HIV and Pregnancy: Prevention of Mother-to-Child Transmission 4/19/2017 HIV and Pregnancy: Prevention of Mother-to-Child Transmission Advances in Maternal and Neonatal Health There are many issues that relate to HIV and pregnancy, but this talk will mainly focus on issues of preventing mother-to-child transmission, particularly the issue of breastfeeding.

4/19/2017 Session Objectives To discuss best practice for antenatal, intrapartum and postpartum care of the HIV-positive mother to reduce mother-to-child transmission To review the evidence supporting these practices HIV and Pregnancy

HIV-Related Counseling Issues During Pregnancy 4/19/2017 HIV-Related Counseling Issues During Pregnancy Educate/counsel regarding HIV and pregnancy before pregnancy: Impact of HIV on pregnancy and pregnancy on HIV Maternal health Long-term health of mother and care for children Perinatal transmission Use of antiretrovirals and other drugs in pregnancy Counseling before pregnancy is important. It should focus on the effects of HIV on pregnancy, health of the mother, long-term health of the mother and child, how perinatal transmission occurs and how to prevent it with medicines. HIV and Pregnancy

Pregnancy Effects on HIV 4/19/2017 Pregnancy Effects on HIV In all women, the absolute CD4 count decreases no matter whether HIV-positive or negative (pregnancy does not make HIV worse) In HIV-positive women, percentage of CD4 cells should not change and viral load should not change because of pregnancy Pregnancy does not the effects that HIV has on the body. HIV and Pregnancy

Adverse Pregnancy Outcomes and Relationship to HIV Infection 4/19/2017 Adverse Pregnancy Outcomes and Relationship to HIV Infection Pregnancy Outcome Relationship to HIV Infection Spontaneous abortion Limited data, but evidence of possible increased risk Stillbirth No association noted in developed countries; evidence of increased risk in developing countries Perinatal mortality No association noted in developed countries, but data limited; evidence of increased risk in developing countries Newborn mortality Limited data in developed countries; evidence of increased risk in developing countries Intra-uterine growth retardation Evidence of possible increased risk There may be association between HIV and: Spontaneous abortion Stillbirth Maternal mortality Newborn mortality Low birth weight Preterm delivery Amnionitis HIV and Pregnancy Anderson 2001.

Relationship to HIV Infection 4/19/2017 Adverse Pregnancy Outcomes and Relationship to HIV Infection (continued) Pregnancy Outcome Relationship to HIV Infection Low birth weight Evidence of possible increased risk Preterm delivery Evidence of possible increased risk, especially w/ more advanced disease Pre-eclampsia No data Gestational diabetes Amnionitis Limited data; more recent studies do not suggest an increased risk; some earlier studies found increased histologic placental inflammation, particularly in those with preterm deliveries Oligohydramnios Minimal data Fetal malformation No evidence of increased risk HIV and Pregnancy Anderson 2001.

Mother-to-Child Transmission 4/19/2017 Mother-to-Child Transmission 25–35% of HIV positive pregnant mothers will pass HIV to their newborns In the absence of breastfeeding: 30% of transmission in utero 70% of transmission during the delivery Meta-analysis showed 14% transmission with breastfeeding and 29% transmission with acute maternal HIV infection or recent seroconversion Most HIV transmission (70%) occurs at the time of delivery, but a substantial amount (30%) occurs antenatally. A significant contributor to transmission is breastfeeding. In 1998, 10% of all new HIV infections were in children, almost all mother-to-child transmissions (90%) were in Africa. These statistics are given to emphasize that this is a serious worldwide problem, and a particular problem in Africa. The percentages given are of all cases of HIV transmission, not of all pregnancies. It suggests to us that we should be focusing our efforts on interventions at the time of delivery and with breastfeeding. In sub-Saharan Africa mortality rates for children under age 5 are now 1/3-2/3 higher than they would be in the absence of AIDS, contributing to the progressive reduction in life expectancy. DeCock et al 2000; Dunn et al 1992; WHO/UNAIDS 1999. HIV and Pregnancy

Risk Factors for Mother-to-Child Transmission 4/19/2017 Risk Factors for Mother-to-Child Transmission Viral load (HIV-RNA level) Genital tract viral load CD4 cell count Clinical stage of HIV Unprotected sex with multiple partners Smoking cigarettes Substance abuse Vitamin A deficiency STDs and other coinfections Antiretroviral agents Preterm delivery Placental disruption Invasive fetal monitoring Duration of membrane rupture Vaginal delivery vs. cesarean section Breastfeeding HIV and Pregnancy Anderson 2001.

Interventions to Reduce Mother-to-Child Transmission 4/19/2017 Interventions to Reduce Mother-to-Child Transmission HIV testing in pregnancy Antenatal care Antiretroviral agents Obstetric interventions Avoid amniotomy Avoid procedures: Forceps/vacuum extractor, scalp electrode, scalp blood sampling Restrict episiotomy Elective cesarean section Remember infection prevention practices Newborn feeding: Breastmilk vs. formula There are many interventions that may help reduce mother-to-child transmission, including obstetric interventions and newborn feeding. Antenatal care and antiretroviral agents play a significant role in reducing transmission. HIV and Pregnancy

HIV Testing during Pregnancy 4/19/2017 HIV Testing during Pregnancy Advantages: Possible treatment of mother Reduce risk of mother-to-child transmission Future family planning issues Precautions against further spread If negative, advise about HIV prevention Counseling is important! Discuss the advantages and disadvantages of HIV testing during pregnancy. There are many disadvantages to consider. A woman who is HIV positive, may be abandoned by her husband and family. HIV and Pregnancy

Antenatal Care Most HIV-infected women will be asymptomatic 4/19/2017 Antenatal Care Most HIV-infected women will be asymptomatic Watch for signs/symptoms of AIDS and pregnancy-related complications Unless complication develops, no need to increase number of visits Treat STDs and other coinfections Counsel against unprotected intercourse Avoid invasive procedures and external cephalic version Give antiretroviral agents, if available Counsel about nutrition When providing antenatal care, there is no need to increase the number of visits unless symptoms or complications develop. If available, antiretroviral agents given during antenatal care can benefit both the mother and child. Good nutrition is important. Anemia is an independent predictor of progression and death in HIV-infected individuals. Vitamin A deficiency has also been associated with increased risk of mother-to-child transmission. HIV and Pregnancy

Antiretrovirals Zidovudine (ZDV): Long course Short course Nevirapine 4/19/2017 Antiretrovirals Zidovudine (ZDV): Long course Short course Nevirapine ZDV/lamivudine (ZDV/3TC) Several antiretroviral regimens exist that have been shown to reduce mother-to-child transmission in clinical trials. Short-course ZDV and nevirapine are most affordable and are associated with good patient compliance. Long course ZDV, given from 14 weeks of pregnancy orally, IV during labor and to the non-breastfed newborn for 6 weeks showed significant decrease in transmission (22.6% in placebo group vs. 7.6% in ZDV group). (Sperling RS et al. 1996. Maternal viral load, ZDV treatment, and the risk of transmission of HIV type 1 from mother to infant. N Engl J Med 335 (22): 1621-1629.) There were no ill effects on the fetus except for mild and temporary anemia. A short-course ZDV trial in Thailand compared placebo group with group given one tablet of ZDV 300 mg twice a day from 36 weeks gestation and every 3 hours from onset of labor until delivery. Newborns were not breastfed. This regimen reduced risk of transmission by 50% at a cost of $50 per patient. (Shaffer N et al. 1999. Short-course ZDV for perinatal HIV-1 transmission in Bangkok, Thailand: A randomized controlled trial. Lancet 353: 773-780.) Combination of ZDV and lamivudine given in mostly breastfeeding population given at 36 weeks and onset of labor and for 1 week postpartum to newborn and mother reduced transmission by about 50% compared to placebo. (Gray G. 2000. The PETRA study: Early and late efficacy of three short ZDV/3TC combinations regimens to prevent mother-to-child transmission of HIV-1. XIII International AIDS Conference, Durban, South Africa.) Nevirapine. A single 200 mg dose at the onset of labor and a single 2 mg/kg dose to the newborn at 48-72 hours resulted in a 47% decrease in transmission compared to ZDV during labor and for 1 week to newborn. The cost is approximately $4 to the patient. HIV and Pregnancy

ZDV Perinatal Transmission Prophylaxis Regimen: ACTG 076 Trial 4/19/2017 ZDV Perinatal Transmission Prophylaxis Regimen: ACTG 076 Trial Antepartum Initiation at 14–34 weeks gestation and continued throughout pregnancy PACTG 076 regimen: ZDV 5 times daily Acceptable alternative regimen: ZDV 2 or 3 times daily (depending on dose) Intrapartum During labor, ZDV IV over 1 hour, followed by a continuous infusion of IV until delivery Postpartum Oral administration of ZDV to newborn for first 6 weeks of life, beginning at 8–12 hours after birth HIV and Pregnancy Anderson 2000.

4/19/2017 Intrapartum vs. Postpartum Regimens for HIV-Infected Women in Labor with No Prior Antiretroviral Therapy Drug Regimen Maternal Intrapartum Newborn Postpartum Data on Transmission Nevirapine One oral dose at onset of labor One oral dose at age 48–72 hours (if mother received nevirapine < 1 hour before delivery, newborn given oral nevirapine as soon as possible after birth and at 48–72 hours) Transmission at 6 weeks 12% with nevirapine compared to 21% with ZDV, a 47% (95% CI, 20–64%) reduction Advantages of nevirapine include: Inexpensive Oral regimen Simple, easy to administer Can give directly observed treatment Disadvantages Unknown efficacy if mother has nevirapine-resistant virus HIV and Pregnancy Anderson 2001.

4/19/2017 Intrapartum vs. Postpartum Regimens for HIV-Infected Women in Labor with No Prior Antiretroviral Therapy (cont’d.) Drug Regimen Maternal Intrapartum Newborn Postpartum Data on Transmission ZDV/3TC ZDV orally at onset of labor followed by dose orally every 3 hours until delivery AND 3TC orally at onset of labor, followed by dose orally every 12 hours ZDV orally every 12 hours AND 3TC orally every 12 hours for 7 days Transmission at 6 weeks 10% with ZDV/3TC compared to 17% with placebo, a 38% reduction Advantages: Oral regimen Compliance easier than 6 weeks of ZDV alone as newborn regimen is only 1 week Disadvantages: Potential toxicity of multiple drug exposure HIV and Pregnancy Anderson 2001.

4/19/2017 Intrapartum vs. Postpartum Regimens for HIV-Infected Women in Labor with No Prior Antiretroviral Therapy (cont’d.) Drug Regimen Maternal Intrapartum Newborn Postpartum Data on Transmission ZDV IV bolus, followed by continuous infusion of every hour until delivery Orally every 6 hours for 6 weeks Transmission 10% with ZDV compared to 27% with no ZDV treatment, a 62% (95% CI, 19-82%) reduction Advantages: Has been standard recommendation based on clinical trial results Disadvantages: Requires IV administration, availability of ZDV IV formulation Compliance with 6 week newborn regimen Anderson 2001. HIV and Pregnancy

4/19/2017 Intrapartum vs. Postpartum Regimens for HIV-Infected Women in Labor with No Prior Antiretroviral Therapy (cont’d.) Drug Regimen Maternal Intrapartum Newborn Postpartum Data on Transmission ZDV and Nevirapine IV bolus, then continuous infusion until delivery AND Nevirapine single oral dose at onset of labor Orally every 6 hours for 6 weeks Nevirapine single oral dose at age 48–72 hours No data Advantages: Potential benefit if maternal virus is resistant to either nevirapine or ZDV Synergistic inhibition of HIV replication with combination in vitro Disadvantages: Requires IV administration, availability of ZDV intravenous formulation Compliance with 6 week newborn regimen Unknown efficacy and limited toxicity data HIV and Pregnancy Anderson 2001.

4/19/2017 Obstetric Procedures Because of increased fetal exposure to infected maternal blood and secretions, increased transmission may come from: Amniotomy Fetal scalp electrode/sampling Forceps/vacuum extractor Episiotomy Vaginal tears During delivery, any procedures that either increase the chance of the mother bleeding or may cause breaks in the skin of the fetus through which there may be direct contact with the mother’s blood or vaginal secretions will increase the risk of transmission of HIV from mother to child. Avoid amniotomy, fetal scalp electrode/sampling, operative vaginal delivery and episiotomy/vaginal trauma. These procedures can increase risk of transmission. HIV and Pregnancy

Delivery: Cesarean vs. Vaginal Birth 4/19/2017 Delivery: Cesarean vs. Vaginal Birth Risk of mother-to-child transmission increased 2% each hour after membranes have been ruptured Cesarean section before labor and/or rupture of membranes reduces risk of mother-to-child transmission by 50–80% compared with other modes of delivery in women on no antiretroviral therapy or on ZDV alone No evidence of benefit with cesarean section after onset of labor or membranes have been ruptured Cesarean section, however, increases morbidity and possible mortality to mother Give antibiotic prophylaxis for cesarean section in HIV-infected women Pregnancy may increase the risk of HIV shedding in maternal cervico-vaginal secretions. In a recent meta-analysis from 15 prospective studies, the risk of mother-to-child transmission increased 2% each hour after membranes have been ruptured. Cesarean section before the onset of labor or ruptured membranes can significantly reduce the risk of transmission from mother to child, especially if antiretroviral agents are not available. Cesarean sections however, have increased the risk of morbidity and possible mortality for the mother, particularly in low-resource settings because of anesthesia risks, blood loss, pain and increased recovery time. International Perinatal HIV Group 1999; Semprini 1995. HIV and Pregnancy

Recommended Infection Prevention Practices 4/19/2017 Recommended Infection Prevention Practices Needles: Take care! Minimal use Suturing: Use appropriate needle and holder Care with recapping and disposal Wear gloves, wash hands with soap immediately after contact with blood and body fluids Cover incisions with watertight dressings for first 24 hours Universal precautions to protect yourself are very important. HIV and Pregnancy

Recommended Infection Prevention Practices (continued) 4/19/2017 Recommended Infection Prevention Practices (continued) Use: Plastic aprons for delivery Goggles and gloves for delivery and surgery Long gloves for placenta removal Dispose of blood, placenta and waste safely PROTECT YOURSELF! HIV and Pregnancy

Newborn Wash newborn after birth, especially face Avoid hypothermia 4/19/2017 Newborn Wash newborn after birth, especially face Avoid hypothermia Give antiretroviral agents, if available Wash maternal blood and secretions off the newborn as soon as possible, particularly off the face. Beware of hypothermia! If available, give antiretroviral agents to the newborn to reduce the risk of HIV transmission. HIV and Pregnancy

Breasfeeding Issues Warmth for newborn Nutrition for newborn 4/19/2017 Breasfeeding Issues Warmth for newborn Nutrition for newborn Protection against other infections Safety – unclean water, diarrheal diseases Risk of HIV transmission Contraception for mother Cost Breastfeeding is associated with a 14% risk of HIV transmission to newborns, yet provides nutrition for the newborn and an inexpensive method of feeding and contraception. Formula feeding also poses risks to the newborn, such as diarrhea from contamination of formula with unclean water or malnutrition from formula being too dilute. Factors associated with breastfeeding and mother-to-child transmission: Cracked nipples/breast abscess or mastitis Newborn oral thrush Duration of breastfeeding Exclusively breastfeeding versus breastfeeding and formula feeding. HIV and Pregnancy

Breastfeeding Recommendations 4/19/2017 Breastfeeding Recommendations If the woman is: HIV-negative or does not know her HIV status, promote exclusive breastfeeding for 6 months HIV-positive and chooses to use replacements feedings, counsel on the safe and appropriate use of formula HIV-positive and chooses to breastfeed, promote exclusive breastfeeding for 6 months HIV and Pregnancy

South Africa Breastfeeding Trial: Objective and Design 4/19/2017 South Africa Breastfeeding Trial: Objective and Design Objective: To assess whether pattern of breastfeeding is a critical determinant of early mother-to-child transmission of HIV 549 HIV-infected women studied Compared newborns at 3 months that had been: Exclusively breastfed Breastfed and formula-fed Never breastfed Coutsoudis et al 1999. HIV and Pregnancy

South Africa Breastfeeding Trial: Results and Conclusion 4/19/2017 South Africa Breastfeeding Trial: Results and Conclusion Risk of transmission in: 156 newborns who were never breastfed: 18.8% (95% CI 12.6–24.9) 288 newborns who were breastfed and formula fed: 24.1% (95% CI 19.0–29.2) 103 newborns who were exclusively breastfed: 14.6 (95% CI 7.7–21.4) Conclusion: Newborns who were exclusively breastfed for at least 3 months did not have any excess risk of HIV infection compared to newborns who were not breastfed Coutsoudis et al 1999. HIV and Pregnancy

Conclusion Voluntary counseling and testing 4/19/2017 Conclusion Voluntary counseling and testing Antenatal, intrapartum and postpartum care to mother can decrease risk of mother-to-child transmission Antiretroviral therapy can also reduce risk of transmission Newborn care: Feeding HIV and Pregnancy

4/19/2017 References Anderson J (ed). 2001. A Guide to the Clinical Care of Women with HIV, 2nd ed. U.S. Department of Health and Human Services, Health Resources and Services Administration: Rockville, Maryland. Coutsoudis A et al. 1999. Influence of infant-feeding patterns on early mother-to-child transmission of HIV-1 in Durban, South Africa: A prospective cohort study. Lancet 354: 471–476. DeCock K et al. 2000. Prevention of mother-to-child transmission in resource-poor countries: Translating research into policy and practice. J Am Med Assoc 283(9): 1175–1182. Dunn D et al. 1992. Risk of HIV-1 transmission through breastfeeding. Lancet 340(8819): 585–588. Gray G. 2000. The PETRA study: Early and late efficacy of three short ZDV/3TC combinations regimens to prevent mother-to-child transmission of HIV-1. XIII International AIDS Conference, Durban, South Africa. HIV and Pregnancy

References (continued) 4/19/2017 References (continued) International Perinatal HIV Group. 1999. The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1. N Engl J Med 340(14): 977–987. Mandelbrot L et al. 1996. Obstetric factors and mother-to-child transmission of human immunodeficiency virus type 1: The French perinatal cohorts. Amer J Obstet Gynecol 175(3 pt 1): 661–667. Semprini AE et al. 1995. The incidence of complications after cesarean section in 156 women. AIDS 9:913–917. Shaffer N et al. 1999. Short-course ZDV for perinatal HIV-1 transmission in Bangkok, Thailand: A randomized controlled trial. Lancet 353: 773–780. Sperling RS et al. 1996. Maternal viral load, ZDV treatment, and the risk of transmission of HIV type 1 from mother to infant. N Engl J Med 335(22): 1621–1629. UNICEF/UNAIDS/WHO Technical Consultation on HIV and Infant Feeding. 1998. HIV and Infant Feeding: Implementation of Guidelines. WHO: Geneva. World Health Organization (WHO)/Joint United Nations Programme on HIV/AIDS (UNAIDS). 1999. HIV In Pregnancy: A Review. WHO/UNAIDS: Geneva. HIV and Pregnancy