Pediatric Annals

HIV Infection in Pregnancy

Pamela J J Boyer, MD, PhD

Abstract

By January of 1993, an estimated 3 million women worldwide were infected with the human immunodeficiency virus (HIV).1 In the United States by December of 1991, more than 20 000 cases of acquired immunodeficiency syndrome (AIDS) in women had been reported to the Centers for Disease Control, accounting for 10.4% of the cumulative cases of AIDS in adults.2 More than 80% of the AIDS cases in women in the United States have occurred in women between the ages of 15 and 44.3 Recent changes in AIDS diagnostic criteria to include cervical cancer, recurrent pneumonia, and pulmonary tuberculosis as well as a CD4 + lymphocyte count <200 cells/mm3 will add many more women in their reproductive years to the number of reportable cases.

Since 1988, the increase in the incidence of AIDS in women has been greater than the increase in men, making women in their reproductive years the fastest growing HIV-infected population in the United States.4 Women of color have been affected disproportionately by the growing epidemic. By 1987, HIV disease was the leading cause of death for black women between the ages of 15 and 44 in New Jersey and New York.5 Nationwide, the death rate due to HIV disease was almost 10 times greater in black women than in white women of the same age group.6 Many of these women have and will become pregnant during the course of their HIV infection. Reproductive decisions have not been shown to be greatly altered by the awareness of HIV infection,5,7 and the children bom to these pregnancies are at risk for vertically acquired HIV infection.

MODE OF TRANSMISSION IN WOMEN

Worldwide, the primary mode of transmission of HIV infection to women in their reproductive years is heterosexual contact.8 In the United States, intravenous drug use has contributed significantly to the spread of HIV infection in reproductive-aged women. In 1990, the US Centers for Disease Control reported that 51% of the AIDS cases in women were associated with intravenous drug use, and 33% of the cases were attributed to sexual contact.9 More recent reports have demonstrated an increasing trend toward heterosexual contact as a primary mode of transmission.10,11 Projection studies also have predicted an increased incidence of HIV infection in the heterosexual, nonintravenous drug-using population.12,13 Prevalence studies of cord blood specimens have documented a substantial undiagnosed population of childbearing HIV-infected women across the United States.14

Parallel to the growing population of infected reproductive-age women is the growing number of HIV-infected children who have been infected by perinatal transmission. Initially, most cases of pediatric AIDS were transfusion-related. With improved blood product screening techniques, the number of transfusion-related cases has dropped dramatically while the total number of pediatric AIDS cases has steadily increased. This shift has been the result of the increasing incidence of perinatally acquired HIV infection.15,16 Currently, more than 80% of pediatric AIDS cases have acquired the infection from an infected mother.15 With an estimated perinatal transmission rate of 30% in the United States, the number of infected children can be expected to continue to increase over the next years.

GENDER-RELATED DIFFERENCES IN HIV DISEASE

Most of what is known about the natural history of HIV disease has been learned through studies of predominantly gay men. Few women participated in these studies or early trials of antiretroviral agents, which provided additional information. Even survival times after the diagnosis of AIDS in women is not clearly established. One study has shown no difference in survival rates between men and women,17 while similar studies have demonstrated shorter survival and more advanced disease at the time of diagnosis in women.18,19 Wasting syndrome, esophageal candidiasis,…

By January of 1993, an estimated 3 million women worldwide were infected with the human immunodeficiency virus (HIV).1 In the United States by December of 1991, more than 20 000 cases of acquired immunodeficiency syndrome (AIDS) in women had been reported to the Centers for Disease Control, accounting for 10.4% of the cumulative cases of AIDS in adults.2 More than 80% of the AIDS cases in women in the United States have occurred in women between the ages of 15 and 44.3 Recent changes in AIDS diagnostic criteria to include cervical cancer, recurrent pneumonia, and pulmonary tuberculosis as well as a CD4 + lymphocyte count <200 cells/mm3 will add many more women in their reproductive years to the number of reportable cases.

Since 1988, the increase in the incidence of AIDS in women has been greater than the increase in men, making women in their reproductive years the fastest growing HIV-infected population in the United States.4 Women of color have been affected disproportionately by the growing epidemic. By 1987, HIV disease was the leading cause of death for black women between the ages of 15 and 44 in New Jersey and New York.5 Nationwide, the death rate due to HIV disease was almost 10 times greater in black women than in white women of the same age group.6 Many of these women have and will become pregnant during the course of their HIV infection. Reproductive decisions have not been shown to be greatly altered by the awareness of HIV infection,5,7 and the children bom to these pregnancies are at risk for vertically acquired HIV infection.

MODE OF TRANSMISSION IN WOMEN

Worldwide, the primary mode of transmission of HIV infection to women in their reproductive years is heterosexual contact.8 In the United States, intravenous drug use has contributed significantly to the spread of HIV infection in reproductive-aged women. In 1990, the US Centers for Disease Control reported that 51% of the AIDS cases in women were associated with intravenous drug use, and 33% of the cases were attributed to sexual contact.9 More recent reports have demonstrated an increasing trend toward heterosexual contact as a primary mode of transmission.10,11 Projection studies also have predicted an increased incidence of HIV infection in the heterosexual, nonintravenous drug-using population.12,13 Prevalence studies of cord blood specimens have documented a substantial undiagnosed population of childbearing HIV-infected women across the United States.14

Parallel to the growing population of infected reproductive-age women is the growing number of HIV-infected children who have been infected by perinatal transmission. Initially, most cases of pediatric AIDS were transfusion-related. With improved blood product screening techniques, the number of transfusion-related cases has dropped dramatically while the total number of pediatric AIDS cases has steadily increased. This shift has been the result of the increasing incidence of perinatally acquired HIV infection.15,16 Currently, more than 80% of pediatric AIDS cases have acquired the infection from an infected mother.15 With an estimated perinatal transmission rate of 30% in the United States, the number of infected children can be expected to continue to increase over the next years.

GENDER-RELATED DIFFERENCES IN HIV DISEASE

Most of what is known about the natural history of HIV disease has been learned through studies of predominantly gay men. Few women participated in these studies or early trials of antiretroviral agents, which provided additional information. Even survival times after the diagnosis of AIDS in women is not clearly established. One study has shown no difference in survival rates between men and women,17 while similar studies have demonstrated shorter survival and more advanced disease at the time of diagnosis in women.18,19 Wasting syndrome, esophageal candidiasis, and herpes simplex viral disease have been reported to occur more frequently in women with AIDS,20'21 while Kaposi's sarcoma occurs less frequently in women than in men.22

Gynecologic disorders occur frequently in HIV-infected women. Recurrent vaginal candidiasis has been reported to be the most common initial opportunistic infection in HIV-infected women, while Pneumocystis carinii pneumonia has been the most common AIDS-defining event in women.20 Since January 1993, cervical cancer in HIV-infected women has been recognized as an AIDS-defining condition. Cervical cancer, often associated with human papillomavirus infection, appears to have an accelerated course in the HIV-infected woman.23 Both decreased survival times after diagnosis and decreased time to recurrence of clinical disease after treatment have been reported in HIV-infected women.24 Gynecologic infections, such as human papilloma virus infection, genital herpes, chlamydia, vaginal candidiasis, and pelvic inflammatory disease, have been reported to be more common among HIV-infected women and may impact negatively on pregnancy outcome.25'27

EFFECT OF PREGNANCY ON DISEASE PROGRESSION

Early studies suggested that HIV-infected women who had given birth to infected infants experienced a more rapid progression to the onset of AIDS.28,29 Although most of these women had been asymptomatic during pregnancy, about a 50% progression to AIDS occurs within a few years of the pregnancy. In comparison, the rate of progression to AIDS in HIV-infected homosexual men had been reported to be 2% to 5% per year,29 suggesting an accelerated course to progression in HIV-infected pregnant women. These studies, however, were limited by a lack of information about the duration of infection prior to pregnancy and lack of correlation with CD4 + counts. A more recent prospective study of progression in HIV-infected pregnant women has shown a progression of 4% per year in asymptomatic pregnant women and a 16% progression per year in pregnant women with lymphadenopathy.30 Other studies have shown no significant difference in disease progression in HIV-infected women who experienced a pregnancy after infection and in those who did not become pregnant.31'33

Although these studies suggest that the impact of an intervening pregnancy is not as ominous as originally thought on disease progression, the issue is unresolved. In noninfected pregnant women, CD4 + counts decrease in the third trimester and rebound to prepregnancy levels after delivery.34 Biggar et al35 have reported a similar decrease in CD4 + counts in the third trimester in HIV-infected pregnant women that, unlike the decrease in noninfected women, did not recover in the postpartum period and remained decreased over the period of observation. This failure to recover to prepregnancy levels also has been observed by Plaeger-Marshall et al.36 Although the clinical impact of this observation is unknown, decreased CD4+ counts have been well-demonstrated to be associated with increased risk for disease progression and opportunistic infections.

EFFECT OF HIV DISEASE ON OBSTETRIC OUTCOME

Early studies on the effect of HIV infection on pregnancy outcome suggested an increased incidence of intrauterine growth retardation, preterm birth, preterm rupture of membranes, and other adverse outcomes. These studies, however, were conducted on populations with high incidences of these outcomes and were not controlled for factors such as maternal substance abuse, poor nutrition, concurrent infections, inadequate access to health care, and maternal socioeconomic status, all of which have been associated with poor obstetrical outcome.

More recent controlled studies have shown no significant differences in pregnancy outcome in asymptomatic HIV-infected women when compared with noninfected women.37,38 Minkoff et al39 found no differences in birthweight, gestational age, or other indices of pregnancy outcome when studying comparable groups of asymptomatic HIV-infected women and noninfected women. Drug, alcohol, and tobacco abuse were found to be greater predictors of poor pregnancy outcome than HIV infection.

A recent study has reported decreased birthweights in HIV-infected infants born to HIV-infected mothers when compared to infants born to non-HIV- infected mothers and seroreverting noninfected infants born to infected mothers.40 Other studies in the United States and Europe have failed to observe this finding.41-42

While the prognosis for pregnancy in HIV-infected asymptomatic women is generally favorable, pregnancy after the diagnosis of AIDS has been associated with frequent obstetric and medical complications, including death.27,31 Preterm delivery occurs most commonly, secondary to maternal deterioration. Pneumocystis carimi pneumonia has been the most frequent cause of death during pregnancy.43 Although obstetric outcomes have been poor, Johnstone et al have reported that maternal survival times do not appear to have been adversely affected by the pregnancy.31

PERINATAL TRANSMISSION OF HIV TO INFANTS OF INFECTED MOTHERS

Vertical transmission of HIV was reported by the Centers for Disease Control as early as 1982.44 Subsequent work has established that transmission of HIV may occur in the antepartum, intrapartum, or postpartum periods. Human immunodeficiency virus has been demonstrated in placental tissue as early as 8 weeks' gestation.45 Other studies of HIV-infected fetal tissue suggest that transmission may occur at various times during intrauterine life.46 It has been postulated that early intrauterine infection is associated with early identification of virus in the infant's peripheral blood lymphocytes and with early onset of symptoms of HlV infection, usually within the first 1 2 months of life.47

A bimodal expression of the onset of clinical and laboratory evidence of HIV infection in infants has lent support for intrapartum as well as intrauterine transmission of HIV. Infants with late onset of disease and late viral identification are believed to have acquired the infection in the intrapartum period. Although virus has been isolated from maternal blood and vaginal secretions,48 there is no evidence that the mode of delivery, either vaginally or by caesarean section, influences its transmission.42,43'49 Current guidelines from the American College of Obstetrics and Gynecology on the delivery of HIV-infected women recommend that caesarean section be performed only for the standard obstetric indications.50 At present, the mechanisms of both antepartum and intrapartum HIV transmission are not well understood. Discordant transmission in twin gestations resulting in one infected and one noninfected twin has been reported by a number of researchers.51'53 Data from an international registry of HIV-exposed twins have shown a greater risk of infection for the firstborn twin, regardless of the mode of delivery.54 Such observations are difficult to explain with available information on the possible mechanisms of transmission.

Various studies have reported vertical transmission rates between 11% and 65% with less recent studies and African studies reporting higher rates.43,55,56 Recent studies in the United States and Europe have reported transmission rates of approximately 30%.56 African studies consistently have reported higher transmission rates than studies done in the United States or Europe. These differences may reflect more advanced maternal disease or as yet undefined transmission promoting factors, such as concurrent disease in the African populations under study.

Maternal factors that may contribute to an increased risk for perinatal transmission are only partly known. Several studies have reported that advanced maternal disease may increase the risk of perinatal transmission.46,57,58 Lallemont et al recently reponed that women with AIDS have a two-and-a-half fold greater risk of transmitting HIV to their infants than HIV-infected women who have not progressed to AIDS.57 Low maternal CD4 + counts also have been associated with an increased risk of perinatal transmission.59 Consistent with these findings are reports that HIVinfected pregnant women with high titers of HIV or high levels of p24 antigenemia are at increased risk for transmission. One group of researchers reported 100% transmission in one study of p24 antigen-positive pregnant women.60 Preterm delivery also has been reported to predispose the infant to transmission.61 In contrast, the presence of high maternal antibody titers to the gpl20 envelope protein may decrease transmission.61,62 Further investigation of predictive risk factors for transmission are needed to provide more accurate counseling to HIV-infected women and to identify the fetus at high risk for transmission.

Postpartum transmission of HIV to a previously uninfected newborn has been associated with breastfeeding. Human immunodeficiency virus has been demonstrated in colostrum and in breast milk, particularly the cellular component of breast milk.63 Transmission of HIV infection from breast-feeding was first reported in 1985 and has been documented subsequently.64,65 Although prohibition of breast-feeding is not feasible in areas of the world where safe alternatives are unavailable, the US Public Health Service recommends that HIV-infected women in the United States not breast-feed their infants.66

ANTEPARTUM AND INTRAPARTUM CARE

The first challenge in providing adequate prenatal care and counseling to HIV-infected pregnant women is identifying those women who are infected with HIV. Many women in their reproductive years do not have regular medical care, and only seek medical attention in the event of symptoms or pregnancy. For this reason, many HIV-infected women are first diagnosed when pregnant. Since 1985, the Centers for Disease Control has recommended HlV testing for pregnant women in high-risk categories, such as intravenous drug users, sexual partners of intravenous drug users, hemophiliacs, and bisexual men and women who received blood transfusions between 1979 and 1985. These guidelines for screening have proven to be inadequate and have failed to identify as many as 70% of HIV-infected pregnant women.67 Nondrug-using heterosexual women are frequently unaware of their sexual partners' HIV status or risk behaviors due to nondisclosure by their partners. Frequent nondisclosure to sexual partners has been reported in surveys of HIV-infected individuals. As a result of these observations, many workers recommend that all pregnant women be offered screening and counseling for HIV, regardless of known risk factors on presentation for prenatal care. Pregnant patients found to be HIV positive should be provided with compassionate counseling and assistance in obtaining further medical care and psychosocial support.

At initiation of prenatal care, all HIV-positive pregnant women should undergo a thorough history and physical examination and be screened for other infectious diseases including tuberculosis, syphilis, hepatitis, chlamydia, genital herpes, human papilloma virus, cytomegalovirus, and candidiasis. A Pap smear should be obtained, and any cytologic abnormalities should be investigated colposcopically. Nutritional counseling and psychosocial support should be provided. Invasive procedures such as amniocentesis, chorionic villus sampling, percutaneous umbilical blood sampling, and fetal scalp electrodes and fetal scalp sampling in labor should be avoided whenever possible.

Absolute CD4 + counts should be followed monthly throughout the pregnancy. Antiretroviral therapy and PCP prophylaxis should be initiated when indicated by maternal condition. Acknowledging the lifethreatening potential of maternal HIV disease, the American College of Obstetrics and Gynecology recommends that standard antiretroviral therapy and PCP prophylaxis be given to women with CD4 + counts <200 and that antiretroviral therapy be considered in pregnant patients with CD4 + counts between 200 and 500. A recently completed phase I trial of zidovudine (ZDV, formerly AZT) in HIVinfected pregnant women, conducted under the auspices of the AIDS Clinical Trial Group, has shown the drug to be well-tolerated in pregnancy and safe in short-term follow-up of both the women and their infants. Although long-term follow-up is not yet available, these findings support the use of zidovudine for maternal indications during pregnancy. Of great additional interest is the possibility that zidovudine, administered antenatally, may prevent or decrease perinatal transmission. A multicenter trial is currently underway to evaluate the efficacy of zidovudine in this capacity.

Much remains to be done to identify and provide adequate care to the HIV-infected pregnant woman and her unborn infant. Our knowledge of the impact of this disease on pregnancy and of pregnancy on the course of disease is only beginning. Perinatal transmission interventions may provide a unique opportunity to prevent a currently incurable disease in the pediatric population.

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