VII: HIV AND REPRODUCTION
Jean R. Anderson, MD

I. INTRODUCTION

The ability to become pregnant and to bear children is uniquely female. With increasing numbers of HIV-infected women, 80% of whom are of childbear-ing age, and concerns about perinatal transmission of HIV, pregnancy in the setting of HIV infection has been a focus of much interest, research, and often discrimination. From 1989 to 1994 it was estimated that 1.5 to 1.7/1000 U.S. childbearing women were HIV-positive (Davis, 1998); however, this number may grow as more women become infected through sexual exposure, often unaware of their risk, and as more women who know they are infected choose to become pregnant because of therapeutic advances in care and prevention of vertical transmission.

     This chapter will review issues related to contraception and pregnancy and will discuss guidelines for care during pregnancy to optimize the health of both the mother and the fetus and infant.

II. COUNSELING

For women known to be HIV-infected, education and counseling about pregnancy and HIV should be done early in the course of HIV care, not delayed until the woman is pregnant, so that decisions about contraception and if or when to get pregnant can be most informed and carefully considered. Over one half of pregnancies in U.S. women are unplanned, and many of the risk factors for unintended pregnancy also place women at increased risk for HIV. These include:

• substance abuse (patient or partner)
  
• mental illness
  
• domestic violence
  

     Women with advanced HIV disease and HIV dementia may be at increased risk for unintended pregnancy if they are dependent on a contraceptive method (such as condom use or oral contraceptives) that requires negotiation with a sexual partner or other ongoing patient action (i.e., remembering to take pills).

     Issues to discuss when counseling about reproductive issues are listed in Table 7-1.

III. CONTRACEPTION

The majority of HIV-infected U.S. women use some form of contraception, most commonly condoms (Wilson, 1999; Watts, 1999). Women using no form of contraception do not necessarily intend to become pregnant but may lack significant power in their sexual relationship, be under pressure from partner or family to have children, be unaware of their options concerning contraception or believe they cannot become pregnant, have a disorganized lifestyle that precludes consistent use of contraception, or simply have decided to take their chances. Unplanned also does not necessarily mean unwanted; several studies show low rates of elective pregnancy termination in HIV-positive women (Smits, 1999; Greco, 1999) and no significant difference in repeat pregnancy rates in HIV-positive compared with HIV-negative women from an inner-city population (Lindsay, 1995). Table 7-2 outlines currently available methods of contraception, their effectiveness, side effects and contraindications, and non-contraceptive benefits.

     Hormonal methods of contraception, particularly oral contraceptives, can have significant drug interactions, resulting in either decreased contraceptive effectiveness or increased or decreased concentrations of the coadministered drug. Use of nelfinavir, ritonavir, amprenavir, lopinavir/ritonavir (Kaletra), and efavirenz may be associated with decrease in effectiveness of oral contraceptives (and possible increase in breakthrough bleeding); an alternative or additional method should be used (CDC, 1998). Other medications known to interact with oral contraceptives (and in some cases with progestin-only contraceptives) include tetracyclines, penicillin, oral hypoglycemic agents, rifampin, tricyclic antidepressants, oral anticoagulants, ß-blockers, methyldopa, vitamin C, benzodiazepines, and seizure medications. Clinicians treating women who are at risk for drug interactions should review the need for possible use of alternative methods of contraception or dose adjustment for the interacting agent.

     Concerns have been raised about possible increased risk of HIV transmission or acquisition in hormonal contraceptive users. There is evidence that both combined oral contraceptives and progestin-only contraceptives may increase genital tract HIV shedding; furthermore, oral contraceptives have been associated with increased cervical ectopy, which has also been linked with genital tract HIV shedding. Similarly, ectopy or other epithelial changes secondary to hormonal contraception or associated effects on immune response may increase susceptibility to HIV, and animal studies have suggested a link between progesterone implants and vulnerability to simian immunodeficiency virus (Mostad, 1998; Plummer, 1998). Data from epidemiologic studies are conflicting and inconclusive regarding the relationship of these methods of contraception and HIV transmission (Martin, 1998; Stephenson, 1998). At the current time, given their effectiveness, overall safety, and ease of use, hormonal methods of contraception remain an appropriate option for HIV-infected or at-risk women. These women should be advised that these contraceptives do not protect against HIV transmission and consistent condom use should be emphasized. 

Use of the intrauterine device (IUD) has been linked to increased susceptibility for HIV transmission (Gervasoni, 1992; Kapiga, 1994) and is associated with increased menstrual flow duration, and a foreign body inflammatory reaction, possibly contributing to transmission risk and anemia in HIV-positive women; furthermore, risk of pelvic inflammatory disease is increased in IUD users who are at increased risk for acquiring other sexually transmitted diseases (STDs). For these reasons, the IUD generally should be avoided in the setting of HIV infection.

     Spermicides have in vitro activity against HIV and significant activity against gonorrhea and chlamydia; however, a recent study of a standard sper-micidal dose of nonoxynol-9 (N-9) daily for 1 wk found an increase in irritation, colposcopic and histologic evidence of inflammation, and decreased numbers of vaginal lactobacilli in N-9 users, compared with placebo recipients (Stafford, 1998). These findings raise concerns that regular use of spermicides may not only negate any protective effect, but may potentially increase risk of HIV transmission. A randomized, double-blind, placebo-controlled study of vaginal film containing N-9 in over 1200 HIV-uninfected sex workers in Africa found no difference in rates of HIV infection between the two groups (Roddy, 1998). Results of a recent UNAIDS trial including 999 women in Africa and Thailand randomized to N-9 or lubrication only found significantly higher HIV seroconversion rates in the N-9 group, as well as more frequent occurance of genital ulcers (Altman, 2000).

     Condoms — used consistently — provide the best known protection against sexual transmission of HIV and should be emphasized for all HIV-infected and at-risk women to decrease risk of HIV transmission/acquisition and transmission/acquisition of other STDs. Other barrier contraceptive methods provide limited STD protection and have not been shown to offer significant protection against HIV transmission.

     Because male and female condoms are used for both prevention of infection and prevention of pregnancy, these two separate issues should be distinguished when counseling patients. Condom use should be reinforced for HIV-positive or at-risk women when prevention of pregnancy is not a concern: postmenopausal women, during pregnancy, despite infertility, and with the use of other methods of contraception.

V. PREGNANCY TESTING

Indications for pregnancy testing in currently or recently sexually active women:

• missed menses (unless on Norplant or Depo-Provera)
  
• irregular bleeding (unless on Norplant or Depo-Provera)
  
• new onset of irregular bleeding after prolonged amenorrhea on Norplant/Depo-Provera
  
• new onset pelvic pain
  
• enlarged uterus or adnexal mass on exam
  
• consider before instituting new therapies
  

     Pregnancy tests are performed on blood or urine and may be qualitative (positive/negative) or quantitative. Quantitative tests are useful in early pregnancy when ectopic pregnancy or abnormal intrauterine pregnancy (e.g., missed abortion) is suspected. Several qualitative urine pregnancy tests are available over the counter. Most pregnancy tests in current use are positive before the first missed menses with normal intrauterine pregnancy. Table 7-3 lists types of available pregnancy tests and their sensitivity.

VI. HIV AND FERTILITY

Recent studies in Africa, as well as in developed countries, have suggested that HIV may have an adverse effect on fertility in both symptomatic and asymptomatic women (Desgrees, 1999; L.M. Lee, 2000; Zaba, 1998). A cross-sectional study from Uganda found likelihood of pregnancy lower in HIV-positive women compared with HIV-negative women and lowest in women who were symptomatic from HIV or were coinfected with syphilis. A prospective study in the same population found that pregnancy rates were lower and pregnancy loss was more common in HIV-infected women (Gray, 1998).

VII. EFFECTS OF PREGNANCY ON HIV INFECTION

A. CD4 COUNT AND HIV RNA LEVELS IN PREGNANCY

In both HIV-positive and HIV-negative women there is a decline in absolute CD4 cell counts in pregnancy, which is thought secondary to hemodilution; on the other hand, percentage of CD4 cells remains relatively stable. Therefore, percentage, rather than absolute number, may be a more accurate measure of immune function for HIV-infected pregnant women (Brettle, 1995; European Collaborative Study and the Swiss HIV Pregnancy Cohort, 1997; Miotti, 1992). When comparing changes in CD4 count/percentage over time, there is no difference between HIV-positive pregnant and nonpregnant women (O’Sullivan, 1995), suggesting that pregnancy does not accelerate decline in CD4 cells. HIV RNA levels (viral load) remain relatively stable throughout pregnancy in the absence of treatment (Burns, 1998). However, one cohort study of 198 women found that plasma HIV RNA levels in many women were higher 6 mo postpartum than during the antepartum period, regardless of zidovudine use during and after pregnancy (Cao, 1997).

B. CLINICAL COURSE OF HIV IN PREGNANCY

Most studies to date examining the impact of pregnancy on HIV disease have been small but have not shown significant differences in HIV progression or survival between pregnant women and nonpregnant women with HIV infection. A recent metaanalysis of seven prospective cohort studies found no overall significant differences in death, HIV disease progression, progression to an AIDS-defining illness, or fall in CD4 count to below 200/mm³ between cases and controls (French, 1998). A subsequently reported prospective study of 331 women with known dates of seroconversion were followed for a median of 5.5 years; during this time 69 women were pregnant. There were no differences in progression between those who were and were not pregnant during follow-up (Alliegro, 1997).

VIII. EFFECT OF HIV ON PREGNANCY COURSE AND OUTCOME

Adverse pregnancy outcomes may occur secondary to underlying disease processes (or their treatment), as well as for unknown reasons. Approximately 10% of U.S. pregnancies end prematurely, and preterm birth is the leading cause of perinatal morbidity and mortality. Data have accumulated that HIV, especially when more advanced, may result in increases in certain pregnancy complications. Furthermore, concerns have been raised that antiretroviral treatment itself may increase some adverse outcomes in pregnancy. A recent study of 497 HIV-infected pregnant women enrolled in a perinatal clinical trial found that risk factors for adverse pregnancy outcomes (preterm birth, low birth weight, and intrauterine growth retardation) in antiretroviral-treated women are similar to those reported for uninfected women (Lambert, 2000). Table 7-4 summarizes the relationship between common pregnancy-related complications and HIV (Brocklehurst, 1998a).

     Both HIV and pregnancy may affect the natural history, presentation, treatment, or significance of certain infections, and these, in turn, may be associated with pregnancy complications or perinatal infection.

A. VULVOVAGINAL CANDIDIASIS

Pregnancy is associated with both increased rates of colonization and an increase in symptomatic infections with species of Candida. HIV infection is also associated with an increase in colonization and possible increased infection rates, especially with declining immune function (Burns, 1997; Cu-Uvin, 1999; Duerr, 1997; Schuman,1998; Spinillo, 1994). Therefore, pregnant women with HIV infection may be particularly susceptible to yeast infections. Only topical azole agents should be used during pregnancy and should be given for at least 7 days. Prophylactic topical therapy should be considered during courses of systemic, especially broad-spectrum, antibiotics.

B. BACTERIAL VAGINOSIS

Bacterial vaginosis (BV) has been associated with several adverse pregnancy outcomes, including preterm labor and birth, premature rupture of membranes, low-birth-weight infants, chorioamnionitis and amniotic fluid infection, postpartum and postabortal endometritis, and perinatal HIV transmission. If BV is diagnosed during pregnancy, preferred therapies are metronidazole 250 mg po tid x 7 days or clindamycin 300 mg po bid x 7 days, since only oral agents have been shown to reduce preterm births in women with BV (Hauth, 1995; McGregor, 1995; Morales, 1994). Because most BV episodes are asymptomatic, screening for BV should be performed at intervals during pregnancy and infection treated if identified. A recent metaanalysis (Caro-Paton, 1997) found no relationship between metronidazole exposure during the first trimester of pregnancy and birth defects.

C. GENITAL HERPES SIMPLEX

Primary herpes simplex virus (HSV) infection during pregnancy has been associated with spontaneous abortion and prematurity. Congenital or intrauter-ine infection is uncommon but maternal HSV shedding at delivery is associated with neonatal HSV infection, which is almost always symptomatic (including skin, eye, central nervous system involvement, or disseminated infection involving multiple organ systems) and frequently lethal. The risk of neonatal herpes is greatest with primary HSV, especially when acquired close to delivery (approximately 50%), whereas only 0–3% of neonates become infected with recurrent maternal disease at delivery; however, because recurrent HSV is more common than primary disease, most neonatal infections are associated with recurrent HSV. Two thirds or more of mothers with infected infants are asymptomatic during pregnancy; only one third have a history of HSV in themselves or their sexual partner. Because most neonatal infection occurs during vaginal delivery, if genital lesions or prodromal symptoms are present at the time of labor or membrane rupture, cesarean section should be performed. Cesarean section is not indicated for recurrent HSV distant from the genital tract (e.g., thigh, buttocks) (ACOG, 2000).

     HIV infection, particularly with evolving immune compromise, is associated with increased HSV shedding and more frequent, severe, and prolonged episodes of genital or perianal herpes (Augenbraun, 1995). Higher doses and/or longer courses of antiviral agents may be required and suppressive therapy is often beneficial in nonpregnant individuals. Infection with HSV-2 is common among pregnant HIV-infected women and reactivation of herpes in labor occurs more frequently in the setting of HIV infection (Hitti, 1997).

     During pregnancy a first clinical episode of genital herpes, especially in late pregnancy, may be treated with antiviral therapy. The use of oral acyclovir pro-phylactically in late pregnancy has been shown to significantly reduce symptomatic recurrences and decrease the need for cesarean section, although not with statistical significance (Brocklehurst, 1998b). Suppressive therapy may be indicated in women with frequent, severe recurrences; antiviral therapy may also be considered at 36 wk and beyond in women at risk for recurrent HSV.

     There is no current evidence of increased risk for major birth defects or other adverse pregnancy outcomes with exposure to acyclovir. Glaxo-Well-come, Inc., in cooperation with the Centers for Disease Control and Prevention (CDC), maintains a registry to assess effects of acyclovir and valacyclovir use during pregnancy. Women who receive either of these drugs in pregnancy should be reported to this registry (telephone [888] 825-5249, ext. 39441).

     Prevention of neonatal herpes should also emphasize prevention of acquisition of herpes in susceptible women in pregnancy. If her sexual partner has a history of oral or genital HSV infection, serologic evidence of HSV infection, or infection status is unknown, the pregnant woman should be counseled to avoid unprotected genital and oral sexual contact during pregnancy.

D. HUMAN PAPILLOMAVIRUS

Genital warts often enlarge and become friable during pregnancy and in some cases may mechanically obstruct the vaginal canal in labor; perinatal exposure can result in laryngeal papillomatosis in infants and children, although a recent prospective study suggests that the risk of perinatal transmission of human papillomavirus (HPV) is low (Watts, 1998). Both HPV infection in general and genital warts are more common in HIV-infected individuals, correlated with level of immunosuppression. Imiquimod, podophyllin, and podofilox should not be used in pregnancy. In women with large volume or bulk of genital warts treatment in late pregnancy with laser, excision, or cavitronic ultrasonic aspiration may be considered. Cesarean section is not currently recommended to prevent neonatal exposure to HPV, although in rare instances cesarean section may be indicated when extensive lesions obstruct the vagina.

E. SYPHILIS

Syphilis is more prevalent in HIV-infected populations and HIV may affect clinical manifestations, serologic response, or response to treatment for syphilis. Pregnancy does not alter the clinical manifestations of syphilis but untreated primary or secondary syphilis during pregnancy affects essentially all fetuses, with 50% rate of prematurity, stillbirth, or neonatal death (Radolf, 1999). Even with later stages of syphilis, there is a significant increase in adverse pregnancy outcomes, although the frequency and severity of fetal disease decrease with longer duration of untreated maternal infection. Manifestations of congenital syphilis in the newborn include mucocutaneous lesions, hepatosplenomegaly, osteochondritis/periostitis, jaundice, petechiae/purpura, and meningitis.

     Congenital syphilis can generally be prevented by identification and appropriate treatment of syphilis during pregnancy. All pregnant women should have serologic testing for syphilis at the beginning of prenatal care and testing should be repeated at 28 wk gestation and at delivery, particularly in women who remain at risk for infection. Any woman with stillbirth after 20 wk gestation should be tested for syphilis. Development of neurologic symptoms mandates evaluation for possible neurosyphilis. Treatment of syphilis during pregnancy should be the penicillin regimen appropriate for the stage of syphilis, although some experts recommend additional weekly doses in women with primary, secondary, or early latent syphilis who are HIV-infected or pregnant. HIV-positive women with late latent syphilis or syphilis of unknown duration should have cerebrospinal fluid examination before treatment (CDC, 1998a).

     Ultrasound evidence of hydrops or hepatosplenomegaly suggesting fetal syphilis increases risk for treatment failure and should be managed with expert consultation. Treatment in the second half of pregnancy is associated with the Jarisch-Herxheimer reaction in up to 40% of cases, with resulting premature labor and/or fetal distress (Myles, 1998); patients should be advised to seek immediate attention after treatment if contractions or decrease in fetal movements occur. Pregnant women with a history of penicillin allergy should be skin tested and, if necessary, desensitized and treated with penicillin, because there are no proven effective alternatives to penicillin for treatment and prevention of congenital syphilis. Even with appropriate treatment of the pregnant woman with syphilis, fetal infection may still occur and neonates should be carefully evaluated for evidence of congenital infection.

     Clinical and serologic follow-up should be performed at 3, 6, 9, 12, and 24 mo after treatment. Treatment failure should be managed with cerebrospinal fluid examination and retreatment.

F. CYTOMEGALOVIRUS

Cytomegalovirus (CMV) is the most common cause of congenital viral infection in the United States: .2–2.2% of liveborn infants acquire this infection perinatally (ACOG, 1993a). Most maternal CMV infections are asymptomatic but may cause a mononucleosis-like illness. Transmission can occur sexually or with injection drug use, because CMV has been recovered from virtually all body fluids. Perinatal transmission can occur with both primary and recurrent infection, but frequency of transmission and severity of infection in the infant are greater with primary infection. Ninety percent of infected infants are asymptomatic at birth, but symptomatic infection is more likely with maternal infection acquired early in pregnancy. Even if asymptomatic, many infected infants subsequently develop deafness, mental retardation, or delayed psy-chomotor development. More severe clinical manifestations include symmetric growth restriction, hepatosplenomegaly, chorioretinitis, microphthalmia, hydrocephaly, microcephaly, and cerebral calcifications.

     In the setting of HIV infection, mothers seropositive for CMV do not appear to be more likely to transmit CMV perinatally than HIV-negative mothers. Furthermore, the frequency of CMV infection at birth is similar between HIV-infected and -uninfected infants born to HIV-seropositive mothers. There have been some reports that cotransmission of HIV and CMV may be related to more rapid HIV progression (Kovacs, 1999; Mussi-Pinhata, 1998).

     There is no effective therapy to prevent or treat perinatal CMV infection. Testing for antibody to CMV should be considered in pregnancy, especially if the CD4 count is < 100/mm³; however, seropositivity is common and does not preclude viral shedding during pregnancy and perinatal transmission. Methods to reduce risk of exposure to CMV include safer sexual practices, careful hand-washing, and transmission of only CMV antibody-negative blood products. Primary prophylaxis is not routinely recommended; however, after CMV disease, chronic suppression is indicated in pregnancy and should be continued with expert consultation concerning choice of agents. (See Opportunistic Infection Prophylaxis below.)

G. TOXOPLASMOSIS

Approximately one third of U.S. women have toxoplasma antibodies, reflecting prior infection. Primary infection occurs in approximately .1–.5% of pregnancies and places the fetus at risk for congenital toxoplasmosis. Congenital infection is more common when infection in the mother occurs during the third trimester (59% in third trimester vs. 9% in first trimester) but is generally more severe when occurring in the first trimester. Although the majority of infected infants are asymptomatic at birth, most will develop some sequelae of congenital toxoplasmosis; two thirds of infants infected after maternal first trimester infection have severe manifestations and 5% are stillborn or die in the perinatal period (ACOG, 1993a).

     Congenital toxoplasmosis may affect all systems, but the most common findings are chorioretinitis, microcephaly, hydrocephaly, and cerebral calcifications.

     Transmission of toxoplasmosis from a mother with antibody evidence of prior infection can occur in the setting of HIV infection, but does not seem to be common, although there are limited data in more immunosuppressed mothers (European Collaborative Study and Research Network in Congenital Toxoplasmosis, 1996; Minkoff, 1997b).

     Testing for IgG antibodies to toxoplasma is recommended for all HIV-infected individuals soon after the diagnosis of HIV is made and should be considered as part of prenatal testing in HIV-positive pregnant women. Primary prophylaxis and prophylaxis against recurrent disease in pregnancy are discussed below (See Opportunistic Infection Prophylaxis). Pregnant women with symptoms including fever, chills, malaise, lymphadenopathy, myalgias, and headache should be evaluated serologically for possible primary toxoplasmic infection. Evidence of primary infection or active toxoplasmosis should be evaluated and managed with expert consultation. Infants born to women infected with HIV and seropositive for toxoplasma should be evaluated for evidence of congenital toxoplasmosis.

     To prevent exposure to toxoplasmosis, pregnant women should be counseled to avoid raw or undercooked meat, wash hands after contact with raw meat or with soil, and wash fruits and vegetables well before eating them raw. Cats should preferably be kept inside and fed only canned or dried commercial food; litter boxes should be changed daily, preferably by someone who is not HIV-positive or pregnant.

H. HEPATITIS B

Approximately 300,000 new cases of hepatitis B virus (HBV) infection occur each year and more than 1 million Americans are chronic carriers. Most patients who become infected have complete resolution of infection and develop protective levels of antibody (anti-HBs). Chronic HBV infection develops in 1–6% of persons who are infected as adults; they are chronically HBsAg+ and are at risk of chronic liver disease, including cirrhosis and hepa-tocellular carcinoma (CDC, 1991). The presence of HBeAg indicates active viral replication and increased infectivity. HBV is transmitted parenterally, sexually, perinatally, and through household or institutional contact. Approximately one quarter of regular sexual contacts of infected individuals will become seropositive and sexual transmission accounts for 30–60% of new infections. Perinatal transmission, usually with intrapartum contact with maternal blood and genital secretions, occurs in 10–20% of women who are HBsAg+, but increases to approximately 90% if the mother is also HBeAg+.

Chronic HBV infection develops in about 90% of infected newborns, who are at high risk of chronic liver disease (ACOG, 1998).

     All pregnant women should be screened for HBsAg. Infants born to women who are HBsAg+ should receive hepatitis B immune globulin and initiate HBV vaccination within 12 hr after birth. HBV vaccine can be safely administered during pregnancy and should be considered in women who are high risk (injection drug use, STDs, multiple sexual partners, household or sexual contact of HBV carrier) and are anti-HBs- or anti-HBc-negative, indicating susceptibility. Some experts argue for more liberal use of vaccination in HIV-infected individuals, because HBV infection in the setting of HIV infection increases risk for chronic HBV infection. HIV can impair response to HBV vaccine; therefore, testing for hepatitis B surface antibody is recommended 1–2 mo after the third vaccine dose. Full revaccination should be considered for those who are nonresponders (ACOG, 1998; Bartlett, 1999).

I. HEPATITIS C

Hepatitis C virus (HCV) infection is primarily transmitted by injection drug use, but may also be transmitted sexually. Approximately 50% of those with acute HCV infection develop biochemical evidence of chronic liver disease, and 20% or more ultimately have chronic active hepatitis or cirrhosis and are at risk for hepatocellular carcinoma (CDC, 1998c). Women newly diagnosed with HIV in pregnancy should have testing for antibody to HCV by enzyme immunoassay; positive results should be confirmed with recombinant immunoblot assay or HCV polymerase chain reaction (PCR) and liver function abnormalities should be documented. Women coinfected with HIV and HCV should avoid alcohol, both during and after pregnancy, because alcohol use increases risk of cirrhosis. Vaccination against hepatitis A, if the woman is anti-HAV-negative, is recommended because the risk for fulminant hepatitis associated with hepatitis A is increased in HCV-infected individuals; this vaccination may be given safely during pregnancy (ACOG, 1998; Bartlett, 1999).

     Perinatal transmission of HCV has been documented and may be more likely in HIV-coinfected women or in HIV-infected infants born to dually infected mothers (Papaevangelou, 1998; Thomas, 1998). Furthermore, maternal coinfection with HIV and HCV may also increase risk for perinatal HIV transmission (Hershow, 1997). Risk of vertical HCV transmission is proportional to the amount of HCV RNA present in maternal blood (Thomas, 1998).

IX. PERINATAL TRANSMISSION

The baseline rate of perinatal HIV transmission without prophylactic therapy is approximately 25%. The timing of transmission is a critical factor impacting on development of preventive interventions. There is evidence that transmission can occur during the course of pregnancy, around the time of labor and delivery, or postpartum through breast-feeding; however, two thirds to three quarters of transmission appears to occur during or close to the intrapartum period, particularly in non-breast-feeding populations (Mofenson, 1997).

A. POTENTIAL VARIABLES IN TRANSMISSION

HIV-RELATED FACTORS

• HIV RNA level: HIV RNA levels correlate with risk of transmission in both antiretroviral-treated and untreated women. The risk of perinatal transmission appears to be extremely low in women with undetectable plasma viral loads, but transmission has been reported at all levels of maternal HIV RNA. There is no upper limit of HIV RNA above which perinatal transmission always occurs (Garcia, 1999; Mofenson, 1999; Shaffer, 1999).
  
• Strain variation (genotype): Each HIV-infected individual’s viral pool is composed of a variety of HIV quasispecies. One recent study found that in utero transmission was associated with transmission of major maternal viral variants, whereas intrapartum transmission was associated with transmission of minor maternal viral variants, suggesting that different selective pressures may be involved in determining the pattern of viral strain transmission depending on timing of transmission (Dickover, 2000). HIV in vaginal secretions can be derived from local expression and may have significant genotypic differences from plasma virus, with possible implications for peri-natal transmission (Subbarao, 1998).
  
• Biologic growth characteristics (phenotype): Fetal blood mononuclear cells may be more susceptible to macrophage-tropic, non-syncytium-inducing HIV phenotypes and this may influence mother-to-infant HIV transmission (Palasanthiran, 1994; Reinhardt, 1995).
  
• Plasma vs. genital tract viral load: There is general correlation between plasma and genital tract viral load but discordance has been reported and may help explain some cases of transmission with undetectable plasma HIV RNA. In the Thai short-course zidovudine (ZDV) clinical trial, both plasma and cer-vicovaginal HIV RNA levels were suppressed by ZDV treatment and both were independently correlated with transmission (Chuachoowong, 2000). The female genital tract can also be a reservoir for virus with a different drug-resistance pattern than that observed in plasma (Fang, 1998). Further studies are needed to assess suppression of genital tract virus with other antiretrovi-ral agents and with highly active retroviral therapy (HAART), and the association of this suppression with perinatal transmission.
  
• Genotypic resistance: Use of antiretroviral regimens (particularly single agents) for the purpose of perinatal prophylaxis has raised concerns about the induction of resistance mutations, possibly increasing the risk for vertical transmission or progression in infected infants. Studies to date of resistance mutations in the setting of ZDV monotherapy during pregnancy have shown increasing prevalence of these mutations over time and an association with length of drug exposure (Eastman, 1998; Fiscus, 1999; Kully, 1999; Palumbo, 1999). Perinatal transmission of virus with known ZDV resistance mutations has been described (Colgrove, 1998), and one recent study found that maternal ZDV use was associated with more rapid disease progression in infants who acquired HIV despite maternal ZDV use (Kuhn, 2000). Most concerning, a recent study from the Women and Infants Transmission Study of women who received ZDV during pregnancy found that 25% of 142 maternal isolates had at least one ZDV-associated resistance mutation; a lower CD4 percentage and higher plasma HIV RNA level were associated with ZDV resistance mutations at delivery and, with multivariate analysis, the presence of resistance mutations was independently associated with vertical transmission (Welles, 2000). Other studies have not found a correlation between a history of prior ZDV therapy or documented ZDV resistance and perinatal transmission (Eastman, 1998; Kully, 1999; Stiehm, 1999).
  
  A subset of Ugandan women in the HIVNET 012 trial (Jackson, 2000a) developed a K103N nevirapine (NVP) resistance mutation after receiving a single dose of nevirapine at the onset of labor for prevention of perinatal transmission. Of 31 transmitting women with available specimens, 7 (23%) had detectable resistance mutations at 6 wk postpartum; of the 16 infected infants in the nevirapine group, NVP resistance mutations were detected in 7 (44%), although maternal and infant mutations differed (Jackson, 2000b). In the PACTG 316 study (protcol similar to HIVNET 012 (see Table 7-8) except that women may receive other anitretroviral agents during pregnancy) 4 of 32 (12.5%) women in the NVP group with delivery HIV RNA > 3000 c/mL had a new NVP resistance mutation at 6 wk postpartum compared with 0 in 38 women who did not receive NVP (Sullivan, 2000). The clinical implications of these findings for perinatal prophylaxis with nevriapine are unclear.
  
• CD4 cell count: Lower CD4 count or decreased CD4:CD8 ratio have been consistently associated with increased risk of transmission.
  
• Maternal immune response: Studies have been inconsistent when evaluating the role of maternal antibodies, including anti-gp120, anti-gp41, anti-p24, and autologous neutralizing antibody titers. ß-chemokine and cytokine responses may affect risk of transmission (Pitt, 2000a; Rich, 1998).
  

• Clinical stage: Maternal symptomatic disease or AIDS-defining illness are consistently associated with higher risk for transmission. Women with primary HIV infection in pregnancy, at which time plasma viremia is high, are also at increased risk for transmission (Nesheim, 1996).
  
• STDs/other coinfections: STDs have been shown to increase genital tract HIV shedding and also increase plasma viremia (Plummer, 1998), both of which may increase risk for perinatal transmission. STDs (Mandelbrot, 1996), syphilis (M.J. Lee, 1998), bacterial vaginosis (Taha, 1998), and placental malaria have been associated with increased risk for vertical transmission, as have increased levels of genital tract inflammatory cells (Panther, 2000).
  
• Vitamin A deficiency: Vitamin A deficiency has been associated with increased risk of perinatal HIV transmission and increased genital tract HIV shedding (Nimmagadda, 1998). However, a recent randomized trial of vitamin A supplementation in South Africa found no overall reduction in mother-to-child transmission of HIV, although vitamin A recipients were less likely to have a preterm delivery, and in preterm deliveries, those infants assigned to the vitamin A group were less likely to be infected (Coutsoudis, 1999).
  
• Substance abuse: Illicit drug use during pregnancy has been associated with increased risk for perinatal transmission (Landesman, 1996; Lyman, 1993; Rodriguez, 1996).
  
• Cigarette smoking: Cigarette smoking has been associated with an increased risk of perinatal transmission (Burns, 1994; Turner, 1997).
  
• Antiretroviral agents: ZDV (antepartum/intrapartum/neonatal) in several different regimens, ZDV/lamivudine (3TC) (intrapartum/neonatal), and nevirapine (intrapartum/neonatal) have all demonstrated effectiveness in reducing perinatal HIV transmission in randomized clinical trials. Early trial results of d4T, ddI, or d4T/ddI given antepartum/intrapartum/neonatal are also promising (Gray, 2000a). In the PACTG 076 study, reduction in plasma viral load accounted for only 17% of ZDV’s effectiveness, suggesting pre- and/or postexposure prophylaxis as other possible mechanisms of action (Sperling, 1996). In the Thai short-course ZDV trial, both plasma and cervicovaginal HIV RNA levels were suppressed by ZDV and both were independently correlated with transmission (Chuachoowong, 2000). Although there are no clinical trials completed with HAART regimens, these regimens result in optimal reductions in viral load, which would be expected to lead to reductions in transmission. A recent evaluation of 1482 women in the Women and Infants Transmission Study found an independent protective effect of antiretroviral agents on prevention of vertical transmission, regardless of plasma viral load levels at delivery. Transmission rates progressively declined with use of more effective regimens. Transmission was 1.1% for 186 women receiving HAART (Blattner, 2000).
  
• Sexual behavior: Unprotected sex with multiple partners has been associated with increased risk for perinatal transmission (Bulterys, 1997).
  
• Gestational age: Preterm delivery has been associated with increased risk for perinatal transmission (Kuhn, 1997, 1999).
  
• Duration of membrane rupture: A recent metaanalysis from 15 prospective cohort studies, including over 7500 deliveries, examined the role of duration of ruptured membranes in perinatal transmission (Read, 2000). The likelihood of transmission increased linearly with increasing duration of ruptured membranes, with a 2% increase in risk for each hour increment. Women with clinical AIDS had the most pronounced increase in risk, with a 31% probability of vertical transmission after 24 hr of ruptured membranes.
  
• Placental disruption-abruption, chorioamnionitis: Clinical and histo-logic chorioamnionitis (Goldenberg, 1998) has been associated with increased risk of transmission. Placental abruption causing disruption of fetal-placental barrier and possible increased exposure of the fetus to maternal blood has also been suggested as a risk factor for transmission.
  
• Invasive fetal monitoring: Use of fetal scalp electrodes or fetal scalp -sampling increases exposure of the fetus to maternal blood and genital secretions and may increase risk of vertical transmission (Maiques, 1999). Amnioscopy and amniocentesis increased risk in the French Perinatal Cohort (Mandelbrot, 1996).
  
• Episiotomy, forceps: Use of episiotomy or vacuum extraction or forceps may potentially increase risk of transmission by increasing exposure to maternal blood/genital secretions with trauma to maternal or neonatal tissue. On the other hand, judicious use of these techniques to shorten duration of labor or ruptured membranes with vaginal delivery may decrease likelihood of transmission.
  
• Vaginal vs. cesarean delivery: Several recent studies (done before routine use of viral load testing and use of combination antiretroviral therapy in pregnancy) indicate that cesarean delivery performed before the onset of labor and rupture of membranes significantly reduces the risk of perinatal HIV transmission by 55–80% (European Mode of Delivery Collaboration, 1999; International Perinatal HIV Group, 1999; Kind, 1998; Mandelbrot, 1998). Rates of transmission were reduced to approximately 2% with scheduled cesarean section and receipt of ZDV (similar risk of 2% or less is seen among women with undetectable HIV RNA levels [less than 500 c/mL], in the absence of systematic use of cesarean section). Whether cesarean delivery offers any benefit when the mother is receiving HAART and/or if she has low or undetectable viral load is unknown.
  

Fetal/neonatal factors, including an immature immune system (particularly in the premature infant) and genetic susceptibility, as expressed by human lymphocyte antigen (HLA) genotype (Just, 1992) or CCR-5 receptor (a co-receptor for macrophage-tropic strains of HIV; a homozygous deletion in this gene confers a high degree of natural resistance to HIV sexual transmission) mutations may play a role in perinatal transmission (Kostrikis, 1999; Mangano, 2000; Philpott, 1999). A recent study from South Africa (Kuhn, 2000b) found that early acquired cellular immune responses to HIV, presumably from in utero exposure, were present in over one third of 86 uninfected infants born to HIV-infected mothers. These detectable immune responses appeared to provide complete protection against subsequent HIV transmission at delivery and through breast-feeding.

D. BREAST-FEEDING

Breast-feeding plays a more significant role in perinatal HIV transmission than was once thought and was estimated to have accounted for up to 50% of newly infected children globally in 1998 (Fowler, 1999). Breast-feeding in the setting of established maternal infection has an estimated additional risk of 14% transmission, whereas the additional risk is 29% in the setting of acute maternal infection or recent seroconverson (Dunn, 1992). HIV DNA can be detected in over 50% of breast milk samples and is correlated with CD4 depletion and vitamin A deficiency. Risk of transmission is highest in the earliest months of breast-feeding but increased duration of breast-feeding increases risk (Kreiss, 1997; Leroy, 1998b). Other potential variables include the presence of cracked nipples or breast abscess, infant oral candidosis, and the use of exclusive breast-feeding vs. mixed feeding. A recent randomized clinical trial of breast-feeding vs. formula in Kenya (Nduati, 2000) found that formula feeding prevented 44% of infant infections and was associated with a significantly improved HIV-free survival.

STRATEGIES FOR PREVENTION OF PERINATAL TRANSMISSION

Based on the potential factors impacting perinatal HIV transmission discussed above, several basic approaches to prevention have been suggested. These include decreasing viral load, decreasing viral exposure, identifying and treating modifiable risk factors, and ultimately, stimulating the immune system, such as with passive or active immunization.

A.  ANTEPARTUM

HISTORY/PHYSICAL EXAMINATION

(See Chapter IV on Primary Medical Care.)

• HIV history: date of diagnosis; history of HIV-related symptoms or opportunistic infections or malignancies; lowest CD4 cell count; complete antiretroviral history, including specific drugs, side effects or toxicity, length of treatment, adherence, and response to treatment
  
• Pregnancy history: previous pregnancies and outcomes, complications, mode of delivery, use of antiretroviral prophylaxis, and HIV status of other children
  
• Signs or symptoms of HIV/AIDS: The initial and follow-up evaluations of HIV-positive women during pregnancy should assess signs or symptoms that suggest symptomatic HIV infection or AIDS (e.g., generalized lym-phadenopathy, thrush, constitutional symptoms such as fever [38.5°C] or diarrhea > 1 mo, herpes zoster involving two episodes or > 1 dermatome, peripheral neuropathy, wasting, dysphagia, shortness of breath, persistent mucocutaneous herpetic ulcerations, cognitive dysfunction, etc.).
  
• Signs or symptoms of pregnancy-related complications: elevated blood pressure, significant edema, severe headache, vaginal bleeding or leakage of fluid, intractable nausea and vomiting, dysuria, abnormal vaginal discharge, persistent abdominal or back pain or cramping, decrease in fetal movement, etc.
  
       Certain symptoms of HIV disease and normal or abnormal pregnancy may overlap, resulting in possible delay in appropriate diagnosis and management.
  
• Relevant family history of possible heritable diseases.

LABORATORY EXAMINATION BY TRIMESTER

See Table 7-5.

ANTEPARTUM FETAL SURVEILLANCE/TESTING

The general purpose of antepartum fetal testing and surveillance is to identify fetal abnormalities or compromise so that appropriate interventions can be undertaken to optimize fetal health and prevent fetal damage or death; or, in some instances, to aid in decisions regarding continuation of pregnancy (ACOG, 1999a).

• Fetal surveillance: Indications include:

• maternal conditions in which risk of fetal death is increased. This includes (but is not limited to) hemoglobinopathies, chronic renal disease, systemic lupus erythematosus, hypertension, and diabetes.
• pregnancy-related conditions in which risk of fetal death is increased.
  This includes pregnancy-induced hypertension, decreased fetal movement, oligohydramnios, polyhydramnios, intrauterine growth retardation, postterm pregnancy, mild to moderate isoimmunization, previous fetal demise, and multiple gestation.
  
       There are no data specifically on the need for and use of fetal surveillance techniques in the HIV-infected woman during pregnancy, and HIV per se is not an indication for fetal testing. However, HIV-infected women who have coexisting medical conditions placing the fetus at increased risk should have fetal surveillance; furthermore, HIV infection, especially when more advanced or associated with substance abuse, may be associated with increased risk for poor fetal growth, which places the fetus at increased risk. Need for fetal surveillance in the HIV-positive pregnancy should be determined on an individual basis.
  Fetal surveillance techniques include:

• Fetal movement assessment: perception of 10 distinct movements in a period of up to 2 hr is reassuring.
• Nonstress test (NST): reactive or reassuring test is defined as two or more fetal heart rate accelerations (at least 15 beats/min above baseline and lasting at least 15 sec on fetal monitor) within a 20-min period.
• Contraction stress test (CST): negative or reassuring test is absence of late or significant variable fetal heart rate decelerations with at least three contractions (lasting at least 40 sec) within 10 min.
• Biophysical profile: consists of an NST combined with observations of fetal breathing, fetal movements, fetal tone, and amniotic fluid volume by real-time ultrasonography. Each component is given a score of 2 (normal or present) or 0 (abnormal or absent); a composite score of 8 or 10 is normal.
• Modified biophysical profile: combines NST and amniotic fluid index (AFI), which is the sum of measurements of the deepest amniotic fluid pocket in each abdominal quadrant; normal AFI is > 5 cm. This test combines a short-term indicator of fetal acid-base status (NST) and an indicator of long-term placental function (AFI); placental dysfunction often leads to poor fetal growth and oligohydramnios.
• Umbilical artery Doppler velocimetry: evaluation of flow velocity wave forms in the umbilical artery; in the normally growing fetus, characterized by high-velocity diastolic flow; of benefit only in pregnancies complicated by intrauterine growth restriction.
  
       Although data from randomized clinical trials are missing, antepar-tum fetal surveillance has been consistently associated with lower rates of fetal death than in untested pregnancies from the same institution or than historic controls with similar complicating factors. Testing should be initiated at 32–34 wk gestation, but may be started as early as 26–28 wk in pregnancies at very high risk. When the condition prompting testing persists, testing should be repeated periodically (weekly or, in some cases, biweekly) until delivery. Fetal reevaluation should also be repeated with significant deterioration in maternal medical condition or acute decrease in fetal movement, regardless of the time elapsed since the previous test.
  
       NST, CST, biophysical profile, and modified biophysical profile are the most commonly used forms of testing and have a negative predictive value > 99%. However, they are not predictive of acute events, such as placental abruption or umbilical cord accidents. On the other hand, the positive predictive value of an abnormal test can be quite low and the response to an abnormal result should be dictated by the individual clinical situation. Any abnormal test result requires further evaluation or action. Maternal perception of decreased fetal movements should be evaluated by NST, CST, biophysical profile, or modified biophysical profile. If normal, the mother can be reassured that the fetus is in no immediate danger. A nonreactive NST or abnormal modified biophysical profile is usually followed by additional testing with a CST or full biophysical profile. Management will be based on results of these tests, gestational age, degree of oligohy-dramnios (if assessed), and maternal condition. Oligohydramnios should prompt evaluation for membrane rupture. Depending on the degree of oligohydramnios, the gestational age, and the maternal medical condition, oligohydramnios warrants either delivery or close maternal/fetal surveillance.

• Ultrasound. Indications for obstetric ultrasound are many. Some of the more common include (ACOG, 1993b): ! pregnancy dating ! evaluation of fetal growth ! evaluation of vaginal bleeding during pregnancy

• determination of fetal presentation
• suspected multiple gestation
• significant uterine size/clinical dates discrepancy
• pelvic mass
• suspected ectopic pregnancy
• document fetal viability/rule out fetal death
• biophysical profile for antepartum fetal surveillance
• suspected polyhydramnios/oligohydramnios
• placental localization
• abnormal serum a-fetoprotein or triple screen
• evaluation for fetal anomalies
• evaluation of fetal condition in late registrants for prenatal care
  With transvaginal ultrasound, an intrauterine gestational sac can be seen by 5 wk after the last menstrual period and fetal heart activity can be detected by 6 wk. First-trimester bleeding is the most common indication for early ultrasound, when the major differential diagnoses are threatened abortion (miscarriage) and ectopic pregnancy. Accurate pregnancy dating is best accomplished in the late first and second trimesters.
  
       In the setting of HIV infection, an ultrasound should be considered in the second trimester for accurate dating, which is important later in gestation if scheduled cesarean section is planned to avoid premature delivery (see below). This will also allow survey of fetal anatomy and screening for anomalies. Depending on the individual situation, including stage of illness, therapeutic regimen, and presence of other maternal/pregnancy-related factors, ultrasonography may be useful in monitoring fetal growth.

• Amniocentesis/chorionic villus sampling/percutaneous umbilical blood sampling: Because of concerns about increasing risk of perinatal transmission with these invasive techniques, they should generally be avoided in pregnancies complicated by HIV infection.
  

ANTIRETROVIRAL TREATMENT

(See Table 7-6.) Although there are special considerations in using antiretro-viral drugs during pregnancy, the basic principle is that therapies of known or possible benefit to the woman should not be withheld during pregnancy unless there are known adverse effects for mother, fetus, or infant that outweigh the potential benefits (Minkoff, 1997a). Pregnant women meeting the criteria outlined for other adults and adolescents should be offered standard combination antiretroviral therapy, usually including two nucleoside reverse transcriptase inhibitors and a protease inhibitor (PI). (See Chapter IV on Primary Medical Care.)

     Nevertheless, there are additional issues to consider with treatment in pregnancy:

• Pharmacokinetics: There are potential changes in dosing secondary to the physiologic changes during pregnancy; at the current time, pharmacoki-netic information on existing antiretroviral agents during pregnancy is limited, but has not suggested need for dose adjustment.
  
• Perinatal transmission: The effect of different drugs and drug combinations on vertical transmission. Current information on the use of antiretro-viral agents during the antepartum period and perinatal transmission are summarized below:

• PACTG 076: ZDV given antepartum, intrapartum by IV infusion, and to the neonate for 6 wk of life reduced risk of vertical transmission by 66%, from 22.6% in placebo recipients to 7.6% in ZDV recipients (Sperling, 1996). All women participating in this trial had CD4 counts > 200/mm³ and were antiretroviral naive. Subsequent studies, including women with more advanced disease and with prior ZDV exposure, confirm the effectiveness of this regimen with transmission rates as low as 3–4%.
• short-course ZDV: ZDV 300 mg twice daily beginning at 36 wk gestation and 300 mg every 3 hr orally in labor reduced transmission by approximately 50% (19% placebo vs. 9% ZDV) compared with placebo in a non-breast-feeding population in Thailand (Shaffer, 1999).
• short-course ZDV: ZDV 300 mg twice daily beginning at 36–38 wk gestation, oral ZDV in labor, and ZDV 300 mg twice daily to the mother for 1 wk after delivery (not all evaluated women received the latter component) reduced transmission by 28% (30.3% placebo vs. 21.9% ZDV) at 18 mo in this breast-feeding population in West Africa (Wiktor, 2000).
• short-course ZDV: ZDV 300mg twice daily beginning at 28 wk gestation, ZDV 300 mg every 3 hr orally in labor, and ZDV to the neonate for 3 days (long-short [LS]) or 6 wk (long-long [LL]) reduced transmission significantly when compared with two ZDV regimens involving maternal therapy starting at 35 wk and similar neonatal regimens (SS, SL) (6.5% LL, 4.7% LS, vs. 8.6% SL, 10.5% SS) in this non-breast-feeding population in Thailand. Secondary analysis showed that shortening maternal treatment was associated with higher in utero transmission (Lallemont, 2000).
• short-course (beginning at 34–36 wk gestation, oral intrapartum, and 6 wk of same drug to newborns) d4T, ddI, d4T/ddI, or ZDV was well tolerated and resulted in transmission rates of 1.9–6.3% at 6 wk of life in a non-breast-feeding South African cohort (n=24) (Gray, 2000a).
• ZDV/3TC: (PETRA trial) ZDV/3TC twice daily beginning at 36 wk gestation and orally in labor (ZDV 600 mg and 3TC 150 mg orally at onset of labor, then ZDV 300 mg orally every 3 hr and 3TC 150 mg orally every 12 hr) and for 1 wk postpartum to the infant and mother reduced transmission by approximately 50% (17% placebo vs. 9% ZDV/3TC) compared with placebo at 6 wk. However, with follow-up to 18 mo, there was no longer any significant difference from placebo in transmission rates (Gray, 2000b). Most infants in this study were breast-fed, and the loss of efficacy over time is likely related to transmission through breast-feeding.
  

• Fetal/infant adverse effects: Potential teratogenicity, carcinogenicity, mutagenicity, or fetal/neonatal side effects/toxicity from transplacentally transferred drugs. The potential for adverse effects may be related to several factors: the drug itself, dose, gestational age at exposure, duration of exposure, interactions with other drugs or agents to which the fetus is exposed, and the genetic make-up of mother and fetus.
  
       Information about the safety of drugs in pregnancy comes from animal toxicity studies, anecdotal experience, registry data, and clinical trials. Preclinical data do not necessarily correlate with adverse effects in humans. There are approximately 1200 known animal teratogens, but only about 30 are known human teratogens. Of currently available drugs, ZDV is the agent for which there is the most information, and information about the other antiretrovirals is limited. Some specific concerns have been raised and are addressed below; for more in-depth discussion of each drug, see Chapter XIV on Pharmacology and the U.S. Public Health Service Task Force Recommendations for the Use of Antiretrovi-ral Drugs in Pregnant Women Infected with HIV-1 for Maternal Health and for Reducing Perinatal HIV-1 Transmission in the United States, which is updated regularly online at http://www.hivatis.org.

• safety of ZDV exposure: In the PACTG 076 study the only side effect significantly different between ZDV and placebo recipients was the presence of anemia in ZDV-exposed infants; however, the anemia was mild and resolved spontaneously without need for transfusion (Connor, 1994). There has been no evidence of increase in congenital abnormalities in infants exposed to ZDV in utero, compared with the general population. Uninfected children who were participants in the PACTG 076 study have now been followed for over 4 yr with no evidence of impact of ZDV on growth, neurode-velopment, or immunologic status (Culnane, 1999).
  
       ZDV carcinogenicity: Two transplacental carcinogenicity studies in mice showed different results: in one study (Olivero, 1997), two very high doses (approximately 25x and 50x daily human therapeutic exposure) were associated with an increase in lung, liver, and female genital tract tumors; in the second study (Ayers, 1997), a much lower dose (approximately 3x human therapeutic exposure) was not associated with an increase in tumors. A consensus conference reviewed all available information and concluded that the known benefits of zidovudine far outweighed the theoretical risks, but recommended long-term follow-up of infants exposed in utero to zidovudine or other antiretrovirals. In a follow-up of over 700 infants with in utero exposure to ZDV, no malignancies were observed in up to 6 yr of age (Hanson, 1999).
  
• Efavirenz: In primate studies efavirenz was associated with anen-cepahaly, anophthalmia, microphthalmia, and cleft palate at doses comparable to human exposure, suggesting that this drug should be avoided during pregnancy, particularly early pregnancy, and in women at risk for pregnancy (trying to get pregnant or unsafe sexual practices). Pregnant women who have conceived while on efavirenz should be counseled about possible fetal risks. It is important to acknowledge that animal studies in primates have not been performed with any of the other antiretroviral agents.
• Hydroxyurea: Although hydroxyurea is not a true antiretroviral drug, it has been used in many antiretroviral regimens, particularly in those containing didanosine. There is limited human information on the use of hydroxyurea in pregnancy and there are reports of exposure during pregnancy without apparent adverse outcome; however, hydroxyurea has been referred to as a “universal teratogen” with evidence of teratogenicity in every animal species studied and defects involving multiple organ systems. This agent should be avoided during pregnancy and in women at risk for pregnancy; pregnant women who have conceived while on a hydroxyurea-containing regimen should be counseled about possible fetal risks.
• Indinavir: Indinavir has been associated with indirect hyperbiliru-binemia and increased risk for renal stones. Because of theoretical concerns about risk for renal stones in neonates who cannot voluntarily hydrate themselves adequately and possible complications associated with exacerbation of physiologic hyperbilirubinemia (especially in premature infants, who are at greater risk for neonatal jaundice and kernicterus), this drug should be avoided in late pregnancy. Because of its short half-life, these concerns may not apply to use of indinavir earlier in pregnancy.
• Amprenavir: Amprenavir oral solution contains high levels of propylene glycol (the capsule form does not contain propylene glycol). Pregnant women and infants and children under the age of 4 are unable to adequately metabolize and eliminate propylene glycol, leading to accumulation and potential serious adverse events, including hyperosmolarity, lactic acidosis, seizures, and respiratory depression. Amprenavir oral solution is contraindicated in pregnancy and in children under the age of 4 yr.
• Preterm delivery: Concerns about possible increased risk for preterm delivery were raised by a small retrospective series of pregnant women receiving combination antiretroviral therapy (ARV) (Lorenzi, 1998); however, some studies have found increased preterm birth rates in women who were not on ARV therapy, especially with more advanced disease (Brocklehurst, 1998b; Leroy, 1998a; Martin, 1997). Furthermore, other factors, such as substance abuse, nutritional status, smoking, and cocaine use, may also increase risk and be confounding variables. Preliminary analyses of multiple PACTG clinical trials do not show an increased rate of preterm birth in women receiving ARV therapy, with or without protease inhibitors (Shapiro, 2000).
• Mitochondrial toxicity: A small series of uninfected infants exposed in utero to nucleoside analogue agents was reported with laboratory or clinical evidence of mitochondrial dysfunction; two developed severe neurologic disease and died (Blanche, 1999). Subsequent studies have been reassuring. A review of 353 deaths in over 20,000 children (with and without ARV exposure) born to HIV-positive mothers followed prospectively in the United States found no evidence of mitochondrial toxicity as a contributing factor in the deaths (Smith, 1999). Neurologic adverse events were reviewed in 1,798 infants exposed to ZDV/3TC or placebo in the PETRA study, an African perinatal prophylaxis trial; no increased risk of adverse neurologic events was observed in infants exposed to ZDV/3TC compared with placebo (Lange, 1999). Although these studies do not rule out the possibility of an association between mitochondrial dysfunction and ARV exposures in utero, the likelihood of severe or fatal manifestations appears to be extremely small.
  
       Given the limited and relatively short-term experience with all anti-retroviral agents in pregnancy, long-term follow-up of infants exposed to these medications in utero is important.
  

• Maternal adverse effects: Lactic acidosis and hepatic steatosis, clinical disorders linked to mitochondrial toxicity in long-term nucleoside analogue users, may have a female preponderance, and a possible genetic susceptibility has been suggested. Recently, Bristol-Myers Squibb has reported three maternal deaths due to lactic acidosis/hepatic steatosis, all in women receiving a combination of d4T/ddI as part of their antiretro-viral regimen at the time of conception and for the duration of pregnancy. It is not known if pregnancy increases the incidence of this syndrome; however, pregnancy itself can mimic some of the early symptoms of lactic acidosis/hepatic steatosis and is also associated with some rare but life-threatening disorders of liver metabolism (acute fatty liver of pregnancy; hemolysis, elevated liver enzymes and low platelets-the HELLP syndrome). Therefore, pregnant women receiving nucleoside analogue drugs should have liver enzymes and electrolytes evaluated more frequently during the last trimester of pregnancy and any new symptoms should be evaluated promptly and thoroughly. Because of the maternal deaths noted above, clinicians should prescribe the combination of d4T/ddI during pregnancy with caution and generally only when other nucleoside analogue combinations have failed or been associated with unacceptable toxicity or side effects.
  
• Interaction of drugs with pregnancy-related side effects/physiologic changes:

• Drugs that cause gastrointestinal upset may not be well tolerated in early pregnancy when morning sickness is common and may increase risk for nonadherence or inadequate blood levels from vomiting.
• Protease inhibitors and hyperglycemia: Protease inhibitors (PIs) have been associated with the development or worsening of existing hyperglycemia or diabetes and pregnancy also increases risk for glucose intolerance. It is unknown whether the use of PIs in pregnancy will exacerbate risk for development of gestational diabetes. Women receiving PIs in pregnancy should have their glucose levels monitored closely.

General Principles for Antiretroviral Treatment in Pregnancy (CDC, 2000)

• Decisions regarding initiation or alteration of antiretroviral therapy should be the same in pregnant and nonpregnant women, with the additional considerations outlined above.
  
• Monitor CD4 count/viral load according to guidelines for nonpregnant adults: in pregnancy, this should be done approximately each trimester, but may be needed more frequently with failing or altered therapy. CD4 percentage may be a more accurate reflection of immune status during pregnancy than absolute CD4 cell count, because of possible variation in absolute CD4 count secondary to dilutional effects associated with hemody-namic changes in pregnancy.
  
• The three-part ZDV chemoprophylaxis regimen (Table 7-7) should be recommended for all HIV-infected pregnant women to reduce the risk of peri-natal HIV transmission. Current clinical trial and epidemiologic data confirm the effectiveness of this regimen; furthermore, no other regimen studied to date in randomized clinical trials has shown superior results.
  

     In women already receiving antiretroviral therapy when they become pregnant and this regimen does not include zidovudine, ZDV should be added or substituted for another nucleoside analogue agent after 14 wk gestation. There is evidence that duration of prior ZDV therapy in women with more advanced disease may not reduce effectiveness of ZDV in decreasing perina-tal transmission (Stiehm, 1999). However, ZDV should not be substituted for another antiretroviral agent when this is likely to reduce the efficacy of this regimen in treatment of maternal disease, i.e., with previous clinical failure of ZDV or history of documented ZDV resistance.

     In some circumstances ZDV cannot be used during the antepartum period (e.g., intolerance to ZDV). Stavudine (d4T) and ZDV appear to be pharmacologically antagonistic and should not be used together; therefore, women on d4T-containing regimens with prior ZDV failure should be continued on the most effective regimen for their disease and ZDV should be excluded if d4T is maintained. ZDV administration is recommended during the intrapartum period and for the newborn regardless of the antepartum antiretroviral regimen.

     Women who present in labor with no prior antepartum antiretroviral therapy may be treated with one of several effective regimens, described below (Intrapartum) and in Table 7-8.

• Women with high CD4 counts and low or undetectable HIV-RNA levels, for whom initiation of antiretroviral therapy for the treatment of maternal infection would be considered optional, should be counseled about the potential benefits and risks of standard combination therapy and offered this therapy, along with the three-part ZDV perinatal pro-phylaxis regimen.

     Using ZDV alone is an option in this situation. This has the advantage of limiting exposure to other drugs during pregnancy but there are theoretical concerns about the selection of ZDV-resistant viral variants and limitation of future maternal therapeutic options, as well as increasing the risk for transmission. A recent study in women with moderately advanced HIV, many of whom had been treated with ZDV before pregnancy, found that maternal ZDV resistance was predictive of transmission (Welles, 2000). However, the development of resistance should be minimized by the relatively short duration of therapy and the more limited viral replication present in individuals with low HIV RNA level and high CD4 count. Follow-up of women enrolled in the PACTG 076 study has shown no significant differences in immunologic status or progression of disease (median follow-up 4.2 yr) in women who received ZDV compared with placebo recipients. (Bardeguez, 1998)

• In antiretroviral-naive patients clinicians may consider delaying initiation of ARV therapy until after 10–12 wk of gestation, based on considerations of the woman’s health status, the potential risk of delaying therapy for several weeks, and the potential benefits of avoiding first trimester drug exposure for the fetus.
  
• In antiretroviral-experienced patients, who become pregnant or are referred into prenatal care while receiving ARV therapy, therapy should be continued or modified, subject to the considerations outlined above. If pregnancy is recognized in the first trimester, some women and their clinicians may consider temporary discontinuation of therapy until after completion of the first trimester because of concerns about potential teratogenicity, or because of significant nausea and vomiting in early pregnancy leading to concerns about inadequate absorption of medications.
  

     Current data are insufficient to either support or refute fetal risk with early exposure to antiretroviral agents. Discontinuation of therapy may lead to viral rebound, which could theoretically increase risk of intrauterine HIV transmission or have an adverse effect on maternal disease. The woman’s clinical, immunologic, and virologic status should also be considered in decisions regarding continuation of therapy in the first trimester.

     If the decision is made to stop therapy temporarily, all agents should be stopped simultaneously and restarted simultaneously in the second trimester to avoid development of drug resistance.

• Decisions regarding use of ARV therapy during pregnancy should be made by the woman after detailed discussion of benefits and potential risks of therapy. This includes discussion of: 

• treatment recommendations for health of the HIV-infected woman, 
• current information regarding effectiveness of antiretroviral therapy in reducing perinatal transmission,
• known or potential effects of antiretroviral drug exposure on the fetus/newborn, and 
• the importance of adherence to any prescribed antiretroviral regimen.

     There continue to be missed opportunities in prevention of transmission of HIV from mother to child. HIV has to first be identified in the woman; situations where counseling and testing have not been available or not utilized because of lack of perception of risk on the part of the woman or her health care provider have been associated with perinatal transmission in some cases. Women who become infected or seroconvert during pregnancy may be missed unless HIV testing is repeated later in pregnancy. Lack of prenatal care and active substance abuse, which frequently coexist, have also been linked to potentially avoidable increased risk for transmission (Bardeguez, 2000).

Antiretroviral Pregnancy Registry

The Antiretroviral Pregnancy Registry is a collaborative effort between pharmaceutical companies, the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and obstetric and pediatric practitioners to collect observational information on antiretroviral exposure during pregnancy in order to assess potential fetal/infant anomalies after exposure to these agents. Patient names are not used and information is confidential. Health care providers who are treating HIV-infected pregnant women are strongly encouraged to report cases of prenatal exposure to antiretroviral drugs to the Registry: 1410 Commonwealth Drive, Wilmington, NC 28403; telephone (800) 258-4263; fax (800) 800-1052.

OPPORTUNISTIC INFECTION PROPHYLAXIS

Indications and recommendations for primary prophylaxis of opportunistic infections in pregnancy are noted in Table 7-9. Once an individual has had the following infections, prophylaxis to prevent recurrence is recommended as standard of care for the life of the individual. (See Chapter IV on Primary Medical Care.) First-choice regimens are outlined.

• Pneumocystis carinii pneumonia: same regimen as for primary prophylaxis.
  
• Toxoplasmic encephalitis: sulfadiazine 500–1000 mg po qid plus pyrimethamine 25–75 mg po qd plus leucovorin 10–25 mg po qd; counsel regarding concerns about potential teratogenicity of pyrimethamine and benefits of life-long therapy.
  
• Disseminated Mycobacterium avium complex: azithromycin 500 mg po qd plus ethambutol 15 mg/kg po qd
  
• CMV: choice of agents should be individualized in pregnancy after consultation with experts; discontinuation of maintenance therapy with history of CMV retinitis may be considered with sustained (> 3–6 mo) elevation of CD4 count above 100–150/mm³ and durable suppression of plasma HIV-RNA levels. Ophthalmologic consultation is recommended if discontinuation of secondary prophylaxis is considered.
  
• Histoplasmosis: amphotericin B 1.0 mg/kg iv qw; may be preferred, particularly during the first trimester, because of craniofacial and skeletal abnormalities in infants after prolonged in utero exposure to fluconazole.
  
• Crytococcosis: amphotericin B 0.6–1.0 mg/kg iv qw-tiw; may be preferred, particularly during the first trimester, because of craniofacial and skeletal abnormalities in infants after prolonged in utero exposure to flu-conazole.
  
• Coccidiomycosis: same regimen as for histoplasmosis.
  

IMMUNIZATIONS (ACOG, 1991; CDC, 1993, 1999)

Immunization should be considered in pregnancy when the risk for exposure is high, risk of infection for mother or fetus is high, and the vaccine is thought unlikely to cause harm. HIV-infected individuals should avoid live virus or live bacteria vaccines. HIV-positive persons who are symptomatic or have low CD4 cell counts may have suboptimal responses to vaccination. Some, but not all, studies have shown a transient (< 4 wk) increase in viral load after immunization. This is of some theoretical concern, given the association between viral load and perinatal transmission. This increase in viremia may be prevented with appropriate antiretroviral therapy (Bartlett, 1999). For this reason, clinicians may consider deferring routine vaccination until after the patient is on an effective antiretroviral regimen and avoiding administration late in pregnancy, close to delivery, when most transmission is thought to occur.

     Current immunization recommendations for HIV-positive pregnant women are:

• pneumococcal vaccine — “generally recommended”
  
• influenza vaccine — “generally recommended”; administer before flu season
  
• tetanus-diphtheria (Td) vaccine — booster dose every 10 yr after completion of primary series
  
• hepatitis B vaccine — “generally recommended” for all susceptible (anti-HBc-negative) patients; three doses at 0, 1, 6 mo
  
• hepatitis A vaccine — “generally recommended” for all susceptible (anti-HAV-negative) patients with chronic hepatitis C ; also indicated before travel to endemic areas, in injection drug users, and with community outbreaks; two doses at 0, 6 mo
  
• enhanced potency inactivated polio vaccine — use if not previously immunized and traveling to areas where risk for exposure is high; oral polio vaccine is a live virus vaccine and is contraindicated in HIV-positive persons
  
• immune globulins

• immune globulin recommended for measles exposure in symptomatic HIV-positive persons and hepatitis A with exposure to HAV in close contact/sex partner or travel to underdeveloped country (especially in patients with advanced HIV, who may have poor antibody response to vaccine)
• hyperimmune globulins recommended:
  • varicella-zoster virus (VZV) immune globulin-susceptible adult (undetectable antibodies to VZV) after significant exposure (household, hospital room, close indoor contact > 1 hr, prolonged face-to-face contact) to chickenpox or VZV; give within 96 hr of exposure
  • hepatitis B immune globulin (HBIG)-needlestick or sexual contact with HBsAg+ person in susceptible individual (anti-HBc-negative); HBIG should be given and HBV vaccine series should be started within 14 days of exposure.
    

REDUCTION OF SECONDARY RISK FACTORS

Treatment of STDs or other coinfections; encouragement of safer sexual practices during pregnancy; discouragement of smoking and drug use; and substance abuse treatment should be employed as measures that may decrease risk of perinatal transmission.

FREQUENCY OF VISITS

Determined on an individual basis, based on gestational age, health of the mother, presence of pregnancy-related complications, antiretroviral regimen and response, and psychosocial needs. In uncomplicated pregnancies visits generally are scheduled monthly in early pregnancy and every 1–2 wk from 28–30 wk of gestation until delivery.

COUNSELING AND SUPPORT

• Support systems: At the initial visit the health care provider should assess the patient’s support system — who knows her HIV status, problems encountered with disclosure, family and/or friends to whom she turns for ongoing support, barriers to disclosure to sexual or needle-sharing partners. These issues should be readdressed at intervals throughout pregnancy as needed. The use of peer counselors may be especially helpful.
  
• Contraception use postpartum: Discussion about postpartum contracep-
  

tive plans should be initiated in early to midpregnancy to allow comprehensive education and counseling about available options and adequate time for informed decision making.

• Condom use during pregnancy: Sexual activity should be reviewed at each visit and condom use reinforced.
  
• Drug use/treatment: History of and/or ongoing substance abuse, including tobacco and alcohol, as well as illicit drugs, should be assessed at the initial visit and at intervals during prenatal care, if indicated. Type of substance(s), amount of use, route of administration, and prior drug or alcohol treatment should be documented. The patient should be counseled about specific risks associated with substance abuse in pregnancy (see Chapter X on Substance Abuse) and drug or alcohol treatment during pregnancy should be encouraged and facilitated for active problems.
  
• Adherence: Each patient should be educated and counseled about the importance of adherence to prescribed medications, particularly antiretrovi-ral drugs, before they are initiated and medication adherence should be assessed and reinforced at each visit. (See Chapter V on Adherence.)
  
• Clinical trials: Pregnant HIV-positive women should be informed about the availability of and offered participation in clinical trials for which they are eligible.
  
• Advance directives: The issue of advance directives for care in the event of sudden deterioration in the woman’s health, as well as guardianship plans for children in the event of the mother’s incapacitation or death, should be discussed; legal assistance should be facilitated, if needed.
  

XI. INTRAPARTUM

A. UNIVERSAL PRECAUTIONS

Gowns, gloves, and eye protection should be used in all deliveries and in examinations or procedures likely to generate splashing blood or amniotic fluid. (See Chapter XIII on Occupational Exposure.)

B. FETAL/MATERNAL MONITORING

External fetal monitoring should be employed but avoid use of fetal scalp electrodes or fetal scalp sampling. Avoid artificial rupture of membranes if possible.

C. MODE OF DELIVERY

Based on data showing a reduction in perinatal HIV transmission (in addition to that seen with ZDV prophylaxis alone) with scheduled cesarean section (see above), all HIV-infected pregnant women should be counseled about the possible benefit vs. risk of scheduled cesarean section and the limitations of current studies. Infants born to mothers with high plasma viral loads benefit most from planned Cesarean delivery. Data are insufficient to demonstrate benefit in women with very low or undetectable viral loads and/or women receiving HAART therapy. There is no evidence that performing cesarean section after onset of labor or ruptured membranes reduces transmission rate; this needs further study given the recent data about duration of ruptured membranes and increasing risk of transmission. Women should be informed that no therapy or combination of therapies can guarantee an uninfected infant.

     Ultimate decisions about the route of delivery must be individualized and the woman’s autonomy must be respected. If scheduled cesarean section is planned, best clinical estimates of gestational age should be used and scheduling is recommended at 38 completed weeks of gestation to minimize the likelihood of labor and membrane rupture (ACOG, 2000).

D. INTRAPARTUM ARV PROPHYLAXIS

Women who have been on an appropriate antiretroviral regimen during the course of pregnancy should receive ZDV in labor: 2 mg/kg ZDV in a 1 hr IV loading dose, followed by 1 mg/kg/hr by IV infusion. If scheduled cesarean section is planned, ZDV infusion should be begun 3 hr preoperatively to achieve adequate blood levels.

     For women who present in labor with no prior antiretroviral therapy, several effective regimens are available. (Guay, 1999; Perinatal HIV Guidelines Working Group, 2000; Wade, 1998) These are outlined in Table 7-8.

     Women of unknown HIV status who present in labor with no prenatal care may be offered rapid HIV testing, after careful counseling and with informed consent. Positive results should be confirmed by standard serologic testing but enable the initiation of an appropriate antiretroviral regimen to reduce the risk of perinatal transmission.

E. ANTIBIOTIC PROPHYLAXIS

Data are limited on the relationship between HIV infection and incidence of peripartum (e.g., chorioamnionitis, postpartum endometritis) infections. Results of histologic placental studies are conflicting but more recent studies do not suggest an increased risk of chorioamnionitis in HIV-positive pregnancies (Hofman, 1998; Ladner, 1998). Several earlier studies (Gichangi, 1993) found an increase in histologic chorioamnionitis in HIV-positive pregnancies, particularly in those with preterm deliveries (Gichangi, 1993; Kumar, 1995). Maternal HIV infection has been associated with an increased risk of postpartum endometritis, particularly in more immunosuppressed women (Temmerman, 1994); furthermore, some studies have shown an increase in post-cesarean section infectious morbidity in HIV-positive women, correlated with lower CD4 counts (Maiques-Montesinos, 1999; Semprini, 1995), compared with HIV-negative controls. A recent analysis of complications according to mode of delivery among 497 HIV-positive women with CD4 < 500/mm³ found peripartum infectious complications were common and were seen more frequently in women delivered by cesarean section compared with vaginal delivery; however, rates of complications were not significantly different from those found in similar HIV-uninfected women; in this study peripartum antibiotic prophylaxis was given in approximately three quarters of patients undergoing cesarean section and in approximately one third of those with vaginal delivery (Watts, 2000). An analysis of almost 1200 women in the Women and Infants Transmission Study found an increased rate of postpartum fever without documented source of infection in women who had elective cesarean section vs. spontaneous vaginal delivery (Read, 2000). Increased rates of infectious complications may be related to confounding factors, such as poor nutritional status, substance abuse, or prevalence of genital tract infections, rather than to the presence of HIV infection (Hanna, 1997). Complications, particularly infection-related, are approximately five- to sevenfold more common among all women undergoing cesarean section after labor or membrane rupture compared with vaginal delivery (Hebert, 1999; Nielson, 1983).

     There are currently no data on the role of prophylactic peripartum antibiotics in reducing risk of infectious morbidity for HIV-positive women. However, because of the concerns about possible increased risk of post-cesarean infections in HIV-positive patients, prophylactic antibiotics are recommended at the time of scheduled cesarean section.

F. VAGINAL CLEANSING

A promising potential intervention to reduce transmission at the time of vaginal delivery is vaginal cleansing to decrease neonatal exposure to maternal blood and genital secretions. A clinical trial of 0.25% chlorhexidine manual vaginal cleansing on admission and every 4 hr until delivery had no significant impact on HIV transmission, except when membranes had been ruptured for more than 4 hr before delivery (Biggar, 1996). Further study is needed.

XII. POSTPARTUM

A. INFANT FEEDING

When safe alternatives are available, breast-feeding is discouraged because of documented risk for transmission from mother to infant.

B. ASSESS HEALING

Assess healing of wound sites, uterine involution, and appropriate cessation of postpartum bleeding

C. CARE FOR MOTHER AND INFANT

HIV-infected mothers may neglect their own care while trying to provide appropriate care for their infant and other children or family members. It is essential that she be linked with comprehensive medical and supportive care services, including HIV specialty care; primary medical and gynecologic care; mental health or substance abuse treatment services; and assistance with food, housing, transportation, and legal/advocacy services, if needed.

     Women who have received ZDV monotherapy during pregnancy should be reevaluated in the postpartum period with clinical assessment, CD4 count, and HIV RNA level to determine need for ongoing antiretroviral therapy. It is essential that access to and continuity of antiretroviral treatment as needed for maternal health be ensured.

     Similarly, the HIV-exposed infant should be linked into ongoing pediatric care, with HIV diagnostic tests as described below and appropriate HIV specialty care if HIV-infected.

D. CONTRACEPTION/CONDOM USE

Discussions about contraception and condom use should be continuous throughout pregnancy and reviewed and reinforced at the time of the post-partum visit.

E. LONG-TERM FOLLOW-UP OF MOTHER AND INFANT

All HIV-positive mothers and infants exposed to ZDV and/or other antiretro-viral drugs or combinations during pregnancy should have long-term follow-up to assess possible late effects of these therapies on HIV progression in the mother or neoplasia or organ-system toxicity in exposed children.

XIII. CARE OF THE HIV-EXPOSED INFANT (CDC, 2000)

A. DIAGNOSIS OF HIV

The standard for diagnosis of HIV infection in exposed infants is the use of viral assays (HIV DNA PCR (preferred), HIV RNA PCR, or viral culture) obtained within 48 hr of birth, at 1–2 mo, and 3–6 mo. HIV can be excluded with two or more negative tests, two of ^{which are performed at age} ³ ^{1 mo, and one performed at age} ³ ^{4 mo. HIV IgG antibody tests will generally be} positive in exposed infants up to 18 mo of age because of transplacental passage; ^{two negative tests performed at} ³ ^{6 mo and at least 1 mo apart will also} exclude infection in infants without clinical evidence of infection. P 24 antigen testing is less sensitive than other virologic tests and has a high frequency of false-positive results in infants < 1 mo of age.

     HIV DNA PCR is the preferred virologic assay for diagnosis with 93% (90% CI=76–97%) sensitivity by age 14 days. Data on use of HIV RNA PCR are more limited. HIV culture is sensitive for early diagnosis but is more complex, expensive, and has a longer turnaround time for results. Using these tests approximately 40% of infected infants can be identified by age 48 hr and are considered to have early or intrauterine infection; infants with initial negative testing during the first week of life and subsequent positive tests are considered to have intrapartum infection. Almost all infected infants can now be diagnosed by the age of 6 mo. ZDV monotherapy for perinatal prophylaxis has not been shown to delay detection of HIV or decrease sensitivity or predictive value of virologic assays (Connor, 1994; Kovacs, 1995), although performance of these tests when the mother has received more intensive combination antiretroviral therapies has not been studied.

B. ARV TREATMENT

All HIV-exposed infants should receive ZDV prophylaxis (2 mg/kg every 6 hr) for the first 6 wk of life as part of the three-part zidovudine regimen to prevent perinatal HIV transmission. If the mother has received no antepartum or intrapartum ZDV, the newborn regimen should be started as soon as possible after delivery, preferably with 12�24 hr of birth. Initiation of ZDV prophylaxis for the neonate within 48 hr of birth resulted in an approximately 50% decrease in infection compared with no therapy (Wade, 1998). When the mother has received no therapy, it is unknown whether combining newborn ZDV with administration of a single dose of nevirapine (2 mg/kg) to the infant as soon as possible after birth, or the use of nevirapine alone (particularly when there are concerns about the infant care provider�s ability or willingness to administer ZDV for 6 wk) will be as effective or more effective than zidovudine only. This approach has some theoretical attractiveness, because nevirapine can decrease plasma HIV-1 RNA concentration by over 1 log by 7 days after a single dose, is active immediately against both intracellular and extracellular virus, and has prolonged elimination in infants. Another theoretical benefit with combining ZDV and nevirapine includes potential efficacy in the presence of virus that is resistant to either drug.

Once infection is documented, more intensive combination antiretroviral therapy is recommended with clinical symptoms of HIV infection or evidence of immunesuppression (immune categories 2 or 3 � Table 7- 10) regardless of age or viral load. Some experts recommend initiating potent ART as soon as the diagnosis is confirmed, regardless of clinical or immunologic status or viral load because HIV-infected infants under the age of 12 mo are considered to be at high risk for disease progression and the prognostic value of standard virologic or immunologic parameters is less than that for older children. Once HIV infection is confirmed, decisions about antiretroviral therapy should be made in consultation with a specialist in the treatment of pediatric HIV infection.

C. PNEUMOCYSTIS CARNII PNEUMONIA PROPHYLAXIS

All HIV-exposed infants should receive P. carnii pneumonia prophylaxis with trimethoprim-sulfamethoxazole (150/750 mg/m²/day in two divided doses po tiw on consecutive days) beginning at 4–6 wk and extending for the first year of life or until HIV infection is excluded. Dapsone or atovaquone are alternatives.

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