 16% without, to over 30% with breastfeeding for up to 24 months), with the risk remaining as long as breastfeeding continues.14–16
Antiretroviral safety Limited safety data are available on antenatal use of antiretroviral medication.
Prevention: identification of HIV-infected women before or during pregnancy is needed for optimum use of interventions to prevent transmission to the baby. In the UK, there has been Government advice to recommend antenatal HIV testing for all pregnant women since 1999. Clinical trials worldwide have shown that antiretroviral drugs, alone or in combinations, are effective in reducing motherto-child transmission.17 Figure 2 gives a summary of considerations
Factors associated with increased risk of mother-tochild transmission of HIV infection Virological/immunological • High maternal HIV RNA plasma viral load • Low maternal CD4+ count Obstetric • Vaginal delivery • Prolonged duration of rupture membrane • Invasive obstetric procedures
Claire Thorne is Lecturer at the Centre for Paediatric Epidemiology and Biostatistics in the Institute of Child Health, University College London. She is co-ordinator of the European Collaborative Study on HIV infected pregnant women and their children, a large cohort study including 4500 mother-child pairs from 10 European countries.
Infant • Prematurity/ low infant birthweight • Female gender • Breastfeeding
Marie-Louise Newell is Professor of Epidemiology at the Institute of Child Health, UCL, London. She has a special interest in issues related to mother-to-child transmission of infections, including HIV, HBV and HCV and leads a programme of research across Europe and in Africa.
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women with CD4+ cell counts >250/mm3, due to risk of serious rash or hepatotoxicity. Uninfected children previously exposed to antiretroviral drugs may have transient anaemia.24,33,34 Recently, a more prolonged effect on haematopoeisis has been suggested.35,36 Reports of mitochondrial dysfunction in a small number of uninfected children previously exposed to anti-retroviral drugs are concerning, and further research is needed.37,38
Management of HIV-infected women Monitoring of HIV disease • follow-up every 4 weeks, with more intensive monitoring if woman is severely immunosuppressed or has clinical disease • quantification of CD4+ cell count and plasma RNA viral load at least every trimester Antiretroviral therapy • all HIV-infected women should be offered antiretroviral therapy to prevent mother-to-child transmission and for their own disease progression if required on the basis of maternal clinical status, CD4+ cell count and plasma HIV RNA levels • when a woman becomes pregnant whilst taking antiretroviral drugs, it is generally recommended to continue with the same therapy • antiretroviral therapy should be continued as per normal regimen right up to the time of delivery Pregnancy management • multidisciplinary approach is best • avoid folate antagonists in first trimester if woman is on HAART • screening for genital infections and hepatitis C virus • non-invasive prenatal testing should be used if possible; avoidance of invasive obstetric procedures unless absolutely indicated • psychosocial support, including support with antiretroviral treatment adherence and avoidance of breastfeeding • clear information regarding follow-up and diagnosis of infant • contraception advice postpartum Delivery • elective Caesarean delivery should be offered, with risks and benefits fully explained so that the woman can make an informed decision • elective Caesarean delivery should be scheduled for 38 weeks Follow-up and diagnosis of HIV-exposed infants • HIV virological testing of peripheral blood lymphocytes at 1 day, 1 month and 3 months is effective in detecting nearly all infections • in infants with negative polymerase chain reaction tests, confirmation of loss of maternal antibodies should take place at 15–18 months of age
Hepatitis C virus Hepatitis C virus (HCV) prevalence among UK pregnant women is estimated to be below 1%. HCV infection is more common among HIV-infected than uninfected individuals. However, co-infection is rare in the UK because of the relatively low HIV prevalence among injecting drug users.4 HCV is a RNA virus, mainly transmitted through exposure to infected blood. Acute HCV infection is usually mild, but persists in most adults, leading to slowly progressive chronic disease with long-term sequelae (e.g. cirrhosis and hepatocellular carcinoma). There is no evidence that pregnancy induces exacerbation of liver disease in women with HCV. Mother-to-child transmission Risk of transmission to the baby is between 3 and 5%, but can reach 15% in HIV co-infected women.39-41 High maternal viral burden is the most important factor determining the risk of transmission, itself associated with HIV co-infection. Both ribavirin and interferon are contraindicated in pregnancy, so no therapeutic intervention for prevention of mother-to-child transmission is currently available. Figure 3 outlines approaches to the management of HCV-infected pregnant women. Based on current evidence, HCV-infected pregnant women without HIV co-infection should not be offered an elective Caesarean section on the basis of their HCV infection alone.41 Although a small risk cannot be excluded, there is little evidence for HCV transmission through breastfeeding, and HCV infected women are not usually advised to refrain from breastfeeding.41
Hepatitis B virus
Teratogenicity: although there appears to be no increased risk of congenital malformations associated with exposure to antiretroviral drugs during pregnancy,24 there have been reports of malformations in fetuses/infants of women receiving a combination of antiretroviral therapy and Pneuomocystis carinii pneumonia prophylaxis in the first trimester.25
Following primary infection with hepatitis B virus (HBV), a DNA virus, around 10% of adults become chronically infected, with detectable hepatitis B surface antigen (HBsAg). Of these, 15–30% may develop serious liver disease, including hepatitis or cirrhosis, with a smaller proportion developing hepatocellular carcinoma. Prevalence of HBV carriers varies substantially: in South-East Asia and Africa up to 20% of pregnant women are chronic carriers, compared to less than 1% in Northern Europe and North America. In the UK, an estimated 0.05–0.15% of pregnant women are HBsAg positive, with the highest prevalences in London.
Other problems: HAART in pregnancy, especially prolonged use, has been associated with an increased risk of premature birth and of other adverse pregnancy outcomes (e.g. gestational diabetes, pre-eclampsia).26-29 Case reports of lactic acidosis (some fatal) in pregnant women receiving HAART (including didanosine and stavudine) resulted in a clinical alert recommending avoidance of this combination in pregnancy.30-32 Nevirapine should be avoided in
Mother-to-child transmission The usual route of transmission to the baby is perinatal exposure to contaminated maternal secretions and blood. Without immunoprophylaxis, 10–20% of women seropositive for HBsAg and up to 90% of those with detectable HBsAg and HBeAg (which reflects presence in the blood of circulating HBV) will transmit infection. Infected infants are usually too immature to mount an adequate
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In the UK, routine screening of all pregnant women is currently recommended, and health authorities are responsible for ensuring complete vaccination coverage for all infants born to infected mothers.
Management of hepatitis C virus (HCV)-infected pregnant women and their infants41,42 Pregnancy • routine antenatal HCV screening cannot be recommended at present • HIV-infected women and those who are injecting drug users should be offered a HCV test in pregnancy • for women with HCV infection, monitoring of viral load during pregnancy is required and discussion of treatment options for after delivery Delivery • HCV-infected women: elective Caesarean not indicated • HCV/HIV-co-infected women: elective Caesarean should be recommended Post partum • HCV-infected women: breastfeeding not contraindicated • HCV/HIV-co-infected women: advised to formula-feed to prevent postnatal HIV transmission Follow-up of HCV-exposed infants • qualitative RNA polymerase chain reaction (PCR) tests every 3 months up to age 12 months • if >1 positive RNA PCR test result, antibody test at 18 months to confirm diagnosis • if negative PCR tests and antibody test positive at 18 months, test antibody again at 24 months to confirm absence of infection
REFERENCES 1 UNAIDS. Report on the global AIDS epidemic, 2004. Geneva: UNAIDS. 2 Unlinked Anonymous HIV Surveys Steering Group. Prevalence of HIV and hepatitis infections in the United Kingdom 2000. London: Department of Health, 2001. 3 Cortina-Borja M, Cliffe S, Tookey P et al. HIV prevalence in pregnant women in an ethnically diverse population in the UK: 1998–2002. AIDS 2004; 18: 535–40. 4 Health Protection Agency. Renewing the focus. HIV and other sexually transmitted infections in the United Kingdom in 2002. An update: November 2003. 5 Center for Disease Control. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morbidity and Mortality Weekly Report 1992; 41(No.RR-17). 6 Porter K, Babiker A, Bhaskaran K et al. Determinants of survival following HIV-1 seroconversion after the introduction of HAART. Lancet 2003; 362: 1267–74. 7 van Sighem A I, van de Wiel M A, Ghani A C et al. Mortality and progression to AIDS after starting highly active antiretroviral therapy. AIDS 2003; 17: 2227–36. 8 Shaffer N, Roongpisuthipong A, Siriwasin W et al. Maternal Viral Load and Perinatal Human Immunodeficiency Virus Type 1 Subytpe E Transmission, Thailand. J Infect Dis 1998; 179: 590–9. 9 European Collaborative Study. Maternal viral load and vertical transmission of HIV-1: an important factor but not the only one. AIDS 1999; 13: 1377–85. 10 European Collaborative Study. HIV-infected pregnant women and vertical transmission in Europe since 1986. AIDS 2001; 15: 761–70. 11 Dorenbaum A, Cunningham C K, Gelber R D et al. Two-dose intrapartum/newborn nevirapine and standard antiretroviral therapy to reduce perinatal HIV transmission. A randomised trial. JAMA 2002; 288: 189–98. 12 Cooper E R, Charurat M, Mofenson L M et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr 2002; 29: 484–94. 13 Ioannidis J P A, Abrams E J, Bulterys M et al. Perinatal Transission of Human Immunodeficiency Virus Type 1 by Pregnant Women with RNA Virus Loads <1000 Copies/mL. J Infect Dis 2001; 183: 539–45. 14 John-Stewart G C, Mbori-Ngacha D, Ekpini E R et al. Breast-feeding and transmission of HIV-1. J Acquir Immune Defic Syndr 2004; 35: 196–202. 15 Nduati R W, John G C, Ngacha D A et al. Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomised clinical trial. JAMA 2000; 283: 1167–74. 16 Coutsoudis A, Dabis F, Gawzi W et al. and the Breastfeeding and HIV International Transmission Study (BHITS). Late postnatal transmission of HIV-1 in breast-fed children: an individual patient data meta-analysis. J Infect Dis 2004; 189: 2154–66. 17 World Health Organization. Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. Guidelines for care,
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immune response, and up to 90% will become chronic carriers, of whom around half will develop chronic liver disease. However, administration of hepatitis B immunoglobulin (HBIG) immediately after birth (before antigenaemia has developed), in combination with a three-dose vaccination schedule starting at birth is highly effective, preventing up to 95% of carrier status. Figure 4 provides a summary of HBV management in pregnant women.
Hepatitis B virus (HBV) infection and pregnancy • Antenatal screening test for hepatits B surface antigen (HBsAg) offered to all women • Confirmatory testing required following a positive result • If positive: testing for HBeAg • HBV immunoprophylaxis for the infant: Mother HBsAg positive & HBeAg positive – HB vaccine and HBIG Mother HBsAg positive without e markers – HB vaccine and HBIG Mother HBsAg positive & anti-HBe positive – HB vaccine only • Vaccination schedule: birth, 1 month, 2 months and booster at 12 months • Written information for parents regarding vaccination schedule should be provided • Referral of mother to hepatologist 4
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Group 076 study. AIDS 1998; 12: 1805–13. 35 Le Chenadec J, Mayaux M J, Guihenneuc-Jouyaux C, Blanche S. Perinatal antiretroviral treatment and hematopoiesis in HIV uninfected infants. AIDS 2003; 17: 2053–61. 36 European Collaborative Study. Levels and patterns of neutrophil cell count over the first 8 years of life in children of HIV-infected mothers. AIDS 2004; 18: 2009–17. 37 Blanche S, Tardieu M, Rustin P et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 1999; 354: 1084–9. 38 Tardieu M, Rustin P, Lacroix C et al. Persistent mitochondrial dysfunction in HIV-1 exposed but uninfected infants: clinical screening in a large prospective cohort. AIDS 2003; 17: 1769–85. 39 Lallemant M, Jourdain G, Le Coeur S et al. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. New Eng J Med 2004; 351: 217–28. 40 Tovo P A, Palomba E, Ferraris G et al. Increased risk of maternal-infant hepatitis C virus transmission for women coinfected with human immunodeficiency virus type 1. Clin Infect Dis 1997; 25: 1121–4. 41 Pembrey L, Tovo P A, Newell M L. Effects of mode of delivery and infant feeding on the risk of mother-to-child transmission of hepatitis C virus. BJOG 2001; 108: 371–7. 42 Pembrey L, Newell M L, Peckham C S. Is there a case for hepatitis C infection screening in the antenatal period? J Med Screening 2003; 10: 161–8.
treatment and support for women living with HIV/AIDS and their children in resource-constrained settings. Geneva: World Health Organization, 2004 18 The International Perinatal HIV group. Mode of delivery and vertical transmission of HIV-1: a meta-analysis from fifteen prospective cohort studies. N Engl J Med 1999; 340: 977–87. 19 European Mode of Delivery Collaboration. Elective caesarean section versus vaginal delivery in preventing vertical HIV-1 transmission: a randomised clinical trial. Lancet 1999; 353: 1035–9. 20 European HIV in Obstetrics Group. Higher rates of post-partum complications in HIV infected than in uninfected women irrespective of mode of delivery. AIDS 2004; 18: 933–8. 21 Read J S, Tuomala R E, Kpamegan E et al. Mode of delivery and postpartum morbidity among HIV-infected women: the women and infants transmission study. J Acquir Immune Defic Syndr 2001; 26: 236–45. 22 Watts D H, Lambert J S, Stiehm E R et al. Complications according to mode of delivery among human immunodeficiency virus-infected women with CD4 lymphocyte counts of < or = 500/microL. Am J Obstet Gynecol 2000; 183: 100–07. 23 Fowler M G, Newell M L. Breast-feeding and HIV-1 transmission in resource-limited settings. AIDS 2002; 30: 230–39. 24 European Collaborative Study. Exposure to antiretroviral therapy in utero or early life: the health of uninfected children born to HIVinfected women. J Acquir Immune Defic Syndr 2003; 32: 380–7. 25 Jungmann E M, Mercey D, DeRuiter A et al. Is the first trimester exposure to the combination of antriretroviral therapy and folate antagonists a risk factor for congenital abnormalities? Sex Transm Inf 2001; 77: 441–3. 26 European Collaborative Study and the Swiss Mother + Child HIV Cohort Study. Combination antiretroviral therapy and duration of pregnancy. AIDS 2000; 14: 2913–20. 27 Lorenzi P, Spicher V M, Laubereau B, et al. Antiretroviral therapies in pregnancy: maternal, fetal and neonatal effects. AIDS 1998; 12: F241–7. 28 Watts D H, Balasubramanian R, Maupin R T et al. Maternal toxicity and pregnancy complications in HIV-infected women receiving antiretroviral therapy: an analysis of the PACTG 316 Study. Am J Obstet Gynecol 2004; 190: 506–16. 29 Coll O, Suy A, Martinez E et al. Increased risk of pre-eclampsia and fetal death in HIV-infected pregnant women receiving highly active anti-retrovial therapy. 11th Conference on Retroviruses and Opportunitistic Infections, San Francisco, 8th–11th February 2004. 30 Sarner L, Fakoya A. Acute onset lactic acidosis and pancreatitis in the third trimester of pregnancy in HIV-1 positive women taking antiretroviral medication. Sex Transm Inf 2002; 78: 58–9. 31 Mandelbrot L, Kermarrec N, Marcollet A, et al. Case report: nucleoside analogue-induced lactic acidosis in the third trimester of pregnancy. AIDS 2003; 17: 272–3. 32 Food and Drug Administration. Important drug warning – Zerit and Videx. www.fda.gov/medwatch/safety/2001/zerit&videx_letter.htm 7 February 2001. 33 Dabis F, Msellati P, Meda N et al. 6-month efficacy, tolerance, and acceptability of a short regimen of oral zidovudine to reduce vertical transmission of HIV in breastfed children in Cote d’Ivoire and Burkina Faso: a double-blind placebo controlled multicentre trial. Lancet 1999; 353: 786–92. 34 Sperling R S, Shapiro D E, McSherry G D et al. Safety of the maternalinfant zidovudine regimen utilized in the Pediatric AIDS Clinical Trial
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FURTHER READING de Swiet M, ed. Medical disorders in obstetric practice. Oxford: Blackwell Science, 2002. McIntyre J. Chapter 22. HIV and pregnancy. In: MacLean A, Regan L, Carrington D, eds. Infection and pregnancy. London: RCOG Press, 2001. Newell, M, McIntyre J, eds. Congenital and perinatal infections. Prevention, diagnosis and treatment. Cambridge: Cambridge University Press, 2000. (These books have chapters which present a useful summary of the diagnosis, epidemiology and clinical management of HIV, HCV and HBV in pregnancy.) Pickering LK, ed. Red Book: 2003 Report of the Committee on Infectious Diseases. 26th edition. Elk Grove Village, IL: American Academy of Pediatrics, 2003.
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HIV, hepatitis and pregnancy
Facts about HIV infection
Claire Thorne
• In January 2004, an estimated 38 million people were living with HIV/AIDS globally, including 17 million women.1 • During 2003, at least two million women became newly infected with HIV, mainly through heterosexual transmission, and 630,000 children acquired infection, mostly through mother-to-child transmission. • The estimated HIV seroprevalence in the UK antenatal population is 0.14% overall,2 but as high as 2% in women from subSaharan Africa living in London3 • There were an estimated 15,000 women with HIV infection living in the UK in 2002, around 4500 of whom were undiagnosed.4
Marie-Louise Newell
HIV HIV is an RNA virus, targeting the cell-associated immune system, particularly CD4+ cells. Once immunodeficiency is established, the risk of opportunistic infections and other serious clinical manifestations becomes great. AIDS is diagnosed according to specific clinical criteria.5 Without antiretroviral therapy, median time between primary infection and AIDS is about 10 years, and time from AIDS to death around 2 years. Use of highly active antiretroviral therapy (HAART) substantially delays disease progression and HIV infection has become a chronic infection in developed countries.6,7
for antiretroviral therapy in pregnant women in developed country settings (where HAART is the standard of care for adults requiring treatment) in addition to other management issues. An elective Caesarean section before labour and before membrane rupture substantially reduces mother-to-child transmission,18,19 even in settings where HAART is easily available. HIV-infected women are at increased risk of postpartum complications compared to uninfected women, especially those with severe immunosuppression, regardless of mode of delivery. However, such complications are predominantly minor and easily managed.20-22 In settings where formula-feeding is safe, affordable and feasible, HIV-infected women are advised to avoid breastfeeding. However, in many resource-poor settings, infants of HIV-infected mothers would be at a greater risk of illness and death if they were not breastfed.23 (If breastfeeding is chosen, it should be exclusive as bottle feeds increase the risk of gastroenteritis and penetration of the virus through the bowel wall.)
Mother-to-child transmission Mother-to-child transmission of HIV can occur: • during pregnancy • around delivery • through breastfeeding. Without specific interventions, the transmission rate ranges from 15 to 40% depending on the prevalence of risk factors, especially breastfeeding (Figure 1). However, with a combination of prophylactic measures, mother-to-child transmission rates of around 1–2% are achievable.10-13 Breastfeeding is associated with an approximate doubling of overall transmission risk (from about 16% without, to over 30% with breastfeeding for up to 24 months), with the risk remaining as long as breastfeeding continues.14–16
Antiretroviral safety Limited safety data are available on antenatal use of antiretroviral medication.
Prevention: identification of HIV-infected women before or during pregnancy is needed for optimum use of interventions to prevent transmission to the baby. In the UK, there has been Government advice to recommend antenatal HIV testing for all pregnant women since 1999. Clinical trials worldwide have shown that antiretroviral drugs, alone or in combinations, are effective in reducing motherto-child transmission.17 Figure 2 gives a summary of considerations
Factors associated with increased risk of mother-tochild transmission of HIV infection Virological/immunological • High maternal HIV RNA plasma viral load • Low maternal CD4+ count Obstetric • Vaginal delivery • Prolonged duration of rupture membrane • Invasive obstetric procedures
Claire Thorne is Lecturer at the Centre for Paediatric Epidemiology and Biostatistics in the Institute of Child Health, University College London. She is co-ordinator of the European Collaborative Study on HIV infected pregnant women and their children, a large cohort study including 4500 mother-child pairs from 10 European countries.
Infant • Prematurity/ low infant birthweight • Female gender • Breastfeeding
Marie-Louise Newell is Professor of Epidemiology at the Institute of Child Health, UCL, London. She has a special interest in issues related to mother-to-child transmission of infections, including HIV, HBV and HCV and leads a programme of research across Europe and in Africa.
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women with CD4+ cell counts >250/mm3, due to risk of serious rash or hepatotoxicity. Uninfected children previously exposed to antiretroviral drugs may have transient anaemia.24,33,34 Recently, a more prolonged effect on haematopoeisis has been suggested.35,36 Reports of mitochondrial dysfunction in a small number of uninfected children previously exposed to anti-retroviral drugs are concerning, and further research is needed.37,38
Management of HIV-infected women Monitoring of HIV disease • follow-up every 4 weeks, with more intensive monitoring if woman is severely immunosuppressed or has clinical disease • quantification of CD4+ cell count and plasma RNA viral load at least every trimester Antiretroviral therapy • all HIV-infected women should be offered antiretroviral therapy to prevent mother-to-child transmission and for their own disease progression if required on the basis of maternal clinical status, CD4+ cell count and plasma HIV RNA levels • when a woman becomes pregnant whilst taking antiretroviral drugs, it is generally recommended to continue with the same therapy • antiretroviral therapy should be continued as per normal regimen right up to the time of delivery Pregnancy management • multidisciplinary approach is best • avoid folate antagonists in first trimester if woman is on HAART • screening for genital infections and hepatitis C virus • non-invasive prenatal testing should be used if possible; avoidance of invasive obstetric procedures unless absolutely indicated • psychosocial support, including support with antiretroviral treatment adherence and avoidance of breastfeeding • clear information regarding follow-up and diagnosis of infant • contraception advice postpartum Delivery • elective Caesarean delivery should be offered, with risks and benefits fully explained so that the woman can make an informed decision • elective Caesarean delivery should be scheduled for 38 weeks Follow-up and diagnosis of HIV-exposed infants • HIV virological testing of peripheral blood lymphocytes at 1 day, 1 month and 3 months is effective in detecting nearly all infections • in infants with negative polymerase chain reaction tests, confirmation of loss of maternal antibodies should take place at 15–18 months of age
Hepatitis C virus Hepatitis C virus (HCV) prevalence among UK pregnant women is estimated to be below 1%. HCV infection is more common among HIV-infected than uninfected individuals. However, co-infection is rare in the UK because of the relatively low HIV prevalence among injecting drug users.4 HCV is a RNA virus, mainly transmitted through exposure to infected blood. Acute HCV infection is usually mild, but persists in most adults, leading to slowly progressive chronic disease with long-term sequelae (e.g. cirrhosis and hepatocellular carcinoma). There is no evidence that pregnancy induces exacerbation of liver disease in women with HCV. Mother-to-child transmission Risk of transmission to the baby is between 3 and 5%, but can reach 15% in HIV co-infected women.39-41 High maternal viral burden is the most important factor determining the risk of transmission, itself associated with HIV co-infection. Both ribavirin and interferon are contraindicated in pregnancy, so no therapeutic intervention for prevention of mother-to-child transmission is currently available. Figure 3 outlines approaches to the management of HCV-infected pregnant women. Based on current evidence, HCV-infected pregnant women without HIV co-infection should not be offered an elective Caesarean section on the basis of their HCV infection alone.41 Although a small risk cannot be excluded, there is little evidence for HCV transmission through breastfeeding, and HCV infected women are not usually advised to refrain from breastfeeding.41
Hepatitis B virus
Teratogenicity: although there appears to be no increased risk of congenital malformations associated with exposure to antiretroviral drugs during pregnancy,24 there have been reports of malformations in fetuses/infants of women receiving a combination of antiretroviral therapy and Pneuomocystis carinii pneumonia prophylaxis in the first trimester.25
Following primary infection with hepatitis B virus (HBV), a DNA virus, around 10% of adults become chronically infected, with detectable hepatitis B surface antigen (HBsAg). Of these, 15–30% may develop serious liver disease, including hepatitis or cirrhosis, with a smaller proportion developing hepatocellular carcinoma. Prevalence of HBV carriers varies substantially: in South-East Asia and Africa up to 20% of pregnant women are chronic carriers, compared to less than 1% in Northern Europe and North America. In the UK, an estimated 0.05–0.15% of pregnant women are HBsAg positive, with the highest prevalences in London.
Other problems: HAART in pregnancy, especially prolonged use, has been associated with an increased risk of premature birth and of other adverse pregnancy outcomes (e.g. gestational diabetes, pre-eclampsia).26-29 Case reports of lactic acidosis (some fatal) in pregnant women receiving HAART (including didanosine and stavudine) resulted in a clinical alert recommending avoidance of this combination in pregnancy.30-32 Nevirapine should be avoided in
Mother-to-child transmission The usual route of transmission to the baby is perinatal exposure to contaminated maternal secretions and blood. Without immunoprophylaxis, 10–20% of women seropositive for HBsAg and up to 90% of those with detectable HBsAg and HBeAg (which reflects presence in the blood of circulating HBV) will transmit infection. Infected infants are usually too immature to mount an adequate
2
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In the UK, routine screening of all pregnant women is currently recommended, and health authorities are responsible for ensuring complete vaccination coverage for all infants born to infected mothers.
Management of hepatitis C virus (HCV)-infected pregnant women and their infants41,42 Pregnancy • routine antenatal HCV screening cannot be recommended at present • HIV-infected women and those who are injecting drug users should be offered a HCV test in pregnancy • for women with HCV infection, monitoring of viral load during pregnancy is required and discussion of treatment options for after delivery Delivery • HCV-infected women: elective Caesarean not indicated • HCV/HIV-co-infected women: elective Caesarean should be recommended Post partum • HCV-infected women: breastfeeding not contraindicated • HCV/HIV-co-infected women: advised to formula-feed to prevent postnatal HIV transmission Follow-up of HCV-exposed infants • qualitative RNA polymerase chain reaction (PCR) tests every 3 months up to age 12 months • if >1 positive RNA PCR test result, antibody test at 18 months to confirm diagnosis • if negative PCR tests and antibody test positive at 18 months, test antibody again at 24 months to confirm absence of infection
REFERENCES 1 UNAIDS. Report on the global AIDS epidemic, 2004. Geneva: UNAIDS. 2 Unlinked Anonymous HIV Surveys Steering Group. Prevalence of HIV and hepatitis infections in the United Kingdom 2000. London: Department of Health, 2001. 3 Cortina-Borja M, Cliffe S, Tookey P et al. HIV prevalence in pregnant women in an ethnically diverse population in the UK: 1998–2002. AIDS 2004; 18: 535–40. 4 Health Protection Agency. Renewing the focus. HIV and other sexually transmitted infections in the United Kingdom in 2002. An update: November 2003. 5 Center for Disease Control. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morbidity and Mortality Weekly Report 1992; 41(No.RR-17). 6 Porter K, Babiker A, Bhaskaran K et al. Determinants of survival following HIV-1 seroconversion after the introduction of HAART. Lancet 2003; 362: 1267–74. 7 van Sighem A I, van de Wiel M A, Ghani A C et al. Mortality and progression to AIDS after starting highly active antiretroviral therapy. AIDS 2003; 17: 2227–36. 8 Shaffer N, Roongpisuthipong A, Siriwasin W et al. Maternal Viral Load and Perinatal Human Immunodeficiency Virus Type 1 Subytpe E Transmission, Thailand. J Infect Dis 1998; 179: 590–9. 9 European Collaborative Study. Maternal viral load and vertical transmission of HIV-1: an important factor but not the only one. AIDS 1999; 13: 1377–85. 10 European Collaborative Study. HIV-infected pregnant women and vertical transmission in Europe since 1986. AIDS 2001; 15: 761–70. 11 Dorenbaum A, Cunningham C K, Gelber R D et al. Two-dose intrapartum/newborn nevirapine and standard antiretroviral therapy to reduce perinatal HIV transmission. A randomised trial. JAMA 2002; 288: 189–98. 12 Cooper E R, Charurat M, Mofenson L M et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr 2002; 29: 484–94. 13 Ioannidis J P A, Abrams E J, Bulterys M et al. Perinatal Transission of Human Immunodeficiency Virus Type 1 by Pregnant Women with RNA Virus Loads <1000 Copies/mL. J Infect Dis 2001; 183: 539–45. 14 John-Stewart G C, Mbori-Ngacha D, Ekpini E R et al. Breast-feeding and transmission of HIV-1. J Acquir Immune Defic Syndr 2004; 35: 196–202. 15 Nduati R W, John G C, Ngacha D A et al. Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomised clinical trial. JAMA 2000; 283: 1167–74. 16 Coutsoudis A, Dabis F, Gawzi W et al. and the Breastfeeding and HIV International Transmission Study (BHITS). Late postnatal transmission of HIV-1 in breast-fed children: an individual patient data meta-analysis. J Infect Dis 2004; 189: 2154–66. 17 World Health Organization. Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. Guidelines for care,
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immune response, and up to 90% will become chronic carriers, of whom around half will develop chronic liver disease. However, administration of hepatitis B immunoglobulin (HBIG) immediately after birth (before antigenaemia has developed), in combination with a three-dose vaccination schedule starting at birth is highly effective, preventing up to 95% of carrier status. Figure 4 provides a summary of HBV management in pregnant women.
Hepatitis B virus (HBV) infection and pregnancy • Antenatal screening test for hepatits B surface antigen (HBsAg) offered to all women • Confirmatory testing required following a positive result • If positive: testing for HBeAg • HBV immunoprophylaxis for the infant: Mother HBsAg positive & HBeAg positive – HB vaccine and HBIG Mother HBsAg positive without e markers – HB vaccine and HBIG Mother HBsAg positive & anti-HBe positive – HB vaccine only • Vaccination schedule: birth, 1 month, 2 months and booster at 12 months • Written information for parents regarding vaccination schedule should be provided • Referral of mother to hepatologist 4
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OTHER PROBLEMS
Group 076 study. AIDS 1998; 12: 1805–13. 35 Le Chenadec J, Mayaux M J, Guihenneuc-Jouyaux C, Blanche S. Perinatal antiretroviral treatment and hematopoiesis in HIV uninfected infants. AIDS 2003; 17: 2053–61. 36 European Collaborative Study. Levels and patterns of neutrophil cell count over the first 8 years of life in children of HIV-infected mothers. AIDS 2004; 18: 2009–17. 37 Blanche S, Tardieu M, Rustin P et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 1999; 354: 1084–9. 38 Tardieu M, Rustin P, Lacroix C et al. Persistent mitochondrial dysfunction in HIV-1 exposed but uninfected infants: clinical screening in a large prospective cohort. AIDS 2003; 17: 1769–85. 39 Lallemant M, Jourdain G, Le Coeur S et al. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. New Eng J Med 2004; 351: 217–28. 40 Tovo P A, Palomba E, Ferraris G et al. Increased risk of maternal-infant hepatitis C virus transmission for women coinfected with human immunodeficiency virus type 1. Clin Infect Dis 1997; 25: 1121–4. 41 Pembrey L, Tovo P A, Newell M L. Effects of mode of delivery and infant feeding on the risk of mother-to-child transmission of hepatitis C virus. BJOG 2001; 108: 371–7. 42 Pembrey L, Newell M L, Peckham C S. Is there a case for hepatitis C infection screening in the antenatal period? J Med Screening 2003; 10: 161–8.
treatment and support for women living with HIV/AIDS and their children in resource-constrained settings. Geneva: World Health Organization, 2004 18 The International Perinatal HIV group. Mode of delivery and vertical transmission of HIV-1: a meta-analysis from fifteen prospective cohort studies. N Engl J Med 1999; 340: 977–87. 19 European Mode of Delivery Collaboration. Elective caesarean section versus vaginal delivery in preventing vertical HIV-1 transmission: a randomised clinical trial. Lancet 1999; 353: 1035–9. 20 European HIV in Obstetrics Group. Higher rates of post-partum complications in HIV infected than in uninfected women irrespective of mode of delivery. AIDS 2004; 18: 933–8. 21 Read J S, Tuomala R E, Kpamegan E et al. Mode of delivery and postpartum morbidity among HIV-infected women: the women and infants transmission study. J Acquir Immune Defic Syndr 2001; 26: 236–45. 22 Watts D H, Lambert J S, Stiehm E R et al. Complications according to mode of delivery among human immunodeficiency virus-infected women with CD4 lymphocyte counts of < or = 500/microL. Am J Obstet Gynecol 2000; 183: 100–07. 23 Fowler M G, Newell M L. Breast-feeding and HIV-1 transmission in resource-limited settings. AIDS 2002; 30: 230–39. 24 European Collaborative Study. Exposure to antiretroviral therapy in utero or early life: the health of uninfected children born to HIVinfected women. J Acquir Immune Defic Syndr 2003; 32: 380–7. 25 Jungmann E M, Mercey D, DeRuiter A et al. Is the first trimester exposure to the combination of antriretroviral therapy and folate antagonists a risk factor for congenital abnormalities? Sex Transm Inf 2001; 77: 441–3. 26 European Collaborative Study and the Swiss Mother + Child HIV Cohort Study. Combination antiretroviral therapy and duration of pregnancy. AIDS 2000; 14: 2913–20. 27 Lorenzi P, Spicher V M, Laubereau B, et al. Antiretroviral therapies in pregnancy: maternal, fetal and neonatal effects. AIDS 1998; 12: F241–7. 28 Watts D H, Balasubramanian R, Maupin R T et al. Maternal toxicity and pregnancy complications in HIV-infected women receiving antiretroviral therapy: an analysis of the PACTG 316 Study. Am J Obstet Gynecol 2004; 190: 506–16. 29 Coll O, Suy A, Martinez E et al. Increased risk of pre-eclampsia and fetal death in HIV-infected pregnant women receiving highly active anti-retrovial therapy. 11th Conference on Retroviruses and Opportunitistic Infections, San Francisco, 8th–11th February 2004. 30 Sarner L, Fakoya A. Acute onset lactic acidosis and pancreatitis in the third trimester of pregnancy in HIV-1 positive women taking antiretroviral medication. Sex Transm Inf 2002; 78: 58–9. 31 Mandelbrot L, Kermarrec N, Marcollet A, et al. Case report: nucleoside analogue-induced lactic acidosis in the third trimester of pregnancy. AIDS 2003; 17: 272–3. 32 Food and Drug Administration. Important drug warning – Zerit and Videx. www.fda.gov/medwatch/safety/2001/zerit&videx_letter.htm 7 February 2001. 33 Dabis F, Msellati P, Meda N et al. 6-month efficacy, tolerance, and acceptability of a short regimen of oral zidovudine to reduce vertical transmission of HIV in breastfed children in Cote d’Ivoire and Burkina Faso: a double-blind placebo controlled multicentre trial. Lancet 1999; 353: 786–92. 34 Sperling R S, Shapiro D E, McSherry G D et al. Safety of the maternalinfant zidovudine regimen utilized in the Pediatric AIDS Clinical Trial
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FURTHER READING de Swiet M, ed. Medical disorders in obstetric practice. Oxford: Blackwell Science, 2002. McIntyre J. Chapter 22. HIV and pregnancy. In: MacLean A, Regan L, Carrington D, eds. Infection and pregnancy. London: RCOG Press, 2001. Newell, M, McIntyre J, eds. Congenital and perinatal infections. Prevention, diagnosis and treatment. Cambridge: Cambridge University Press, 2000. (These books have chapters which present a useful summary of the diagnosis, epidemiology and clinical management of HIV, HCV and HBV in pregnancy.) Pickering LK, ed. Red Book: 2003 Report of the Committee on Infectious Diseases. 26th edition. Elk Grove Village, IL: American Academy of Pediatrics, 2003.
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