Human immunodeficiency virus infection in pregnancy

Human Immunodeficiency Virus Infection in Pregnancy Howard L. Minkoff

The pace at which our knowledge and treatment o f the human immunodeficiency virus (H1V) has advanced has been staggering. A disease that was unknown two decades ago, that was untreatable only a decade ago, and whose rate o f mother-to-child t r a n s m i ~ i o n was immutable just 5 years ago, is now readily diagnosed, treated with increasing effectiveness, and blocked from transmi~ion in the large majority o f cases. N o n e o f these advances can be provided to patients unless their physicians actively screen patients and, for those identified as HIV infected, assure them o f access to the latest therapies. This article is a p r i m e r for those obstetricians who would engage in such efforts. The data that form the basis o f therapy are provided as well as clinical guidelines for the care o f the pregnant woman infected with H1V. Copyright 9 1 9 9 8 by W.B. S a u n t e r s Company

he last several years have b o r n e witness to

T a p a r a d i g m shift in the care of p r e g n a n t

w o m e n infected with h u m a n immunodeficiency virus (HIV). Therapies that can dramatically reduce transmission of the virus to children and substantially improve the prognosis of w o m e n are now readily available in the United States. However, this powerful new therapeutic armam e n t a r i u m is comprised of diagnostic and treatm e n t regimens that are increasingly complex. Public health agencies and professional organizations have stressed the i m p o r t a n t role obstetricians should play in identifying and caring for seropositive women. Therefore, to assure their patients the best possible outcomes, obstetricians must stay abreast of the rapidly e x p a n d i n g list of diagnostic and therapeutic tools. An understanding of the newest t r e a t m e n t strategies requires a basic familiarity with current concepts of HIV pathogenesis. This r e p o r t provides an introductory treatise on virology and pathophysiology on which will be built strategies for the obstetric care and antiretroviral therapy of HIVinfected p r e g n a n t women.

Epidemiology

By the end of 1995, 71,818 cases of acquired i m m u n o d e f i c i e n c y syndrome (AIDS) occurring a m o n g adolescent and adult w o m e n had b e e n r e p o r t e d to the Centers for Disease Control (CDC), 13,764 of which were r e p o r t e d in 1995.1 It is estimated that between 107,000 and 150,000 US w o m e n currently are living with HIV. In 1995

w o m e n accounted for 19% of AIDS cases in adults, up f r o m 7% (534 of 8,153) in 1984. T h e greatest increases in AIDS incidence rates were in heterosexually infected w o m e n b o r n between 1970 and 1974, ie, w o m e n who were 14- to 18years-old in 1988. 2 Although the annual HIV incidence a m o n g w o m e n and minorities is remaining relatively constant, ~ trends vary across the country. In New York State, for example, there is some evidence that the n u m b e r of pregnancies to infected w o m e n is declining, whereas in some parts of the South the n u m b e r of infected w o m e n continues to rise. T h e w o m e n at greatest risk in the United States are w o m e n of color, w o m e n in relationships with users of injectable drugs, and w o m e n of younger ages. T h e rate of increase in AIDS cases a m o n g w o m e n between 1990 and 1994 (89%) was m o r e than three times the increase r e p o r t e d a m o n g m e n (29%), and the male to female ratio of AIDS incidence decreased f r o m 7.5:1 in 1990 to 5.1:1 in 1994/ By 1995, HIV infection had bec o m e the third leading cause of death a m o n g all US w o m e n aged 25 to 44 years and the leading cause of death a m o n g African American w o m e n of this age group, as well as a m o n g all reproductive-age w o m e n in some u r b a n centers. 4 From the Department of Obstetrics and Gynecology, SUNY Health Science Center at Brooklyn, Maimonides Medical Center, Brooklyn, ~ 1 ~.

Address reprint requests to Howard L. Minkoff MD, Department of Obstetric.sand Gynecology,Maimonides Medical Center, 96748th St, Brooklyn, NY 11219. Co/o'right 9 1998 t9' W.B. Saunders Company 0146-0005/98/2204-0008508. 00/0

Seminars in Perinatology, Vol 22, No 4 (August), 1998: pp 293-308

293

294

Howard L. Minkoff

In addition to g e n d e r shifts, the ethnic profile of the HIV epidemic is also evolving. 5 Between 1990 and 1994, AIDS incidence a m o n g AfricanAmerican w o m e n doubled, with 1994 rates double those of Hispanic w o m e n a n d 17 times those a m o n g white women. 6 By 1995, the racial-ethnic distribution of r e p o r t e d AIDS cases was 22.6% white women, 55.8% black women, and 20.7% Hispanic women. AIDS incidence rates p e r 100,000 w o m e n in 1995 were 3.8 a m o n g white women, 59.2 a m o n g black women, and 61.9 a m o n g Hispanic women. 1 T h e majority of new cases of AIDS a m o n g w o m e n are r e p o r t e d a m o n g those 20 to 29 years o f age, indicating that their HIV infection was probably acquired by late adolescence. Increasingly, w o m e n are acquiring H I V heterosexually, with cases attributable to that m o d e of acquisition growing by 146% in 1994, as comp a r e d with a 59% growth in AIDS incidence a m o n g w o m e n who use injectable drugs. 3 T h e risk g r o u p assignation of w o m e n with AIDS diagnosed in 1995, which would reflect HIV acquisition in the mid 1980s, was 36% injection drug users, 47% heterosexual contact with either a drug user or a bisexual man, a n d 15% w o m e n who either d i d n ' t r e p o r t or c o u l d n ' t identify their exposure category. T h e HIV seroprevalence a m o n g p r e g n a n t w o m e n in 1991, as d e t e r m i n e d by a n o n y m o u s heel stick data, was 1.5 per 1,000 child-bearing w o m e n in the United States. T h e highest rates were seen a m o n g w o m e n delivering in the Northeast, and the lowest rates were n o t e d in the Midwest. 7 Based on c o m b i n e d metropolitan national data surveys f r o m 1992 and back calculation data, HIV seroprevalence rates a m o n g all w o m e n in the United States were estimated to be 1.1 to 1.4 per 1,000 w o m e n ] T h e majority of cases of pediatric AIDS are secondary to vertical transmission of HIV f r o m m o t h e r to fetus. H1V infection is now a m o n g the 10 leading causes of death a m o n g children aged 1 to 4. s As of 1990, estimates of the n u m b e r of children with HIV infection in the United States r a n g e d f r o m 5,000 to 10,000. 9 T h e World Health Organization (WHO) estimates that there is a 30% excess infant and child mortality rate in m a j o r United States, Western European, and sub-Saharan African cities where AIDS has b e c o m e the leading cause of death for w o m e n aged 20 to 40 years, a~

Virology and Pathogenesis H1V is one of five known h u m a n retroviruses. These organisms are single-stranded RNA-envel o p e d viruses that have the ability to b e c o m e inc o r p o r a t e d into cellular DNA. HIV-1, which used to be called h u m a n T cell lymphotrophic virus III (HTLV-III), has a d i a m e t e r of a b o u t 100 nm. T h e o t h e r retroviruses, all of which are significantly less c o m m o n than HTLV-III, are HTLV-I, which causes adult T cell leukemia-lymphoma and tropical spastic paraparesis; HTLV-II, which causes hairy cell leukemia; HTLV-IV (also called HIV-2), which causes AIDS; a n d HTLV-V, which causes cutaneous T cell lymphoma-leukemia. HIV can be reverse transcribed into DNA and i n c o r p o r a t e d into the host g e n o m e . It is composed o f core (p18, p24, and p27) and surface (gp120 and gp41) proteins, genomic RNA, and the reverse transcriptase enzyme s u r r o u n d e d by a lipid bilayer envelope. T h e virion contains three structural genes (gag, pol, a n d env), and a c o m p l e x set of regulatory genes, including tat, v/f nef, vpu, and ref, that control the rate ofvirion production. It preferentially infects cells with the C D 4 + antigen, particularly helper lymphocytes, but also macrophages, cells of the central nervous system, and cells of the placenta. 11 Recent research has shown that at least two o t h e r cell surface molecules help HIV enter cells. These coreceptors for HIV, called CXCR4 a n d CCR5 are receptors for chemokines, a2 It has also b e e n discovered recently that individuals who are homozygous for a deletion at the CCR5 gene are less likely to acquire HIV, whereas deletion heterozygotes progress less rapidly if infected. HIV infection leads to progressive debilitation of the i m m u n e system, rendering the individual susceptible to opportunistic infections (eg, Pneumocystis ca~inii p n e u m o n i a and central nervous system toxoplasmosis) and neoplasias (eg, Kaposi's sarcoma) that rarely afflict patients with intact imm u n e systems. An HIV-infected patient with one of several specific opportunistic infections, neoplasia, dementia encephalopathy, or wasting syndrome receives the diagnosis of AIDS. The diagnosis of AIDS can also be made in the absence of laboratory evidence of infection if the patient has no other known cause of i m m u n e deficiency and has the definitive diagnosis of one of a n u m b e r of indicator diseases. 13 In 1993 the CDC changed the case definition to include all individuals with HIV

HIV and Pregnancy

infection whose CD4 counts drop below 200 CD4 lymphocytes/mm 3 as well as HIV-infected individuals with advanced cervical cancer, pulmonary tuberculosis, and recurrent pneumonia. 14 At the time of initial infection, an individual may be asymptomatic or may acquire an acute mononucleosislike syndrome that can be accompanied by aseptic meningitis. Recent studies have shown that there is an immediate viremia o f substantive proportions (up to 10 billion viral particles turned over per day) and an equally impressive i m m u n e responsive with similar levels of T cell turnover. 15'16 After the initial viremia, the level o f virus will return to a "set point." T h e level o f virus in the plasma at that time can provide an estimate of the probability that AIDS will develop in an individual within 5 years. Antibodies are usually detectable 1 m o n t h after infection a n d are almost always detectable within 3 months. After seroconversion has occurred, an asymptomatic period of variable length usually follows. T h e m e d i a n clinical latency is estimated at approximately 11 years. 17 Very few infected persons ( < 5 % ) acquire AIDS within 3 years. TM Evidence of i m m u n e dysfunction may be followed by clinical conditions ranging f r o m fever, weight loss, malaise, lymphadenopathy, and central nervous system dysfunction to infections such as herpes simplex virus or oral candidiasis. These nonspecific conditions are usually progressive and are a prelude to an opportunistic infection that is diagnostic o f AIDS. Studies o f infected individuals have n o t e d that 5 years after infection was confirmed, up to 35% had progressed t o A I D S . 19'20'21 A study of subjects with h e m o p h i l i a d e m o n s t r a t e d that the incidence rate of AIDS after seroconversion was 2.67 p e r 100 person-years and was directly related to age (AIDS developed in younger individuals at a slower rate). 19 It should be n o t e d that all these statistics antedate the use of new, m o r e powerful antiretroviral agents that have already b e e n shown to have a significant effect on surrogate markers of disease progression. O n c e AIDS is diagnosed, the short-term prognosis is m u c h better than it was in the past, although the long-term prognosis remains poor. T h e effect that the newest antiretrovirals, including protease inhibitors, will have on survival cannot yet be clearly gauged but do provide reason for cautious optimism. Most data on the natural history o f HIV disease predate the newer thera-

295

pies and are based on studies of men. T h e cumulative probability of survival in m e n has b e e n estimated at 49% at 1 year after diagnosis and only 15% after 5 years. 22 In o n e study of 4,323 patients, the median r e p o r t e d survival time after diagnosis was 12.5 months, with a 5-year survival rate of 3 . 4 % . 17 T h e time of initial diagnosis, age of the patient, and use of zidovudine (Retrovir; formerly called azidothymidine, or AZT), the only antiretroviral available at the time, were significant predictors of survival. Those with P carinil p n e u m o n i a survived longer than those with Kaposi's sarcoma. At the current time there is no convincing evidence the natural history o f HIV infection is influenced by gender.

AIDS in Pregnancy Prenatal HIV Testing Tests for detection of the antibody to HIV became available for clinical use in the United States in 1985. T h e two m e t h o d s most frequently used remain (1) enzyme-linked i m m u n o s o r b e n t assay (ELISA) for initial screening and, (2) Western blot for confirmation. These tests all use antigens derived f r o m disrupted whole virus. T h e published sensitivity and specificity of the combined tests are a b o u t 99%. Serum samples are first tested and c o n f i r m e d by the ELISA technique, which d e p e n d s on a colorimetric change mediated by an antigen-antibody reaction. T h e Western Blot test is perf o r m e d if the ELISA is repeatedly positive. T h e Western Blot identifies antibodies against specific portions o f the virus. T h e Western Blot is considered positive if the patient has antibody to multiple virus-specific b a n d s - - p 2 4 , p31, a n d either gp41 or gpl60. If fewer bands are identified, the test is called indeterminate. A small n u m b e r (15% to 20%) of tests from low-risk patients will be indeterminate and remain so even if repeated over m a n y months. Individuals recently infected may also have indeterminate resuits, but repeat tests in 6 m o n t h s usually will show a positive Western Blot result. T h e patient's final results are considered positive only if both the ELISA a n d the Western Blot results are positive. If the result is indeterminate, PCR testing can be used to detect virus and make a final diagnosis. Recently rapid screening tests have bec o m e availableY These tests may eventually be

296

Howard L. Minkoff

shown to have clinical utility in settings such as labor and delivery suites where they could be used to help identify HIV infection a m o n g patients with no prenatal care. 112

Counseling Pretest counseling should be provided to all patients, regardless of their decision to be tested. Such counseling provides an opportunity to educate patients a b o u t behaviors that may put t h e m at risk for H W infection or any other sexually transmitted disease (STD) and to discuss riskreduction practices. This information can be imparted through clinician-patient discussion, the use of written educational materials or videotapes, or some combination of these methods. T h e particular mix will d e p e n d on the clinical setting and the prevalence o f H I V in the c o m m u nity. Patients should be counseled a b o u t HIV and offered the antibody test as early in their p r e g n a n c y as possible. Pretest counseling and patients' decisions a b o u t testing should be docum e n t e d in the medical record. Informational c o n t e n t of pretest counseling should include the following: (1) Spectrum of HIV disease and relationship to AIDS, (2) Modes of H1V transmission, (3) What the H W antibody test is and the implications of a negative or positive result, (4) T h e i m p o r t a n c e o f knowing o n e ' s HIV status with regard to pregnancy and perinatal transmission, and (5) Risk-reduction behaviors, b o t h sexual and drug related. T h e counseling session can generally be p e r f o r m e d in a relatively brief period of time (5 minutes) so that even busy clinicians can include it as a part of their routine practice at a first prenatal visit. HIV testing should be r e c o m m e n d e d to all prenatal patients. Attempts to selectively offer the test to w o m e n who acknowledge risk behaviors inevitably fail to identify large n u m b e r s of infected women, because individuals do not routinely acknowledge behaviors that are not socially sanctioned. 24 Federal legislation has mandated that all states must either d o c u m e n t that they have increased the n u m b e r of w o m e n tested and r e d u c e d the n u m b e r of children tested or they will lose Federal funds e a r m a r k e d for AIDS care. T h e post-test session should cover the implications of the patient's positive H I V antibody test result, a brief review of HIV infection and how it is transmitted (and not transmitted), discus-

sion of "safer sex" and "safer needle u s e " if appropriate, and the implications of HIV infection during pregnancy. T h e most i m p o r t a n t information to share with the patient is the dramatically improved prognosis for the woman, with a p p r o p r i a t e care, a n d h e r ability to reduce mother-to-child transmission o f H I V to as low as 5% if she accepts pharmacological intervention. Studies of seropositive w o m e n ' s reproductive decisions have shown that w o m e n frequently do not choose to terminate the p r e g n a n c y and that decisions a b o u t abortion are i n d e p e n d e n t of serostatus. ~5'26 Now that interventions to reduce transmission are available, it is even m o r e unlikely that HIV infection will be a critical determin a n t of the decision to continue or terminate a pregnancy.

Interaction of HIV Disease and Pregnancy Several investigators have studied the effect of H I V disease on p r e g n a n c y outcomes. Most such reports have not f o u n d significant effects. In o n e study, follow-up of 31 asymptomatic seropositive p r e g n a n t w o m e n a n d their infants showed that the prevalence of p r e m a t u r e delivery, fetal growth retardation, and early neonatal disease was c o m p a r a b l e to that of p r e g n a n t seronegative d r u g addicts, z7 O t h e r investigators, when comparing 50 asymptomatic seropositive p r e g n a n t w o m e n and 64 seronegative controls, r e p o r t e d that except for an increased incidence of spontaneous abortion in the seropositive g r o u p attributed to the small sample size, there were no differences in pregnancy outcome, z8 However, they did note that the incidence of prematurity a n d low birth weight (LBW) infants in b o t h groups of intravenous drug users was a b o u t twice that r e c o r d e d in the general population. In a study that included b o t h drug users and n o n d r u g users, ~9 it was r e p o r t e d that when c o m p a r i n g HIVinfected p r e g n a n t w o m e n a n d m a t c h e d controls there were no differences in birth weight, gestational age, or other o u t c o m e parameters. Some reports f r o m the developing world, however, have shown a disproportionate n u m b e r of adverse outcomes a m o n g HIV-infected pregnancies. In a r e p o r t on 466 HIV-positive w o m e n in Zaire, an increased rate of p r e m a t u r e births, low birth weight and higher neonatal death rate was n o t e d when c o m p a r e d with 606 HIV-negative women. 3~ This study population has a signifi-

HIV and Pregnancy

cantly greater n u m b e r of women with AIDS who are most p r o n e to adverse perinatal events. Concern has been raised not only about the effects of HIV on pregnancy outcomes, but on the effect of pregnancy on HIV disease as well. Pregnancy is associated with perturbations in the i m m u n e system and is one of several examples of the sexual dimorphism of the i m m u n e response. Most investigators agree that there is a decrease in cell-mediated immunity during pregnancy, which is probably mediated through an altered relationship between T helper cells and T suppressor cells. O t h e r factors contributing to the immunosuppression of pregnancy may be increased levels of total steroids and other pregnancy-specific plasma proteins and h o r m o n e s such as HCG, alpha-feto protein, and pregnancyassociated alpha 2-glycoprotein. 31 Partially in response to these concerns, many investigators have assessed the relationship of HIV serostatus and pregnancy to lymphocyte subset changes. In a study of 416 pregnant HIV1 - i n f e c t e d women and an age- and paritymatched HIV seronegative group of 407 pregnant women, T e m m e r m a n 32 reported that CD4 percentage was lower postpartum than antenatally in both HIV-seropositive and seronegative women. T h e differences between HIV-l-seropositive and seronegative women in changes during pregnancy in CD4 and CD8 cell counts and ratios were not statistically significant. In an analysis o f prospectively collected immunologic and clinical data from 145 women seen in Edinburgh between 1985 and 1992, Brettle 33 reported there were differences between marker paths of women according to risk activity. W o m e n who had acquired HIV from drug use had a higher level of absolute CD4 cells, CD4 percentage, and total lymphocytes at seroconversion than those who had acquired HIV via heterosexual intercourse, whereas immunologic markers declined more steeply in the f o r m e r group. However, there was no evidence that pregnancy, either before or after seroconversion, had an adverse effect on marker paths of HIV disease. Rich et al ~4 assessed T cell function by interleukin-2 (IL-2) production in vitro and three color flow cytometry. All uninfected n o n p r e g n a n t subjects, 74% of uninfected pregnant subjects, and only 54% of HIV-infected pregnant subjects responded to all stimuli. All uninfected subjects 2 to 6 months postpartum had normal function versus 27% of

297

infected subjects (trend, P < .001). Uninfected pregnant subjects had reduced levels of C D 4 + C D 4 5 R A - R O + (memory) and elevated levels of C D 4 + C D 4 5 R A + R O - (naive) lymphocytes. Infected pregnant subjects had elevated levels of memory, reduced levels of naive and increased C D 4 + H L A - R + C D 3 8 + (activated) lymphocytes. Increased C D 4 + D R + C D 3 8 + cells correlated best with p o o r IL-2 function, HIV infection, and being postpartum (R2 = .79). Thus, T helper function and phenotype were altered in pregnancy and returned to baseline postpartum in uninfected but not HIV-infected women. More recently, Burns ~5 r e p o r t e d on a c o h o r t o f 192 H I V - l - i n f e c t e d w o m e n and 148 seronegative w o m e n who had lymphocyte subset analysis d u r i n g p r e g n a n c y and the p o s t p a r t u m period. Consistent with prior reports that CD4 levels decline d u r i n g pregnancy and r e t u r n to n o r m a l postpartum, these investigators rep o r t e d that p e r c e n t levels increased between the third trimester and 12 m o n t h s p o s t p a r t u m a m o n g HIV-1 seronegative w o m e n (1.98%, P = .04). However, CD4 levels declined steadily d u r i n g p r e g n a n c y and p o s t p a r t u m a m o n g seropositive w o m e n ( - 1 . 5 7 % , P = .02 between the third trimester and 12 m o n t h s postpartum; - 2 . 6 5 % , P = .0004 between 2 and 24 m o n t h s p o s t p a r t u m ) , d e m o n s t r a t i n g that HIV disease continues to progress d u r i n g pregnancy. In fact, the rate o f decline d u r i n g p r e g n a n c y was twofold to threefold greater than in the postp a r t u m period, but power considerations prevented these differences from being statistically significant. T h e p e r c e n t o f CD8 levels increased at or n e a r delivery and declined to baseline between 2 and 6 m o n t h s p o s t p a r t u m in both seronegative and seropositive women, although only the declines were statistically significant in b o t h groups ( - 2 . 6 6 % , P = .004; and - 2 . 0 2 % , P = .02, respectively). Finally, Tuomala et a136 reported on total, CD4+, and CD8+ lymphocytes during pregnancy and at 1-year follow-up among HIV infected women in the W o m e n and Infants Transmission Study (WITS). Assessments were made in each of 226 women during pregnancy and at 1-year postpartum and in each of 100 nonpregnant women during 1-year of follow-up. Trends over time were c o m p a r e d between pregnant women with and without multiple covariates. T h e r e was a mean increase of 2.76 per week in

298

Howard L. Minkoff

the C D 4 + cell c o u n t during p r e g n a n c y (P = .04). No other characteristics c h a n g e d significantly during pregnancy. T h e m e a n CD4+ and CD8+ cell counts, the CD8 percent, and the total lymphocyte c o u n t and p e r c e n t increased immediately post delivery. During the first postpartum year there were statistically significant declines in the absolute CD4+ and CD8+ cell counts, the relative CD4 and CD8 percentages, and the total lymphocyte c o u n t and percent. T h e rate of change for C D 4 + and C D 8 + counts, but not for CD4 p e r c e n t was less during 1 year in the n o n p r e g n a n t cohort than in the first p o s t p a r t u m year, a n d the CD8 p e r c e n t increased in the nonp r e g n a n t women. A wide variability in trends of all m e a s u r e m e n t s during p r e g n a n c y was seen. T h e investigators concluded that there were no clinically significant changes during p r e g n a n c y or the p o s t p a r t u m period in any of the lymphocyte p a r a m e t e r s they assessed. These data, meticulously collected and eloquently analyzed, are p e r h a p s the strongest evidence to date that any effect of pregnancy on i m m u n o l o g i c p a r a m e t e r s is marginal, at most.

The Natural History of HIV Disease in Pregnant and Nonpregnant Women In one of the earliest reports on HIV infection a m o n g p r e g n a n t w o m e n it was n o t e d that a m o n g 34 HIV-positive m o t h e r s followed-up for a m e a n of 27.8 + 21.6 months, 15 had acquired AIDS or AIDS-related c o m p l e x (ARC).37 This was higher than the expected progression of the disease in n o n p r e g n a n t patients and suggested that perhaps p r e g n a n c y was responsible for the acceleration of the w o m e n ' s illness. However, a definitive conclusion could not be drawn f r o m that r e p o r t because the m o t h e r s were identified through the birth of a child who had AIDS so that these findings may have b e e n representative of those in a cohort of w o m e n with advanced i m m u n o c o m promise. Evidence has b e e n presented that suggests that the course of illness in a child relates to the stage of maternal illness, with the infant's risk of death correlated inversely with the mother's CD4+ c o u n t a n d directly with her p24 antigen level at delivery. 3s Subsequently, several controlled studies have b e e n r e p o r t e d in which HIV-positive m o t h e r s have b e e n evaluated prospectively. Schaeffer et al 3~ followed up 32 HIVpositive w o m e n and 40 HIV-negative w o m e n during pregnancy and for 6 m o n t h s after delivery

and observed no clinical progression o f illness during p r e g n a n c y a m o n g seropositive women. However, signs of clinical deterioration during p o s t p a r t u m observation developed in 9% of patients. T h e investigators believed that pregnancy had only a m i n o r effect on the course of H W disease. Bigger et al 4~ showed that the direction of i m m u n o l o g i c changes seen in HW-positive m o t h e r s were the same as that in HW-negative control pregnancies except that drops in CD4 counts were 10% to 20% greater a m o n g seropositive women. O t h e r investigators have failed to show any evidence of progression of disease during pregnancy. 4a In a follow-up of 88 p o s t p a r t u m patients, McCalllum et a142 were unable to d e m o n strate any adverse effect of pregnancy on the course of HIV disease. Similarly, in a study of 23 p r e g n a n t patients followed-up for 2 years after delivery, c o m p a r e d with m a t c h e d seropositive n o n p r e g n a n t controls, no significant differences were observed in the n u m b e r of opportunistic infections between the two groups. 41 In a prospective study f r o m Bordeaux, France, 57 w o m e n who c o m p l e t e d a pregnancy during the course of their H I V infection were c o m p a r e d with 114 HW-infected w o m e n who never conceived. 43 T h e two groups were m a t c h e d on CD4 lymphocyte count, age, and year of H W diagnosis. T h e main o u t c o m e measures were death, occurrence of a first AIDS-defining event, and a d r o p of the CD4 below 200 m m 3. T h e m e a n follow-up period in p r e g n a n t w o m e n was 61 m o n t h s f r o m H W diagnosis (median CD4 at entry 4 5 5 / m m 3) and 54 m o n t h s f r o m beginning of pregnancy. N o n p r e g n a n t w o m e n were followedu p for 50 m o n t h s since H W diagnosis (median CD4 460/mm3). T h e p r o p o r t i o n of asymptomatic w o m e n at entry in the study was 51 of 57 (90%) in p r e g n a n t and 87 of 114 (76%) in nonp r e g n a n t women. No significant difference was observed in the two groups with regard to the different end points studied, even after adjustm e n t for other prognostic variables. Adjusted hazards ratio ( p r e g n a n t / n o n p r e g n a n t ) were 0.92 for death (95% confidence interval [CI] 0.40 to 2.12), 1.02 for occurrence of a first AIDSdefining event (95% CI 0.48 to 2.18), and 1.20 for d r o p in CD4 to less than 200 m m 3 (95% CI 0.63 to 2.27). Recently, the results of the Italian serconversion cohort were reported. 44 In a g r o u p

H1V and Pregnancy

of 331 w o m e n followed up f r o m the time of seroconversion, p r e g n a n t w o m e n (38 p r e g n a n t at the time of seroconversion and 31 b e c a m e pregn a n t after seroconversion) did not experience a m o r e rapid rate of progression of disease even when adjusting for age, exposure group, CD4 cell count, or use o f treatment. Currently, a significant biological influence of pregnancy on the course o f HIV disease has not b e e n d o c u m e n t e d . T h e available evidence suggests that pregnancy may exert only a m i n o r influence on the progression of disease. More prospective, long-term studies are n e e d e d before the impact of p r e g n a n c y on the disease will be clearly delineated. Transmission o f H I V

Currently, available diagnostic tools such as polymerase chain reaction, virus culture, in vitro antibody p r o d u c t i o n assay, and IgA allow for definitive diagnosis o f pediatric HIV infection in the first m o n t h s of life. 45'46 Using those tools, as well as older antibody assays, prospective studies of mother-to-child transmission of H I V p e r f o r m e d before the advent of pharmaceutical interventions, r e p o r t e d relatively u n i f o r m rates o f transmission in the range o f 25% t o 3 5 % . 47"51 Although lower results have been r e p o r t e d from Europe (13%) 52 and higher rates f r o m Africa. T h e higher rates f r o m Africa have b e e n linked, at least in part, to the frequency of long-term breast feeding on that continent. Over the past several years, in addition to m o r e information being m a d e available in regard to the frequency of transmission, a great deal has b e e n learned a b o u t the timing of transmission. Bryson et al 5~ have p r o p o s e d a provisional definition o f early versus late transmission o f HIV. Early transmission is defined as d e t e c t i o n of H I V within the first 48 h o u r s of life, with c o n f i r m a t i o n outside the n e o n a t a l period, a n d late transmission is defined as negative virological evaluations d u r i n g the first week of life followed by H I V detection between 7 a n d 90 days o f age. Evaluation o f eight p u b l i s h e d studies r e p o r t i n g serial follow-up on 10 or m o r e HIVinfected infants in w h o m b l o o d s p e c i m e n s were first o b t a i n e d d u r i n g the first 7 days o f life indicates that H I V detection d u r i n g the first week o f life occurs in 31% to 59% o f infected infants, in u p to 91% by 12 to 30 days, a n d in nearly 100% by 30 to 90 days o f age. 54-5s Similar find-

299

ings have b e e n r e p o r t e d f r o m a study evaluating detection o f HIV proviral DNA f r o m G u t h r i e card dried b l o o d spots, in which HIV was d e t e c t e d in only 52% o f n e o n a t a l specim e n s f r o m infected infants. 59 T a k e n together, the a c c u m u l a t e d clinical, virological a n d serological data suggest that at least 40%, a n d perhaps as m u c h as 80%, o f perinatal HIV transmission occurs d u r i n g or close to the i n t r a p a r t u m period. O t h e r data, such as the h i g h e r acquisition rate o f HIV by first b o r n twins c o m p a r e d with their second b o r n siblings, s u p p o r t the supposition that i n t r a p a r t u m events are often d e t e r m i n a n t s o f transmission. T h e duration o f r u p t u r e d m e m b r a n e s has b e e n the specific focus of research regarding the role of i n t r a p a r t u m events in the determination o f rates o f transmission. Several studies have now b e e n published that suggest that there is a link between the duration of r u p t u r e d m e m b r a n e s and the transmission of HIV. These preliminary analyses have d e m o n s t r a t e d a substantial increase in transmission after the m e m b r a n e s have b e e n r u p t u r e d over 4 hours. 6~ As a consequence of these findings some investigators have suggested that there may be a role for surgical delivery as a potential strategy for the prevention of intrapartum transmission. T h e relationship o f cesarean section to perinatal transmission of HIV has been e x a m i n e d by a n u m b e r of investigators. However, n o n e of these studies were designed to address the relationship of m o d e of delivery to transmission. T h e first reports on pregnancies in HIV-infected women, p e r f o r m e d before the availability of antibody tests, focused on w o m e n whose infection status was known because of the birth of infected children. These reports n o t e d that many HIX~ infected children had b e e n delivered by cesarean section, thereby d o c u m e n t i n g that surgical delivery was not fully protective. 62 Given the clear evidence that some p r o p o r t i o n of HIV transmission occurs in utero, the absence of complete protection is not surprising. Subsequent reports evaluated both HIV-uninfected as well as infected infants b o r n to HIV-seropositive women, making it possible to consider issues of " p a r t i a l " protection, ie, differential rates of transmission related to m o d e o f delivery. Many of the reports that addressed this issue were summarized in a meta-analysis p e r f o r m e d by Villari et a l Y T h e i r publication focused on

300

Howard L. Minkoff

seven reports (primarily f r o m Europe) that m e t their criteria for accuracy of pediatric diagnosis (H1V status) and m o d e of delivery. 64-69Although no study individually d e m o n s t r a t e d significant protection by cesarean section, when the over 900 evaluable cases were evaluated in combination, statistical significance was achieved (odds ratio 0.65, 95% confidence interval 0.43 to 0.99, P = .04), suggesting a protective effect f r o m surgical delivery. However, a critical flaw in the meta-analysis was the failure of most individual studies to control for potential c o n f o u n d e r s by randomization or multivariate analysis. Clinicians caring for HIV-infected w o m e n may use cesarean section differentially based on maternal i m m u n e status, being quite liberal with surgery in the face of an i m m u n o c o m p e t e n t m o t h e r a n d avoiding surgery except in dire circumstance in the setting of severe maternal i m m u n e c o m p r o mise. Because maternal i m m u n e status has b e e n associated with transmission risk by a n u m b e r of investigators, 67'7~ differential rates of transmission because of i m m u n e status may be falsely attributed to m o d e of delivery. In addition, dystocia is a significant indication for cesarean section. 71'72 If HIV-infected infants are smaller, m o t h e r s of infected infants would be less p r o n e to that complication, which would lead to an overestimate o f the benefit of cesarean section. In some cohorts, prematurity and low birth weight have b e e n r e p o r t e d to be m o r e c o m m o n in infants b o r n to HIV-seropositive w o m e n , 7~'75'32 a reflection, perhaps, m o r e of the health status of the HIV-infected w o m e n than the HIV infection status o f the fetus. In general, studies f r o m the United States, Europe, and some African cohorts enrolling less symptomatic HIV-infected w o m e n have not observed these p h e n o m ena, 28,29,7e'7s although it is possible that a subset of infected infants (perhaps those with intrauterine infection) may be b o r n small for gestational age. An additional shortcoming of the meta-analysis is that most studies did not separately analyze elective and e m e r g e n t cesarean section. In contradistinction to e m e r g e n c y cesarean section, elective cesarean section occurs before labor and m e m b r a n e rupture. Because elective section would prevent materno-fetal blood transfusions occurring during labor as well as exposure to infectious maternal genital secretions, it m i g h t be expected to be m o r e effective in preventing

transmission. However, in o n e of the larger studies included in the meta-analysis the seemingly contradictory observation was made: infection rates were lower only in w o m e n with e m e r g e n c y cesarean section, whereas those with elective surgical delivery h a d rates similar to w o m e n with vaginal delivery. T h e intrinsic biases present in these observational studies prohibit any definite conclusion regarding protective benefit of cesarean section. Therefore, although there is some evidence to suggest a role for cesarean section, given the i n h e r e n t risks thereof, and the absence of docum e n t e d benefit in the setting of ZDV, it would seem p r u d e n t to await the results of ongoing trials before r e c o m m e n d i n g u n i f o r m cesarean section. It would certainly seem a p p r o p r i a t e however, to avoid artificial rupture of m e m branes in almost all circumstances. As noted, there is also a great deal of data that suggest that rates of perinatal transmission may be increased in w o m e n with i m m u n o c o m promise as m e a s u r e d by low CD4 cell counts, viral load, or clinical status. ~1'7~ Some studies have also focused on the pattern of antibodies of m o t h e r s and r e p o r t e d an association of certain patterns with lower rates of transmission to infants, 2~176 although the results have often b e e n in conflict. Recently a great deal of attention has b e e n focused on the relationship between viral load and transmission. Dickover et al s~ r e p o r t e d that transmission increased as viral load increased, although it was not a u n i f o r m p h e n o m e n o n at any level. More recently the viral load data f r o m the A C T G 076 trial (discussed below) have b e e n reported. In that r e p o r t 84 it was concluded that a high m a t e r n a l plasma concentration is a risk factor for the transmission of HIV1 f r o m an untreated m o t h e r to her infant. It was also f o u n d that the reduction in transmission associated with ZDV use could only be partially explained by the reduction in plasma levels o f HIV RNA. Transmission was also r e p o r t e d to occur at all levels of plasma HIV, including undetectable levels. T h e presence and a m o u n t of virus in the genital tract could affect transmission risk. Free virus and infected cells have b e e n identified in cervicovaginal secretions of H I V - l - i n f e c t e d women, s5 In a study in p r e g n a n t w o m e n f r o m Nairobi, HIV-1 DNA was detected in 32% of cervical a n d 10% o f vaginal samples, s6 T h e presence

HIV and Pregnancy

o f H I V - l - i n f e c t e d cells in genital secretions was associated with i m m u n o s u p p r e s s i o n , anemia, abn o r m a l cervical or vaginal discharge, and severe vitamin A deficiency. Local genital tract viral burden was not directly correlated with systemic viral load or CD4+ count. In one study, 17% of w o m e n with high plasma H1V-1 RNA levels did not have detectable HIV-1 RNA in cervicovaginal secretions, and 26% of w o m e n without detectable plasma RNA had significant levels o f cellfree virus in genital secretions. 87 Intensive exposure of the infant's thin skin or mucosal surfaces to maternal blood and secretions during the birth process could provide a significant route for viral transmission, s5 Langerhans cells in the skin and gastrointestinal tract have b e e n shown to express CD4+ and be infectable by HIV-1. Primate studies have d e m o n strated that fetal skin and mucous m e m b r a n e s may provide a route for HIV-1 infection. In a rhesus m o n k e y model, Simian immunodeficiency virus, (SIV) was injected into the amniotic fluid of uninfected mothers during late gestation; six of seven newborns were infected, ss Additionally, transmission via the oral route has b e e n d e m o n s t r a t e d in newborn animals; four of four monkeys who were b o r n by cesarean section to uninfected mothers and administered SIV orally immediately after birth b e c a m e infected. 89 This indicates that swallowing of infectious maternal fluids during birth may be a n o t h e r m e c h a n i s m of transmission. By 7 days after oral exposure, SW was identified by in situ hybridization in lymphoid follicles in the ileum and mesenteric lymph nodes, but not peripheral lymph nodes of these animals. This suggests that mucosal Langerhans cells within the small bowel may play a major role in initial infection by this route in newborn animals. Consistent with a possible route of HIV-1 transmission by oral exposure in humans, in one study, HW-1 was detected in gastric aspirates from two o f four newborns who were subsequently shown to be infected. 9~ T h e i m p o r t a n c e of mucosal HIV-1 antibody in genital secretions in reducing infection risk during the birth process is unknown. In a m o u s e m o d e l of genital herpes simplex virus (HSV), vaginal application of HSV antibody protected mice against vaginal inoculation with HSV-2. 91 However, intermittent cervicovaginal shedding o f H W - 1 occurs despite the presence o f mucosal H I V - l - s p e c i f i c IgA antibodies, suggesting the

30 1

antibody is not neutralizing the virus. 9~ In one study, anti-H1V-1 secretory IgA in maternal genital secretions was associated with increased risk of transmission (Miotti et al 1993); however, increased local antibody may be a reflection of higher levels of local viral replication. 9z Invasive p r o c e d u r e s that breach the infant skin barrier could provide a n o t h e r m e c h a n i s m for viral entry. In a large French cohort, invasive procedures (particularly amniocentesis and amnioscopy) were associated with increased transmission risk; o t h e r obstetric-related risk factors were p r e m a t u r e m e m b r a n e rupture, h e m o r rhage in labor, a n d bloody amniotic fluid. 94 As noted above, p r o l o n g e d duration of m e m b r a n e rupture could p e r m i t increased exposure to HW-1 in secretions. Transmission via Breast Milk Although perinatal acquisition o f HIV seems to be the major route o f pediatric infection, there are m a n y reports o f infection acquired by ingestion of infected breast milk. 95-98 In most of these reports the mothers were infected postnatally by blood transfusions f r o m donors who had H1V disease. Although pretransfusion serostatus was generally u n d o c u m e n t e d , no other source of maternal infection was suspected and no o t h e r family m e m b e r s were known to be infected. In one prospective study 98 mothers who seroconverted in the p o s t p a r t u m period and who breastfed were found to be efficient transmitters of HIV. These pediatric infections, along with reports of the isolation of free virus f r o m the breast milk of healthy carriers of HIV, make it p r o b a b l e that H W infection can be acquired by breast feeding. Cell-associated a n d cell-free virus are reported to be m o r e c o m m o n in early milk, obtained up to 7 days postpartum, than in m a t u r e milk samples. 99'~~176 T h e presence of HIV-infected cells in breast milk has b e e n associated with an increased risk o f H W transmission in at least one study. Some researchers have suggested that postnatal transmission f r o m mothers who acquired HIV while lactating is 25% (95% confid e n c e interval 13% to 39%) a n d may be in the range of 8% to 18% from mothers who were infected before b e c o m i n g pregnant. 1~ It is possible that maternal infectivity is maximal at the time o f initial acquisition of infection when a viral a n t i g e n e m i a occurs. Because it remains probable that breast feeding can be a source of

302

Howard L. Minkoff

transmission of H1V, the Centers for Disease Control has r e c o m m e n d e d that m o t h e r s known to have HIV disease avoid breast feeding. Unfortunately, although these r e c o m m e n d a t i o n s may make sense in countries in which safe alternatives to breast feeding are readily available, they are not appropriate in areas where breast feeding is the only realistic source of nutrients.

Preventing Perinatal Transmission In 1994, the results of ACTG Protocol 076 were released demonstrating that a regimen of zidovudine (ZDV) given during pregnancy, labor, and to the newborn for 6 weeks was able to remarkably reduce the risk of perinatal HIV-1 transmission; almost a 70% reduction in transmission risk was observed, f r o m 25% in the placebo g r o u p to 8% in the ZDV group. 1~ More recently, ACTG 185 d e m o n s t r a t e d that similar results could be seen even a m o n g w o m e n who had previous exposure to AZT or who had CD4 counts below 200 m m z. T h e ZDV regimen f r o m ACTG 076 has b e g u n to be successfully integrated into clinical practice in the United States and E u r o p e and has b e e n a c c o m p a n i e d by dramatic declines in perinatal transmission rates in these countries. T h e 076 r e g i m e n consists of AZT, 100 m g five times a day, 200 m g three times a day, or 300 m g twice a day in the a n t e p a r t u m period (beginning after 14 weeks). In the intrap a r t u m period a loading dose of 2 m g / k g is given over the first h o u r followed by a mainten a n c e dose of 1 m g / k g per h o u r thereafter. In the neonatal period the infant receives an AZT syrup for 6 weeks at a dose of 2 m g / k g every 6 hours. Preliminary data regarding the safety of this r e g i m e n have b e e n reassuring. Almost 1,000 children have b e e n tracked for 4 years with no increase in risks of n e u r o d e v e l o p m e n t a l delay or carcinogenesis. Some c o n c e r n has b e e n raised, however, as a result of data r e p o r t e d f r o m studies on mice p e r f o r m e d at the National Cancer Institute (NCI). T h a t r e p o r t suggested that mice exposed to high dose rates of AZT in the third trimester gave birth to pups who were subsequently f o u n d to have high rates of liver, lung, skin and genitourinary tumors in midlife. Alt h o u g h other investigators have r e p o r t e d conflicting findings, the NCI data should chasten those who would dismiss all concerns regarding these therapies, a n d they reinforce the n e e d for

t h o r o u g h counseling and long-term follow-up. In regard to m o n i t o r i n g of the m o t h e r on AZT, it is only necessary to measure the blood c o u n t on a monthly basis and assess liver functions intermittently. T h e only abnormality that occurs with any frequency is anemia. T h e majority of perinatal HIV-1 infection occurs in the developing world. Unfortunately, the ACTG 076 ZDV r e g i m e n is too costly a n d logistically complex for m a n y nonindustrialized countries to i m p l e m e n t o n a widespread scale, and its efficacy in a breast-feeding population is unknown. An ideal preventive intervention would be cheap, nontoxic to m o t h e r and fetus, be easy to administer, only n e e d to be given once or for a limited period of time, a n d have utility in preventing p o s t p a r t u m transmission. T h e results of A C T G 076 have spurred the worldwide evaluation of multiple o t h e r modalities to reduce transmission. Several studies are currently ongoing to d e t e r m i n e if m o r e abbreviated, affordable regim e n s would have utility in countries in which costs make utilization of the full r e g i m e n unrealistic. Recently, an abbreviated course of ZDV has b e e n shown to have efficacy in a trial in Thailand. Recently, concerns a b o u t the ethics o f using placebo groups in these trials have b e e n raised. Potential interventions to reduce transmission have focused on reduction of maternal viral load, e n h a n c e m e n t of maternal and infant HIV1-specific i m m u n e response, prophylaxis of the newborn, a n d attempts to reduce p e r i p a r t u m and p o s t p a r t u m exposure to the virus, s6 At the m o m e n t , only AZT has b e e n proven to significantly reduce the rate of mother-to-child transmission of HIV. T h e future challenge for researchers is to use the increasing understanding of the pathogenesis o f perinatal HIV-1 transmission to design preventive regimens that will be applicable on a global basis.

Management of Pregnancies Complicated by HIV Infection T h e guiding principle in the care of HI-V-infected p r e g n a n t w o m e n is to adhere rigorously to the standards of care that apply to all o t h e r HI-V-infected individuals. Perhaps of m o s t importance is the m o n i t o r i n g of i m m u n e status with CD4 counts a n d viral loads. These should be p e r f o r m e d at regular intervals because they pre-

H1V and Pregnancy

dict the course o f disease and allow for rational decisions regarding therapeutic interventions. If the CD4 c o u n t stays over 500 m m 3 and the viral load below 5,000, the obstetrician can anticipate an u n r e m a r k a b l e course. AZT would be required as part of a r e g i m e n to prevent transmission of HIV but additional therapy can be deferred. If those conditions are not met, then multidrug antiretroviral therapy should be instituted. T h e r e is now clear and compelling evidence that triple therapy, including a protease inhibitor, in b o t h AZT-naive and AZT-experienced patients results in slower progression of HIV disease) ~176 Although protocols for antiretroviral therapy are n o t agreed on uniformly, several references are available to guide the clinician in the m a n a g e m e n t of the HIV-infected p r e g n a n t woman. 105 H e r e is a s u m m a r y of one possible a p p r o a c h to the use of antiretrovirals in pregnancy. It is based on guidelines p r o p o s e d for n o n p r e g n a n t individuals by the International AIDS SocietyUSA P a n e l ) ~ It must be u n d e r s t o o d that new agents will a p p e a r shortly on the market and m o r e information on risks may also be discerned in the n e a r future. T h e obstetrician must stay abreast of an evolving literature if he or she is to provide optimal care to their patient. Pending the publication of additional information supporting early intervention with antiretroviral agents, most w o m e n with CD4 counts above 500 m m ~ and low viral loads, who are not pregnant, will not receive antiretroviral therapy. T h e panel r e c o m m e n d e d that therapy be initiated in all patients with HIV RNA levels above 5,000 to 10,000 copies p e r milliliter of plasma and should be considered for all HIV-infected patients with detectable HIV RNA in plasma. Therefore, the focus o f therapy in p r e g n a n t w o m e n with no detectable virus and high CD4 counts would be on the prevention of mother-to-child transmission of HIV. This is the circumstance that most closely matches that o f 076 participants and for which the most empiric information exists regarding efficacy for prevention of perinatal transmission. Accordingly, r e c o m m e n d a t i o n s for the use of ZDV in pregnancy, as p r o m u l g a t e d by a public health task force, are most directive for this group. T h e specific r e g i m e n r e c o m m e n d e d by the task force should be prescribed in the a n t e p a r t u m , intrapartum, and neonatal periods. It should be noted, however, that data showing

303

r e d u c e d efficacy of m a n y t r e a t m e n t regimens a m o n g patients previously treated with ZDV ( c o m p a r e d with ZDV naive) raise concerns, even in this group, regarding the use of m o n o t h e r a p y during the a n t e p a r t u m period. For the p r e g n a n t w o m e n whose HIV RNA is over 5,000 copies per milliliter plasma or whose CD4 c o u n t falls below 500 m m s, as for all individuals with similar counts, consideration should be given to the use of combination therapy. If m o n o t h e r a p y has limited clinical or virological effects and hastens the d e v e l o p m e n t of resistance it would be inappropriate to continue such substandard care solely because a w o m a n is pregnant. T h e panel r e c o m m e n d e d the use of two nucleosides and a protease inhibitor. Whichever regimen is eventually shown to provide optimal care should be considered for use in pregnancy as well. Only in rare circumstances should considerations related to pregnancy lead clinicians to choose o n e a p p r o a c h over another. O n e such consideration could be differences in r e p o r t e d side effects. For example, indinavir is associated with hyperbilirubinemia and nephrolithiasis, potentially serious perinatal events, particularly because neonatal levels may be high given the metabolism of these agents in the liver. Thus, in pregnancy, nelvinavir m i g h t m a k e a m o r e appropriate first choice a m o n g protease inhibitors. Although definitive evidence of the safety of the newer antiretroviral agents when used during pregnancy is lacking, no greater reassurance regarding the safety of ZDV was available at the time clinicians first used it in p r e g n a n c y ) ~ As noted, a reasonable first-line regimen would include two nonnucleoside reverse transcripatase inhibitors and a protease inhibitor. Because of the relative simplicity of the regimen a n d the low rate of side effects, the initial regim e n used at o u r institution at the current time is AZT 300 m g twice a day, Epivir 250 mg twice a day, and Nelvinavir 750 m g three times a day. Pharmacokinetic studies have been p e r f o r m e d with b o t h AZT and Epivir, and, although resistance can develop quickly to Epivir, when it is given with AZT it tends to delay the d e v e l o p m e n t of resistance to the latter drug. If the regimen chosen to treat HIV disease does not include ZDV, it would seem judicious to continue its use anyway, per the r e g i m e n reco m m e n d e d by the public health panel, if the patient is pregnant. Alternate agents may eventu-

304

Howard L. Minkoff

ally be shown to have efficacy in preventing mother-to-child transmission, but until that effect is demonstrated, it would be i m p r u d e n t to use them. T h e r e c o m m e n d a t i o n to use ZDV, as o p p o s e d to o t h e r antiretroviral agents for the prevention of mother-to-child transmission of HIV, is based on two considerations. First, there are empiric data that strongly support its use in that regard. No o t h e r agent has b e e n studied similarly. Second, pharmacokinetic studies demonstrate that high levels of drug are available in the fetal c o m p a r t m e n t , l~ Similar information is unavailable for most other agents. T h e i m p o r t a n c e of placental passage of drug is not certain. If viral load thresholds are truly central to transmission risk, then viral dynamics on the maternal side of the placenta m i g h t be as i m p o r t a n t as placental passage o f drug. Several recent publications 1~ suggest that a correlation exists between maternal viral load a n d rates of mother-to-child HIV transmission and, further hint at the existence of a clinically relevant threshold. O t h e r researchers disagree. H~ Differences in study populations and techniques for storing and assaying samples may explain some of the conflicting results. T h e ACTG 076 data suggest that AZT's effect on viral loads were responsible for only a small p e r c e n t a g e of the drug's observed effect on transmission rates. If appropriately designed studies confirm the initial reports of a threshold, it may have bearing on the choice of therapeutic r e g i m e n for use by p r e g n a n t women. If, for example, viral load remains above the " t h r e s h o l d " for transmission despite initial therapy, clinicians may n e e d to consider the addition of o t h e r antiretroviral agents that m i g h t reduce the load. T h a t possibility, however, remains conjecture. Currently, there are insufficient data to justify the substitution of any agent for ZDV in most circumstances. Even if there is evidence of ZDV resistance, which m i g h t make therapy for the prevention of mother-to-child transmission seem futile, ZDV m i g h t still have a role. The d e m o n stration of transmission of escape mutants f r o m m o t h e r to child 111 suggests that an individual ZDV-susceptible virus m i g h t be transmitted even if the p r e d o m i n a n t strain in the m o t h e r is not susceptible. Further research is n e e d e d to see if there is advantage to combination therapy as part of a strategy to prevent transmission of resistant strains. If the m o t h e r is intolerant of ZDV,

it may be reasonable to consider using an alternative agent, which could potentially reduce viral load during the a n t e p a r t u m period, and then adding ZDV for the i n t r a p a r t u m ( d e p e n d i n g on the type of toxicity e x p e r i e n c e d by the m o t h e r ) and neonatal periods. If a t r e a t m e n t r e g i m e n fails (ie, fails to d r o p HIV RNA levels below the detectable range or there is an increase in levels after an initial decline), then there is a n e e d to alter the entire regimen, not just change a single agent. In the setting of p r e g n a n c y however, it m i g h t be p r u d e n t to continue the AZT along with the o t h e r c o m p o n e n t s of the new regimen. P r e g n a n t w o m e n should be the beneficiaries of any clinical advantage offered by new regim e n s and should not be restricted to single drug therapy. However, the continued use of the public health service panel's r e c o m m e n d e d ZDV r e g i m e n as part of any therapeutic strategy should be assured. In regard to prophylaxis for opportunistic infections, if the c o u n t drops below 200 m m s, Pneumocystis carinii p n e u m o n i a prophylaxis should be instituted, and below 100 m m s MAC prophylaxis should be given a n d an o p t h a m o l o g y consult obtained. T h e specific details of m a n a g e m e n t of the myriad infections to which these w o m e n are p r o n e is beyond the scope of this chapter.

Conclusion With appropriate care, 95% of the children of HIV-infected w o m e n will be b o r n uninfected by H1V. With a p p r o p r i a t e care, the prognosis for the HIV-infected w o m a n is now substantially better than it was just a few years ago. A p p r o p r i a t e care, however, is not as simple as it was several years ago when few, if any therapeutic options were available to H1V-infected patients or their obstetricians. Only by making the c o m m i t m e n t to master the c o m p l e x new regimens that now comprise the standard of care for HIV-infected w o m e n can obstetricians maintain their primacy as advocates for the health of w o m e n and child r e n a n d assure that potential benefits b e c o m e a reality for those in their care.

References 1. Centers for Disease Control a n d Prevention: H1V/AIDS Surveillance Report, 7:2-36, 1995

HIV and Pregnancy

2. Wortley PM, Fleming FL: AIDS in women in the United States: Recent trends JAMA 278:911-16, 1997 3. Ward JW, Karon J, Fleming P, et al: Trends in AIDS incidence in the United States, 1990-1994. XI International Conference on AIDS, Vancouver, British Columbia, July 7-12, 1996, Abstract # Mo.C.332, p 36 4. Centers for Disease Control and Prevention: Morbidity and Mortality Weekly Report. Update: Mortality attributable to HIV infection among persons aged 25-44 Years--United States, 1994. 45:121-125, Feb 16, 1996 5. Fowler MG, Melnick SL, Mathieson BJ: Women and HIV: Epidemiology and global overview. Obstet Gynecol Clin North Am 24:705-730, 1997 6. Rosenberg PS: Scope of the AIDS epidemic in the United States. Science 270:1372-1375, 1995 7. Gwinn N, Pappaioanou M, George JR, et al: Prevalence of HIV infection in childbearing women in the United States. JAMA 265:1704, 1991 8. Centers for Disease Control: AIDS weekly surveillance report. MMWR 39:28, 1991 9. HIV screening of pregnant women and newborns, in Hardy LM (ed): Institute of Medicine Report. Washington, DC, National Academy Press, 1991 10. Chin J: Current and future dimensions of the HIV/ AIDS pandemic in women and children. Lancet 336:221, 1990 11. Maury W, Potts BJ, Rabson AB: H1V-1 infection of the first-trimesterand term human placental tissue: A possible mode of maternal-fetal transmission. J Infect Dis 160:583-588, 1989 12. LevyJA: Infection by Human Immunodeficiency VirusCD4 is not enough. N EnglJ Med 335:1528-1530, 1996 13. Liu R, Paxton WA, Choe S, et al: Hoozygous defect in HIV-1 co-receptor accounts for resistance for some multiply-exposed individuals to HIV-1 infection. Cell 86:367-377, 1996 14. Centers for Disease Control: 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR 41:1-19, 1992 15. Ho DD, Neumann AU, Perelson AS, et al: Rapid turnover of plasma virons and CD4 lymphocytes in HIV-1 infection. Nature 373:123-126, 1995 16. Ho DD, Pomerantz RJ, Kaplan JC: Pathogenesis of infections with human immunodeficiency virus. N Engl J Med 317:278, 1987 17. Lemp GF, Payne SF, Neal D, et al: Survival trends for patients with AIDS. JAMA 263:402-406, 1990 18. Hessol NA, Lifson AR, O'Malley PM, et al: Prevalence, incidence, and progression of human immunodeficiency virus infection in homosexual and bisexual men in hepatitis B vaccine trials, 1978-1988. AmJ Epidemiol 130:1167-1175, 1989 19. GoedertJJ, Biggar RJ, Weiss SH, et al: Three-year incidence of AIDS in five cohorts of HTLV-III-infected risk group members. Science 231:992-995, 1986 20. GoedertJJ, Kessler CM, Aledort LM, et al: A prospective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with hemophilia. N Engl J Med 321:1141-1148, 1989 21. Lifson AR, Rutherford GW, Jaffe HW: The natural history of human immunodeficiency virus infection. J Infect Dis 158:1360-1367, 1988

305

22. Rothenburg R, Woelfel M, Stoneburner R, et al: Survival with the acquired immunodeficiency syndrome. Experience with 5833 cases in New York City. N Engl J Med 317:1297-1302, 1987 23. Irwin K, Olivo N, Schable CA, et al: Performance characteristics of a rapid HIV antibody assay in a hospital with a high prevalence of HIV infection. Ann Intern Med 125:471-475, 1996 24. Landesman S, MinkoffHL, Holman S, et al: Sero survey of human immunodeficiency virus infection in parturients. JAMA 258:2701, 1987 25. Sunderland A, Minkoff HL, Handte J, et al: The influence of serostatus on women's reproductive decisions. Obstet Gynecol 79:1027, 1992 26. Selwyn DA, Carter RJ, Shoenbaum EE, et al: Knowledge of HIV antibody status and decisions to continue or terminate pregnancy among intravenous drug users. JAMA 261:2567, 1989 27. Semperini AE, Sucetich A, Parti GL, et al: HIV infection and AIDS in newborn babies of mothers positive for HW antibody. Prey Med 294:610, 1987 28. Johnstone FD, McCallum L, Brettle R, et al: Does HIV infection affect the outcome of pregnancy. Br Med J 296:467, 1988 29. Minkoff HL, Henderson C, Mendez H, et al: Pregnancy outcomes among mothers infected with human immunodeficiency virus and uninfected control subjects. Am J Obstet Gynecol 163:1598-1604, 1990 30. Ryder RW, Nsa W, Hassig SE, et al: Perinatal transmission of the human immunodeficiency virus type 1 to infants of seropositive women in Zaire. N Engl J Med 320:1637-1642, 1989 31. Weinberg ED: Pregnancy-associated depression of cellmediated immunity. Rev Infect Dis 6:814, 1984 32. Temmerman M, Nageklkerke N, Bwayo J, et al: HIV-1 and immunologic changes during pregnancy: A comparison between HIV-l-seropositive and HIV-l-seronegative women in Nairobi, Kenya. AIDS 9:1057-1060, 1995 33. Bretfle RP, Raab GM, Ros A, et al: HIV infection in women: Immunologic markers and the influence of pregnancy. AIDS 10:1177-1184, 1995 34. Rich KC, Siegel JN, Jennings C, et al: CD4+ lymphocytes in perinatal human immunodeficiency virus (HIV) infection: evidence or pregnancy induced immune depression in uninfected and H1V-infected women. J Infect Dis 172:1221-1227, 1995 35. Burns D, Nourjah P, Minkoff H, et al: Changes in CD4 and CD8 cell levels during pregnancy and postpartum in women seropositive and seronegative for human immunodeficiency virus-1. AmJ Obstet Gynecol 174:14611468, 1996 36. Tuomala RE, Kalish LA, Zorilla C, et al: Changes in total CD4+ and CD8+ lymphocytes during pregnancy and one year postpartum in HIV infected women. Obstet Gynecol 89:967-974, 1997 37. Minkoff H, Nanda D, Menez R, et al: Pregnancies resulting in infants with acquired immunodeficiency syndrome or AIDS related complex. Obstet Gynecol 69:285, 1987 38. Blanche S, Mayaux MJ, Rouzioux C, et al: Relation of the course of HIV infection in children to the severity of the disease in their mothers at delivery. N Engl J Med 330:308-312, 1994

306

Howard L. Minkoff

39. Schaefer A, Grosch-Woerner, Friedman I, et al: The effect of pregnancy on the natural course of H1V disease. Fourth International Conference on AIDS, 1988, Stockholm (Abst 4039) 40. Biggar RJ, Pahava S, Minkoff HL, et al: Immunosuppression in pregnant women infected with human immunodeficiency virus. Am J Obstet Gynecol 161:12391244, 1989 41. Berrebi A, PuelJ, Grandjean H, et ah The influence of pregnancy on the evolution of H1V infection. Fourth International Conference on AIDS, 1988, Stockholm (Abst 4041) 42. McCallum LR, France AJ, Jones ME, et al: The effects of pregnancy on the progression of HIV disease. Fourth International Conference on AIDS, 1988, Stockholm (Abst 4032) 43. Hocke C, Morlat P, Chene G, et al: Prospective cohort study of the effect of pregnancy on the progression of human immunodeficiencyvirus infection. Obstet Gynecol 86:886-891, 1995 44. Mliegro MB, Dorrucci M, Philips AN, et al: Incidence and consequences of pregnancy in women with known duration of HIV infection. Arch Intern Med 157:25852590, 1997 45. Landesman S, Weiblen B, Mendez H, et ah Clinical utility of HIV-IgA immunoblot assay in the early diagnosis of perinatal H1V infection. JAMA 266:3443-3446, 1991 46. Quinn TC, Kline RL, Halsey N, et al: Early diagnosis of perinatal HIV infection by detection of viral-specific IgA antibodies. JAMA 266:3439-3442, 1991 47. European Collaborative Study. Mother-to-child transmission of HIV infection. Lancet 2:1039-1042, 1988 48. Italian Multicentre Study: Epidemiology, clinical features, and prognostic factors of pediatric HIV infection. Lancet 2:1043-1046, 1988 49. Cowan MJ, Walker C, Culver K, et ah Maternally transmitted H1V infection in children. AIDS 2:437-441, 1988 50. Ryder R, Nsa W, Hassig SE, et al: Perinatal H1V transmission in two African hospitals: One-year follow-up (Abst 4128), in Final Program and Abstracts of the 1V International Conference on AIDS. Book 1. Stockholm, Sweden: Swedish Ministry of Health and Social Affairs, National Bacteriologic Laboratory, Karolinska Institute, World Health Organization: 291, 1988 51. Blanche S, Rouzioux C, Moscato ML, et al: A prospective study of infants born to women seropositive for human immunodeficiency virus type 1. HIV Infection in Newborns French Collaborative Study Group. N Engl J Med 320:1643-1648, 1989 52. European Collaborative Study: Children born to women with HIV-1 infection: Natural history and risk of transmission. Lancet 337:253-260, 1991 53. Bryson Y, Luzuriaga K, Sullivan JL, et al: Proposed definition for in-utero versus intrapartum transmission of H1V-1 (letter). N EnglJ Med 327:1246-1247, 1992 54. McIntosh K, Pitt J, Brambilla D, et al: Usefulness and timing of blood culture in the first six months of life for the diagnosis of vertically transmitted HIV infection. Proceedings of the Ninth International Conference on MDS; 1993June 6-11; Berlin, Germany (Abstr PO-B051062)

55. Burgard M, Mayaux MJ, Blanche S, et ah The use of viral culture and p24 antigen testing to diagnose human immunodeficiency virus infection in neonates. N Engl J Med 327:1192-1197, 1992 56. Krivine A, Firtion g, Cao L, et al: HIV replication during the first few weeks of life. Lancet 339:1187-1189, 1992 57. Shaffer N, ou C-Y, Abrams E, et al: PCR and H1V-IgA for early infant diagnosis of perinatal HIV infection. Proceedings of the Eighth International Conference on AIDS; 1992 July 19-20; Amsterdam, the Netherlands (Abstr ThC 1580) 58. Levine M, Denamur E, Simon F, et ah Conversion of HIV viral markers during the first months of life in HIV-infected children born to seropositive mothers. Proceedings of the Ninth International Conference on AIDS; 1993 June 6-11; Berlin, Germany (Abstr 1063) 59. Comeau AM, Hsu HW, Schwerzler M, et al: Identifying human immunodeficiency virus infection at birth: Application ofpolymerase chain reaction to Guthrie cards. J Pediatr 123:252-258, 1993 60. Minkoff H, Burns D, Landesman S, et al: The relationship of the duration of ruptured membranes to vertical transmission of HIV. AmJ Obstet Gynecol 173:585-589, 1995 61. Landesman S, Kalish L, Burns D, et al: The relationship of Obstetrical factors to the mother-to-child transmission of HIV. N EnglJ Med 334:1617-1623, 1996 62. Minkoff H, Nanda D, Menez R, et al: Pregnancies resulting in infants with acquired immunodeficiency syndrome or AIDS related complex. Obstet Gynecol 69:285, 1987 63. Villari P, Spino C, Chalmers TC, et al: Cesarean section to reduce perinatal transmission of human immunodeficiency virus: A meta analysis. OnlineJ Curr Clin Trials Jul 8 1993 (Doc No. 74) 64. Lindgren S, Anzen B, Bohlin A, et ah HIV and childbearing: Clinical outcome and aspects of mother to infant transmission. AIDS 5:1111-1116, 1991 65. Kind C, Brandle B, Wyler CA, et al: Epidemiology of vertically transmitted HIV infection in Switzerland: Results of a nationwide prospective study. Eur J Pediatr 151:442-448, 1992 66. Gabiano C, Tovo P, de Martino M, et ah Mother to child transmission of HIV 1: Risk of infection and correlates of transmission. Pediatrics 90:362-374, 1992 67. Ryder RW, Nasa E, Hassig SE, et al: Perinatal transmission of the human immunodeficiency virus type 1 to infants of seropositive women in Zaire. N Engl J Med 320:163%1642, 1989 68. Turner MJ, Rasmussen MJ, Boylan PC, et ah The influence of birth weight on labor in nulliparas. Obstet Gynecol 75:944-947, 1990 69. Goedert JJ, Duliege AM, Amos CI, et ah High risk of infection with human immunodeficiency virus type I for first-born vaginally delivered twins. Lancet 338:14711475, 1991 70. Burns D, Landesman S, Muenz LR, et al: Cigarette smoking, premature rupture of membranes, and vertical transmission of HIV-1 among women with low CD4+ levels. J Acquir Immune Defic Syndr 7:718-772, 1994 71. Goedert JJ, Duliege AM, Amos CI, et ah High risk of

HIV and Pregnancy

72.

73. 74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

HIV infection for first-born twins. Lancet 338:1171, 1991 Read AW, Prendiville WJ, Dawes VP, et al: Cesarean section and operative vaginal delivery in low-risk primiparous women, Western Australia. Am J Public Health 84:37-42, 1994 Hra SK, KamanagaJ, Bhat GJ, et al: Perinatal transmission of HIV-1 in Zambia. Br MedJ 299-1250-1252, 1989 Temmerman M, Plummer FA, Mirza NB, et al: Infection with HIV as a risk factor for adverse obstetrical outcome. AIDS 4:1087-1093, 1990 Braddick MR, Kreiss JK, Embree JE, et al: Impact of maternal HIV infection on obstetrical and early neonatal outcome. AIDS 4:1001-1005, 1990 Mayers MM, Davenny K, Schoenbaum EE, et al: A prospective study of infants of human immunodeficiency virus seropositive and seronegative women with a history of intravenous drug use or of intravenous drugusing partners, in the Bronx, New York City. Pediatrics 88:1248-1256, 1991 Lallemant M, Lallemant-Le-Coeur S, Cheynier D, et al: Mother-child transmission of H1V-1 and infant survival in Brazzaville, Congo. AIDS 3:643-646, 1989 Lepage P, Dabis F, Hitimana D-G, et al: Perinatal transmission of HIV-1: Lack of impact of maternal HIV infection on characteristics of livebirths and on neonatal mortality in Kigali, Rwanda. AIDS 5:295-300, 1991 Minkoff H, Mofenson M: The rote of obstetrical interventions in the prevention of pediatric human immunodeficiency virus infection. Am J Obstet Gynecol 171:1167-1175, 1994 Devash Y, Calvelli TA, Wood DG, et al: Vertical transmission of human immunodeficiency virus is correlated with the absence of high-affinity/avidity maternal antibodies to the gpl20 principal neutralizing domain. Proc Nail Acad Sci USA 87:3445-3449, 1990 Mann DL, Hamlin-Green G, Willoughby A, et al: Immunoglobulin class and subclass antibodies to HIV proteins in maternal serum: Association with perinatal transmission. J Acquir Immune Defic Syndr 7:617-622, 1994 Lallemant M, Baillou A, Lallemont Le Couer S, et al: Maternal antibody response at delivery and perinatal transmission of human immunodeficiency virus typed in African women. Lancet 343:1001-1005, 1994 Dickover RE, Garraty EM, Hermann SA, et al: Identification of levels of HIV-1 RNA associated with risk of perinatal transmission: Effect of maternal zidovudine treatment on viral load. JAMA 275:599-605, 1996 Sperling RS, Shapiro DE, Coombs RW, et al: Maternal viral load, zidovuvudine treatment and the risk of transmission of human immunodeficience virus type 1 from mother to infant. N EnglJ Med 335:1621-1629, 1996 Mofenson LM: Mother-child HIV-1 transmission: Timing and determinants. Obstet Gynecol Clin North Am 24:759-784, 1997 John GC, Nduati RW, Mbori-Ngacha D, et al: Genital shedding of human immunodeficiency virus type 1 DNA during pregnancy: Association with immunosuppression, abnormal cervical or vaginal discharge, and severe vitamin A deficiency.J Infect Dis 175:57-62, 1997 Rasheed S, Li Z, Xu D, et al: Presence of ceU-free hu-

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

307

man immunodeficiency virus in cervicovaginal secretions is independent of viral load in the blood of human immunodeficiency virus-infected women. Am J Obstet Gynecol 175:122-130, 1996 Fazely F, Sharma PL, Fratazzi C, et al: Simian immunodeficiency virus infection via amniotic fluid: A model to study fetal immunopathogenesis and prophylaxis. J Acquir Immune Defic Syndr 6:107-114, 1993 Baba TW, Koch J, Mittler ES, et al: Mucosal infection of neonatal rhesus monkeys with cell-free SIV. AIDS Res Hum Retrovir 10:351-357, 1994 Nielsen K, Boyer P, Dillon M, et al: Presence of human immunodeficiency virus (HIV) type 1 and HIV-l-specific antibodies in cervicovaginal secretions of infected mothers and in the gastric aspirates of their infants. J Infect Dis t73:1001-1004, 1996 Whaley KJ, Zeiflin L, Barratt RA, et al: Passive immunization of the vagina protects mice against vaginal transmission of genital herpes infections. J Infect Dis 169:647-649, 1994 Miotti P, Yolken R, Canner J, et al: Mucosal factors and transmission of HIV from mother to infant. Proceedings of the First Nadonal Conference on Human and Other Retroviruses, Washington, DC, Dec 12-18, 1993 (abstr 673) Belec L, Meillet D, Gaillard O, et al: Decreased cervicovaginal production of both IgAl and IgA2 subclasses in women with AIDS. Clin Exp Immunol 101:100-106, 1995 Mandelbrot L, Mayauz M-J, Bongain A, et al: Obstetric factors and mother-to-child transmission of human immunodeficiency virus type 1: The French perinatal cohorts. A m j Obstet Gynecol 175:661-667, 1996 Friedland GH, Saltzman BR, Rogers MF, et al: Lack of transmission of HTLV111/LAV infection to household contacts of patients with AIDS or ARC with oral candidiasis. N Engl J Med 314:3444, 1986 Zeigler JB, Cooper DA, Johnson RO, et al: Postnatal transmission of AiDS-associated retrovirus from mother to infant. Lancet 1:896, 1984 Lepage P, Van de Perre P, Careel M, et al: Posmatal transmission of HIV mother to child. Lancet 2:400, 1987 Van de Perre P, Simonon A, Msellati P, et al: Postnatal transmission of HIV type 1 from mother to infant. N EnglJ Med 325:593, 1991 Ruff AJ, CoberlyJ, HalseyJA, et al: Prevalence of HIV1 DNA and p24 antigen in breast milk and correlation with maternal factors. J Acquir Immune Defic Syndr 7:68-73, 1994 Van de Perre P, Simonon A, Hitimana D-G, et al: Infective and anti-infective properties of breastmilk from HIV-1 infected women. Lancet 341:914-918, 1993 Van de Perre P: Postnatal transmission of human immunodeficiency virus type 1: The breast-feeding dilemma. Am J Obstet Gynecol 173:483-487, 1995 Connor EM, Sperling RS, Gelber R, et al: Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 331:1173-1180, 1994 Hammer SM, Squires KE, Hughes MD, et al: A controlled trial of two nucleoside analogues plus indinavir

308

104.

105.

106.

107.

108.

Howard L Minkoff

in persons with human immunodeficiency virus and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 337:725-733, 1997 Gulick RM, MellowsJW, Havlir D, et al: Treatment with indinavir, zidovudine and lamivudine in adults with immnnodeficiency virus infection and prior antiretroviral therapy. N EnglJ Med 337:734-739, 1997 Minkoff H, Augenbraun M: Antiretroviral therapy of the pregnant women. Am J Obstet Gynecol 176:478489, 1997 Carpenter CC, Fischcl lvIA, Hammer S, et al: Antiretroviral therapy for HIV infection in 1997: Updated recommendations of the International AIDS Society-USA Panel. JAMA 277:1962-1969, 1997 Sperling RS, Stratton P, O'Sullivan J, et al: A survey of Zidovudine use in pregnant women with immunodeficiency virus infection. N Engl J Med 326:857-861, 1992 O'Sullivan MJ, Boyer PJJ, Scott GB, et al: The pharma-

109.

110. 111.

112.

cokinetics and safety of zidovudine in the third trimester of pregnancy for women infected with human immunodeficiency virus and their infants: phase I ACTG study (protocol 082). Am J Obstet Gynecol 168:15101516, 1993 Fang G, Burger H, Grimson R, et al: Maternal plasma human immunodeficiency virus type 1 RNA level: A determinant and projected threshold for mother-tochild transmission Proc Natl Acad Sci USA 92:1210012104, 1995 Landesman S, Burns D: Quantifying HIV. JAIVIA 275:640-641, 1996 Wolinsky SM, Wike CM, Korber BT, et al: Selective transmission of human immunodeficiency virus type-1 variants from mothers to infants. Science 28:255:1069, 1992 Minkoff H, O'Sullivan MJ: The case for rapid H1V testing during labor. JAMA 279:1743-1744, 1998