The provision of comprehensive women’s health services constitutes the third pillar of PIH’s approach to integrated programming. By the end of 2004, women of childbearing age represented nearly half of the 39.4 million adults living with HIV/AIDS worldwide.72 In regions where ART prophylaxis is not readily available, rates of MTCT of HIV range from 25 to 40 percent.73 Programs to prevent MTCT will have the greatest impact if the vulnerability of the whole family is taken into account. Ideally, HIV prevention and care, including pMTCT, should be integrated with primary health care and women’s health services.
Family planning and pMTCT go hand-in-hand: clinical visits for one are an ideal time to address the other. If a female patient is found to be HIV-positive, the patient (ideally, the couple) should be counseled about birth spacing and contraception. Both barrier and hormonal methods should be discussed.
At the ZL clinics in Haiti, all presenting women of childbearing age receive family planning counseling. Methods of contraception available to these patients include oral contraceptives, medroxyprogesterone acetate (Depo-Provera®), levonorgestrel (Norplant®), and male and female condoms. All women desiring to use oral contraceptives should also be given and counseled to use condoms, especially since PIs, rifamycins, and NNRTIs may decrease the effectiveness of oral contraceptives. 74–76 During the initial and subsequent clinic visits, all women are counseled regarding proper usage and possible side effects of their chosen method(s) of contraception. For those receiving medroxyprogesterone acetate, subsequent clinic visits should be scheduled immediately to avoid interruption of the medication.
If a pregnant woman is found to be HIV-positive, it is critical to preserve and improve the mother’s health as well as to decrease the risk of transmission of the virus to the infant. HIV-positive pregnant women should receive medical care and extended social support, including an assessment of the family’s living situation, nutritional assistance, and testing of any children and sexual partner(s). If the mother’s immunologic state is deemed poor based on CD4 monitoring or clinical status, three antiretroviral medications should be started as soon as possible per Protocol 2.3. Alternatively, if the mother is not ill, ART can be deferred until the 28th week of gestation, then administered to prevent MTCT of HIV.
Nutritional supplementation should be provided to pregnant women beginning at the 12th week of gestation and continued through the pregnancy. This supplementation should be in the form of a daily multivitamin containing B1 (20 mg), B2 (20 mg), B6 (25 mg), niacin (100 mg), B12 (50 mcg), C (500 mg), E (30 mg), and folic acid (0.8 mg). This regimen has been found to reduce the risk of fetal death, severe preterm birth, small size for gestational age, and low birth weight among children of HIV-positive women.77 Because vitamin A has been shown to increase the risk of MTCT of HIV, particularly in women who take it during breastfeeding,78 nutritional supplements that include vitamin A should not be given.
The presence of STIs, anemia, increased viral load, and low CD4 count have all been associated with increased rates of HIV transmission from mother to child and should be addressed accordingly.79–82 Obstetric risk factors for transmission include prolonged rupture of amniotic membranes, vaginal rather than elective cesarean delivery (in particular, among women not receiving ART), chorioamnionitis, and obstetric complications.83–85 Thus, the provision of obstetrical services should be improved concurrently with the scale-up of ART if maternal mortality and vertical transmission of HIV are to be decreased.
Prenatal testing, prenatal care, and appropriate screening and treatment for STIs are clearly linked to better outcomes. However, of all known factors, high maternal viral load is the strongest predictor of vertical HIV transmission. Specifically, the risk of MTCT is increased 2.4-fold for every log increase in viral load at the time of delivery.86 Antiretroviral therapy is thus the most important intervention for pMTCT.
The use of maternal ART has led to perinatal transmission rates of less than 2 percent, compared to rates as high as 36 percent in the absence of ART.87,88 The literature regarding choice of ART during pregnancy, labor, and delivery continues to evolve rapidly. The landmark ACTG 076 study used a three-part AZT monotherapy regimen—antepartum and intrapartum for the mother, postpartum for the newborn—and reduced MTCT rates from 26 percent to 8 percent. 89 Since that trial, a number of other studies have attempted to determine whether shorter courses of monotherapy for the mother and/or infant, or combinations of ART, have equal or greater efficacy.90 Efficacy has been shown for regimens involving AZT alone, AZT and lamivudine (3TC), NVP alone (single-dose to mother and infant), AZT with single-dose NVP, and AZT and 3TC with single-dose NVP.91–101 In wealthy countries, the current standard of care for pMTCT is triple-drug maternal ART.102 In a multivariate analysis, adjusting for maternal viral load and duration of therapy, the odds-ratio of MTCT for women receiving potent triple therapy compared with AZT mono-therapy was 0.27, supporting the benefit of using three drugs. 103 Furthermore, data from PACTG 367 demonstrated that the use of two or more drugs is superior to monotherapy.104
In addition to lowering the risk of MTCT, combination therapy also diminishes the risk of developed drug resistance in the mother. After the use of single-dose NVP for pMTCT, strains of HIV resistant to NNRTIs have been found (at least temporarily) in just under 50 percent of babies and a little more than 50 percent of women.105–107 The clinical significance of this finding with regards to future pregnancies and future management of maternal and pediatric disease is currently unknown.
Decisions regarding maternal ART should made based upon the timing of presentation for care and maternal indications for therapy. Women who are already receiving ART at the time of conception should continue on the same regimen, unless it includes EFV, in which case NVP or a PI should be substituted. Section 2.5.5 presents additional information about ART toxicity during pregnancy.
Per Protocol 2.3, newly identified HIV-positive pregnant women with maternal indications for ART (that is, either clinical symptoms or CD4 below 350 cells/mm3) should immediately start combination therapy with three antiretroviral drugs. The preferred—and most widely available—regimen is AZT, 3TC, and NVP. AZT has the longest track record for use by pregnant women and is a preferred component for all regimens.
Women presenting in pregnancy who are not already receiving ART and who do not have maternal indications for therapy (i.e., CD4 above 350 cells/mm3) may be started on therapy at the 28th week of gestation for pMTCT. Triple therapy with AZT, 3TC, and a PI is preferred.
HIV-positive women who present after the 28th week of gestation should be started on treatment as soon as possible, even before the results of CD4 testing are available; liver function tests (LFTs) should be closely monitored. Women who present in labor and have not yet received ART should receive single-dose NVP.108,109 In addition, based on reports of developed NVP resistance, any woman who received any NVP for pMTCT is now also given one week of AZT and 3TC.110 The ZL protocol recommends the continuation of AZT and 3TC for two weeks after the postpartum cessation of NVP.
The management of HIV-exposed infants is presented in Protocol 2.4. All HIV-exposed infants are given AZT syrup for one week. If the mother did not receive ART prior to the 34th week of gestation, the infant should also receive single-dose NVP; AZT should be continued for a total of six weeks of therapy. If the mother is suspected of having resistant virus, alternative drug combinations may be considered for the infant. Infant protocol is determined by the available information about the mother’s prior exposure to antiretrovirals, viral load, and presence or absence of resistance mutations.
Cohorts of HIV-positive pregnant women given ART (specifically, AZT and 3TC) have demonstrated little in the way of maternal or fetal toxicity. However, several antiretroviral agents and combinations should be avoided or used with caution during pregnancy. The use of EFV in pregnant monkeys has been associated with abnormalities in their offspring;111 a single case of myelomeningocele has also been reported in a human infant exposed to EFV in utero.112,113 Generally, pregnant women and women of childbearing age who are not using contraception should not be given EFV. If a woman becomes pregnant while receiving an EFV-containing regimen, NVP or a PI should be substituted. While this particular use has not been studied, efavirenz may possibly be given in the third trimester, as the development of the infant’s neural tube occurs during the first trimester.
NVP has been associated with an increased risk of hepatotoxicity in women with a CD4 count above 250 cells/mm3; thus, a regimen containing AZT, 3TC, and NVP may not always be recommended for pMTCT in women with high CD4 counts.114–117 However, NVP is the most widely available nonteratogenic third agent in resource-poor settings and in ZL clinics is used in the first-line regimen for ART and pMTCT regardless of maternal CD4. A recent study from Brazil demonstrated minimal toxicity from this approach.118 When NVP-based triple therapy is given to women with a CD4 count above 250 cells/mm3, close monitoring of liver function tests—one week after the initiation of ART and then every two weeks subsequently or if symptoms develop—is strongly recommended. Another reasonable alternative is to initiate AZT at the 28th week of gestation, with the addition of maternal NVP at labor and after birth for the infant.119
The use of d4T and didanosine (ddI) in combination is associated with increased mitochondrial toxicity during pregnancy and should be avoided.120–122 In addition, tenofovir (TDF) should not be used during pregnancy, due to concerns about osteopenia in infants and a general lack of safety data. 123
Elective cesarean sections prior to rupture of membranes can reduce MTCT in HIV-positive women who are not receiving ART.124,125 For women receiving ART, however, cesarean sections do not decrease the risk of MTCT. Recent data from PACTG 367 indicate that transmission rates are significantly lower when multi-agent therapy is being administered and when lower maternal plasma HIV RNA levels are observed; rates do not differ significantly according to mode of delivery.126 Cesarean sections should therefore be reserved for women who are likely to have a detectable viral load at the time of labor—that is, those women who are not receiving effective ART or who demonstrate nonadherence during pregnancy—and women who have an obstetric indication for a cesarean section. This stipulation is particularly important given that women with HIV infection may be at increased risk of febrile complications after a cesarean section.127,128
The rate of MTCT of HIV through breastfeeding can be as high as 0.7 percent per month.129 In breastfeeding populations, 30 to 50 percent of MTCT is attributable to breastfeeding.130 Although the U.S. Centers for Disease Control and Prevention has recommended since 1986 that women with HIV infection avoid breastfeeding, 131 breastfeeding is heavily implicated in fueling ongoing vertical transmission in resource-poor settings. The Petra study (in which AZT and 3TC were given during pregnancy only) revealed that most of the impact of preventive ART was negated when infants breastfed for 18 months, with comparable rates of transmission among interventions and placebo. 132 Risk of transmission via breastmilk has been found to be dependent on factors such as maternal viral load, maternal immune status, and infant feeding patterns, as well as by the presence of infant oral candidiasis or maternal breast pathologies such as mastitis or fissure. 133–135
Debate over breastfeeding is especially fierce with regard to resource-poor settings, where the availability of infant formula and potable water is limited. However, obtaining formula and improving water sources is less complicated than administering lifelong care to HIV-infected infants. The provision of clean water also has a positive impact on the health of the mother, the family, and the community at large. We believe that the provision of clean water and aggressive diarrheal prevention is a critical cornerstone of linking HIV programs to evidence-based primary care. Similarly, the medical management of diarrheal diseases and close monitoring of growth and nutritional status is central to all child survival programs, whether or not infants have HIV. Given these considerations, recommending formula-feeding for infants born to HIV-infected mothers makes sense both practically and ethically.
While we strongly recommend that HIV-infected women not breastfeed their infants, we recognize that certain circumstances, such as fear of HIV status disclosure or unmitigable lack of access to potable water, may result in women continuing to breastfeed. As part of comprehensive HIV care, evaluation of the social and economic barriers that might lead to such a decision is encouraged.
UNICEF and other organizations recommend exclusive breast-feeding for six months, as some studies have demonstrated increased MTCT through mixed (i.e., breast and formula) feeding. However, studies have found that 75 percent of HIV infections from breastfeeding occurred during the first six months.136 In addition, if early weaning is indeed promoted and nutritional supplementation is not provided, the infant is also at high risk for diarrhea and kwashiorkor.
In our 11 years of experience in providing infant formula, fewer than five percent of women have elected to breastfeed. For women who choose to breastfeed, weaning at six months is encouraged and nutritional support is given during the weaning period. Because malnutrition, mastitis, and breast lesions are all associated with increased risk of HIV transmission through breast milk, a multivitamin supplement (containing vitamins B, C, and E) as well as basic instructions on the prevention of mastitis and breast lesions should be provided to all breast-feeding women.137,138 Single-dose NVP for the mother during labor and for the infant within 72 hours of birth has been associated with a sustained reduction in the transmission of HIV in breastfed babies through 18 months of age.139 Studies are currently ongoing to determine if triple-drug maternal ART can reduce the risk of viral transmission to infants who continue to breastfeed.