Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome in Pregnant Women Sten H. Vermund, MD, PhD, Miriam A. Galbraith, RN, MPH, Susan C. Ebner, Amy R. Sheon, MPH, and Richard A. Kaslow, MD, MPH A pregnant woman experiences selective immunosuppression as a physiologic response to the presence of a genetically heterologous fetus. Case reports early in the acquired immunodejiciency syndrome (AIDS) ep’Ide mic suggested that adverse human immunodeficiency virus (HIV)-related clinical outcomes might be causally associated with pregnancy. A review of relevant published data indicates that: (I) Adverse clinical outcomes of pregnancy are common among HIV-infected pregnant women, but no studies to date have fully disentangled the many confounding factors. (2) HIV-related complications are common in pregnancy only among immunosuppressed (< 300 CD4+ ceMmm3) women. (3) The distinct effect of pregnancy on the expression of HIV infection cannot be evaluated in the absence of appropriarely controlled observations. (4) Cofactors for perin& transmission are poorly understood. (5) Research into the motives for reproductive decisions and behaviors is of critical importance for improving our health education and outreach efforts for high-risk women. (6) Adequate clinical treatment and prophylactic health care services must be made easily accessible and available to women at high risk of HIV disease. (7) Treatment with available antiviral and anti-Pneumocystis drugs is advisable for HIV-infected pregnant women with fewer than 300 to 350 CD4 + ceWmm3, though data to definitively guide therapeutic decision making are not available. (8) Large multicenter studies are needed to recruit patients and to retain them in sufjicient numbers, allowing fur better evaluation of the many variables determining clinical outcomes for HIV-infected mothers and their infants. The natural history of HIV in pregnant women must be studied to facilitate clinical decision making, and to design and implement interventions, including prevention (behavior change, vaccines) and treatment (chemotherapy, immunotherapy). Ann Epidemiol 1992;2:773-803. KEY WORDS: HIV, acquired immunodeficiency abuse, pregnancy complications.

syndrome, pregnancy,

women, substance

INTRODUCTION

AIDS/HIV

Infection

in Women

In 1987, acquired

immunodeficiency syndrome (AIDS) was one of the ten leading causes of death among women (1). By the end of December 1991, a total of 21,225 women in the United States with AIDS had been reported to the Centers for Disease Control (CDC), representing 10.5% of all adult cases ever reported. AIDS in women has disproportionately affected Americans of African, Caribbean, and Hispanic ethnic/ racial origin, who represent 73% of the cumulative female total (2). The annual rate of AIDS cases reported to CDC in 1991 for black women (24.6 per 100,000) was about double the rate for Hispanic women (12.6 per 100,000) and about fourteen times the rate for white women (1.7 per 100,000) (2). The highest rates of AIDS and human immunodeficiency virus (HIV) infection in women are reported in urban East Coast

From the Division of AIDS (S.H.V., S.C.E., A.R.S) and Microbiology and Infectious Diseases (R.A.K.), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD. Address reprint requests to: Sten H. Vermund, MD, PhD, VTEB/DAIDS/NIAID/NIH, Boulevard, Room 24OP, Bethesda, MD 20892. Received February 8, 1991; revised March 3, 1992. 0 1992 Elsevier Science Publishing Co., Inc.

6003 Executwe

1047-2797/92/$05.00

774

Vermund et al. HIV/AIDS IN PREGNANT WOMEN

TABLE

1

Reported

AEP Vol. 2, No. 6 November 1992: 773-803

AIDS cases by sex, 1981-1991 Year of report

1981

1982

1983

182 6 188 3 30

597 52 649 8 12

1917 158 2075 8 12

Males Females Total % Female Male-female ratio From Public Information

Data Set, ClX,

areas where

1984

1985

4209 300 4509 7 14

1986

1987

intravenous

and other

parenteral

is most prevalent.

the age-adjusted

Surveillance

women

aged 15 to 44 years was 40.7 per 100,000

Community-based among

prevention

and New York, homosexual

death

men

continued

drug users serve,

as do bisexual

A recent

of male

revealed

that

In the United

men,

have

use among

States,

sexual

continued

heterosexuals

resembles

Women

the male-female

is highly

AIDS

like San related

to

Male injection female

5 years,

from men to women

(8), and the fact that

sex partners

who do not use injection

review noted

that when compared

sex partners

was decreased

spread. partners and 73%

from approximately

as the numbers

the ratio

of infected

States

approaches

where

drug

1 : 1 (7). This

and Haiti,

where

hetero-

acquired

AIDS

cases in

of HIV transmission. heterosexually

due to both the greater than

many

from women

drugs,

rather

than

efficiency

America

drug users have female

the converse

of male hemophiliacs

drug users had higher

with which

to men in North

more male injection

to sex partners

of injection

l),

areas of the United

men by 1.6 : 1 among

HIV is transmitted

(9- 11). One and transfusion

rates of HIV infection

(12).

Transmission

By the end of December

1991, 79% off emales

reported

the ages of 13 and 44 years (Z), the prime reproductive period of HIV (13), asymptomatic women may transmit prevalence

“steady”

cases seen in Africa

mode

and Europe

knowing

black

of the virus

for heterosexual

current

in the preceding

concentrated,

(2). This is presumably

Risk of Vertical

1980s in cities

of new infections

of infection

ratio

to rise (2). In certain

States

recipients,

is New

among

transmission

in this time period.

7 : 1 in 1990 (Table

is the predominant outnumber

the United

the number

drug users with

the ratio of male-female

activity

“injection

localization

in 1987 (1, 3). in the early

five or more partners

39,461 6045 45,506 13 6.5

or AIDS

slow sexual

as a reservoir

38,094 5258 43,352 12 7.2

(6).

14 : 1 in 1984 to approximately females

began

infection

to rise markedly

injection

60% reported

did not use condoms

efforts

(4, 5). In contrast,

IDU in males and females study

rate for HIV

and may have helped

1991

termed

of this geographic

where

1990

Report, January 1992:1-22.

drug use, collectively

An example

Jersey,

Francisco

1989

7683 12,175 19,459 28,599 31,268 600 1076 1852 3530 3948 8283 13,251 21,311 32,129 35,216 7 8 9 11 11 13 11 11 8.1 7.9

October 1990, and CDC. HIV/AIDS

drug use” (IDU),

1988

they are themselves survey conducted

infected

(14).

in the United

Preliminary States

to have AIDS

were between

years. Given the long latency infection to offspring without data from a nationwide

sero-

in 1988 to 1989 of over 1.2 million

parturient women suggested that 140 per 100,000 pregnant women were infected with HIV (15). The highest HIV seroprevalence rate among parturient women is seen in major cities along the Atlantic Coast, such as New York City at 580 per 100,000 women. Based on data from 25 states, investigators estimated that over 5600 HIVinfected women delivered babies in the United States during a l&month period, from mid-1988 to mid-1989. Estimating vertical transmission rates in the United States at

AEP Vol. 2. No. 6 November 1992: 773-803

Vermund et al. HIV/AIDS IN PREGNANT WOMEN

775

30%, they calculated that approximately 1700 infected infants were born during this 12-month period (15). The growth rate of the epidemic of AIDS in children infected during the perinatal period reflects the proportionately rapid rise in HIV-infected females of reproductive age in recent years (16). The proportion of AIDS in children under 13 years born to mothers known or thought to be infected with HIV rose from 79% in 1988 to 85% in 1989 as a consequence of both increased perinatal transmission and decreased HIV contamination of blood and blood products since 1985 (17).

Risk Factors for Acquisition of HIV Infection among Women The distribution of all females with AIDS reported to the CDC by January 1992 according to exposure category reveals that 50% had been exposed to HIV via IDU; 34%, through heterosexual contact with an infected partner; 8%, through transfusion of HIV-contaminated blood products; while 7% did not have a determined risk factor. Through December 1991, among women who reported heterosexual exposure as the main risk factor for transmission, 62% stated that their sex partner(s) injected drugs (2). Minority women are at particular risk for exposure via sex with IDUs, representing 81% of women with AIDS who report this risk behavior without personal IDU (2). One study found a 22.fold relative risk for AIDS via heterosexual relations with a male injection drug user for black and Hispanic women, compared with white women (18). Nonetheless, the proportion of incident AIDS cases among white women from heterosexual exposure has also risen markedly from 10% in 1983 to 29% in 1988 (19). Female-to-female transmission is probably rare though relevant data are sparse (1, 20). High-risk sexual practices related to nonparenteral drug use may be associated with significant HIV exposure (21). In the mid-1980s the free-base form of cocaine known as “crack” became easily accessible with street prices of $5 to $10. Young women addicts often resort to bartering sex in exchange for drugs to support their habits (22). In one sample of prostitutes, women who practiced nonparenteral drug use (i.e., snorting or smoking cocaine and crack) and injection drug users exhibited similar HIV seropositivity rates (23). Experimentation with illicit drugs that coincides with onset of sexual activity poses particular risks for adolescents (16, 24, 25). The geographic distribution of heterosexually acquired AIDS cases in the United States parallels that of sexually transmitted diseases (STDs), and is most prevalent in inner-city African-American and Hispanic women of lower socioeconomic status (19). Untreated personal health problems, including STDs and genital ulcers, may increase HIV risk (21). Rates of many STDs such as syphilis (26) and penicillin-resistant gonorrhea (27) have risen during the 1980s. Both cross-sectional and prospective studies in Africa (28-30), Europe (31-33), and the United States (34, 35) have provided epidemiologic evidence of a relationship between HIV transmission and presence of genital ulcerative diseases, especially chancroid and syphilis (9). Aral and Holmes described a cycle of events in which genital ulcerative diseases (e.g., syphilis, chancroid, and genital herpes) facilitate transmission of HIV; and the immunosuppression caused by HIV infection, in turn, increases susceptibility to some STDs (36). Transmission of STDs can thereby increase the pool of vulnerable individuals for acquisition of HIV. Other postulated risk factors of particular importance to women include gonorrhea (37), vaginal trichomoniasis, chlamydia infection (38), and human papillomavirus (which causes anogenital warts) (39-42). Among Nairobi professional sex workers, use of oral contraceptives appeared to facilitate HIV transmission, possibly by promoting cervical ectopy, a common side effect of oral contraceptive use (38). Lack of circumcision in the male may increase risk to female partners (43). Prospective

776

Vermund et al. HIV/AIDS IN PREGNANT WOMEN

studies are needed to sort out cause and effect, and the interactions HIV transmission (9, 12, 44, 45).

EFFECT OF PREGNANCY

AEP Vol. 2, No. 6

November 1992: 773-803

between STDs and

ON HIV PROGRESSION

This section reviews how pregnancy may affect the course of HIV infection. Major published studies are reviewed in Table 2. Univariate odds ratios (ORs) are calculated from the published data in both tables. In the absence of access to the raw study data, only univariate associations could be assessed. The summary table suggests marked discrepancies in studies done to date depending on (1) whether intravenous drug users were the major group studied, (2) precisely which outcomes were studied, (3) whether selected data compared pregnant with nonpregnant HIV-infected women or HIVinfected with uninfected pregnant women (4) which geographic area was being studied, and (5) how criteria for outcome variables were defined.

Pregnancy and the Immune System A pregnant woman harbors heterologous tissue (her fetus may be considered an allograft) without rejecting it, unless its development is markedly abnormal. Selected lymphocyte responses are diminished in pregnancy, presumably as an accommodation of the foreign tissue, whose gradual growth permits the maternal immune system to adapt. Other quantitative and qualitative changes in immunologic responses are seen during pregnancy, but not completely understood. T lymphocytes not only help regulate the immune system but also direct cytotoxic functions against cancerous, otherwise genetically aberrant, and infected body cells. “Helper” T4 (CD4+) ce 11s are crucial to activating many type of immune cells [i.e., natural killer (NK) cells, B cells, other T cells, macrophages] (48). T4-cell numbers decline moderately during the latter stages of pregnancy. “Suppressor” T8 (CD8+) cells have direct cytotoxic effects through the release of cytokines and can suppress the activity of cells induced by T4 cells. Levels of helper T cells may fall and suppressor T cells may rise during pregnancy, lowering the CD4+/CD8+ cell ratio, though CD4’ cells can rebound somewhat in the last weeks of a normal 40-week gestation (49). This immunosuppression may partially account for increased susceptibility of women to the clinical complications of several viral infections, including varicella, herpes simplex viruses (HSV) , cytomegalovirus (CMV),and rubella (50). However, not all studies consistently demonstrate these changes (51), and more work is indicated, particularly in inner-city women of minority ethnic background. NK cells are large lymphocytes that target tumorous and infected body cells, yet do not require recognition of specific antigens in order to initiate a destructive response (48). In vitro experiments demonstrate that sera drawn from pregnant women seem to delay the maturation of NK cells; in vivo NK-cell activity is suppressed in pregnancy (52). NK-cell modulation in pregnancy may have a role in HIV pathophysiology. A slight decrease in B-cell functions with lowered immunoglobulins has been reported during pregnancy (53). Complement-mediated bacteriolysis is yet another immunologic feature altered in pregnancy, with some increased function reported (54, 55). Paradoxically, other immunologic functions are enhanced during pregnancy, particularly certain features of cell-mediated immunity (CMI) (55). Nonspecific activation of the monocyte-macrophage system is noted in association with the regulation of trophoblastic proliferation. This placental phenomenon is characterized by aggressive monocytes, drawn to the trophoblastic decidua and activated by cytokines.

2

DC

Studies

NO

Yes

IDU

Outcome

pregnant

Immunologic serologic variables IgA Transient p24 antigen

CD4 lymphocytes T4/T8 ratio

IgC IgM IgA

p24 Antigen Progression from one CDC stage to another Progression to CIX stage 4Cl CD4 lymphocytes &-microglobulin HTLV- 1 4 (8) NA NA NA NA NA NA

1 (2)

NA NA NA 15 (18)

n = 84

0 (0)

NA NA NA

n = 94

14 (27)

13 (24)

NA NA NA NA NA NA

11141 (27)

n = 51

3136 (16)

n=5

Nonpregnant

Status or no (%) with indicator

women

Pregnant

HIV-seropositive

Indicator

and nonpregnant

and

Immunologic, serologic, and clinical parameters

comparing

a 0.5 added to each cell IDU = injection drug use; NA = not available

France

Washington,

TABLE

42 (2.5-717)”

0.2 (0.02-2.00)

0.3 (0.1-1.0) 0.8 (0.3-2.0)

Odds ratio

No difference in progression of HIV disease was observed between pregnants and nonpregnants.

Pregnancy (single or multiple) did not appear to affect progression of HIV infection No difference in progression of HIV disease was observed between pregnants and nonpregnants.

Notes/conclusions

Berrebi et al. (47)

Bledsoe et al. (46)

Reference

Vermund et al. HIV/AIDS IN PREGNANT WOMEN

Immunosuppression

AEP Vol. 2, No. 6 November

can result from exposure

tigens,

a possible

tecting

a fetus from maternal

are repetitively with semen nents.

evolutionary

inoculated,

exposure

Pregnancy

While

progression

from Bronx,

seropositive

is evident,

The

postpartum

CD4+

on disease

of pregnancy

Stratification

range

noted

CD4+

among

the may

severe

includ-

HIV-related on HIV

attempted.

A study

of HIV as rare during pregnancy program

done,

(64). However, (duration

a range

20 HIV-

of 117 to 753/

and suggests

must continue

only

of infection)

ZOO/mm’ among with

of HIV was noted,

cell count

infectious

than

had

permitted

diseases

infection

suggests

further serious

drops the CD4+ medical problem

that

to follow

studies

women

of

after

internal

after cesarean

(65).

The inves-

with fewer than lobar pneumonia,

section.

in the HIV-infected

HIV-infected

300 and

(In an addendum,

of the manuscript.)

suppression

studied

comparisons.

16 women

two were confirmed,

if the physiologic

NY, in a population

previously

toxoplasmosis,

after completion

cell count for those

been

among

cerebral

more immunocompetent

women

immunosuppression. In the Brooklyn

been

was 388 t

progression

PCP cases, of which

that

have

maintenance

assessments

PCP in two women,

group were observed

infection

and other

progression

cell count

abscesses/wound

four additional

in the literature,

study to date was done in Brooklyn,

of CD4+

five serious

intra-abdominal

serious

to protect

of pregnancy

(58, 64).

by baseline

cells/mm’:

suppressed

effects

The

antigens

for the effect of pregnancy

studies

cell count

progression

of pregnancy

a greater

tigators

HLA)

in the mother

and time of seroconversion

who had T-cell

The most comprehensive

CD4+

(MHC,

appear

listeriosis,

few controlled

serious clinical

mean

subjects

Rapid

with

fluid compostimulus.

(56, 57).

women

plausibility

drug users in a methadone

was unknown.

completion

complex

progression

(PCP),

with HIV were studied,

the effect

anal intercourse

with seminal

response

in pregnant

the biologic

NY, described

injection

mm3.

HIV disease

(58-63).

39 women

receptive

inoculation

the immunosuppressive

or HIV disease

alloanby pro-

of CM1 can occur if HLA antigens

histocompatibility

carinii pneumonia

ing Pneumocystis

among

(HLA) fetogenesis

with the fetus as the alloantigenic

Hence,

773-803

and Disease Progression of virulent

conditions

Suppression

uninhibited

be true in unprotected

immunosuppressive

rejected.

HIV transmission

Anecdotes

to histocompatibility

to permit

by bloodstream

major

an appropriate

Pregnancy

disease

followed

acquired

fetus from being facilitate

rejection. as might

may be analogous,

fetus’ paternally may produce

adaptation

1992:

The

immunoabsence

of

and HIV-seronegative

of pregnancy

(see next

section)

below a critical threshold, pregnancy could be a women with an already substantial HIV-related

study the HIV-seronegative

control

group was chosen

to mimic

the risk exposure category of the HIV-seropositive group, for example, IDU and pattern II country origin. Two of 76 control women had fewer than 300 CD4+ cells/mm3. When

a CD4+

cell count

under

300/mm3

(and

not

HIV

status)

is considered

the

independent variable, with serious infection as the dependent variable, our calculation of the odds ratio is 7.9 [95% confidence interval (CI): 4.6 to 14.0). Results of this study suggest the need for prospective subjects, immune

studies with nonpregnant,

HIV-infected

control

to address whether pregnancy and HIV act synergistically to debilitate system. Larger control groups of immunosuppressed, seronegative women

also needed. Other studies

suggest

Washington,

DC,

study

nonpregnant

women

little

impact

of pregnancy

of 55 HIV-infected

assessed

clinical

and

on HIV disease

pregnant immunologic

women

the are

progression.

A

and 51 HIV-infected

parameters

and

noted

no

AEP Vol. 2. No. 6 November 1992: 773-803

Vermund et al. HIV/AIDS IN PREGNANT WOMEN

increase in progression of disease in the pregnant

779

group (46). Most of the subjects used

injection drugs and were followed for fewer than 2 years. In an analogous study, 84 HIVseropositive pregnant and 94 age-matched, HIV-seropositive nonpregnant women were followed for 3 years, with no clinical or immunologic differences noted (47, 66). Both studies reported appearance of p24 antigenemia in a few of the pregnant women, though the Washington study reported comparable p24 antigen data from both the nonpregnant and pregnant women (46).

Helper T-Cell Depletion It will be important to study pregnant women with a variety of helper T-cell numbers to assess prognosis by baseline T-cell counts and by prior symptomatology. For immunologic and selected clinical outcome variables, data from HIV-infected nonpregnant women and from HIV-uninfected pregnant women who are otherwise similar to the HIV-infected pregnant women should be compared. Few data are available on rates of CD4+ cell depletion in pregnant women with HIV. Both maternal immune reaction to the fetal alloantigenic exposure and other pregnancy-related immune alterations could accelerate the rate of T-cell decline by stimulating HIV production in infected persons. A recent study reports an average 2% decline per month of CD4+ cells in pregnancy (49), compared to less than 1% per month noted among HIV-infected homosexual men (67) or persons with hemophilia (68). Data on HIV-seronegative women with similar exposures to drugs, coinfections, and other potential confounders are important as another relevant comparison group. CD4+ cell counts can rise in the last 6 weeks of pregnancy, a rise that was blunted in a study of HIV-seropositive pregnant women (49). CDB’ cells increased slightly during pregnancy in both HIVinfected and uninfected women, but increased abruptly among HIV-seropositive women immediately post partum (49). Although CD4+ cell changes in pregnancy may be important, further quantification of these changes is needed in different groups of women with various backgrounds compared both to nonpregnant HIV-infected women and to pregnant HIV-seronegative women. Furthermore, CD4+ cell counts may decline in a nonlinear fashion depending on duration of infection and on other cofactors for immune activation, important methodologic and biostatistical complexities (49, 69-71). Both of the largest US studies suggest few serious complications for relatively immunocompetent pregnant women with HIV (i.e., >300 CD4+ cells/mm3) (64, 65). Future studies of pregnancy and HIV must include adequate numbers of the most immunosuppressed women to fully appreciate those clinical outcomes that are modulated by HIV and pregnancy. Asymptomatic and comparatively immunocompetent women will need to be assessed using nonclinical outcomes since clinical events will be infrequent in the brief period of pregnancy. These would include surrogates of clinical progression, such as rates of CD4+ cell decline, p24 antigenemia, and immune activation markers like neopterin or beta-2-microglobulin (57, 72). A research design now used in the Multicenter AIDS Cohort Study (MACS) [for background, see article by Kaslow and coauthors (73)] calls for careful clinical follow-up in men with CD4+ cell counts in the 200 to 300/mm3 range and among men with HIV-related symptoms (MACS. Unpublished protocols, 1990). A n analogous strategy to carefully track clinical outcomes in those women with symptoms or with fewer than 350 CD4+ cells/ mm’, and to assess surrogate markers of adverse outcome in asymptomatic women with counts above this threshold may help focus research resources.

780

Vermund et al. HIV/AIDS IN PREGNANT WOMEN

AEP Vol. 2, No. 6 November 1992: 773-803

Sample Size Concerns Generalizability of prospective studies is likely to suffer from a conundrum familiar to epidemiologists: loss to follow-up is substantial in the groups at highest overall risk (e.g., women who use drugs or whose partners use drugs). Women who are not in drug treatment programs or whose sex partners are not in such programs are especially hard to recruit and retain in studies. Since these women may have greater risks from a variety of cofactors for progression of disease during pregnancy, this differential loss to follow-up may bias data toward the null hypothesis by excluding data from women most likely to have their HIV disease exacerbated by pregnancy. Given the extremely difficult personal circumstances faced by many women, compliance with research protocols will require substantial social and medical services, including drug addiction treatment. However, such interventions are likely to influence the natural history of HIV and the pregnancy under study. Costs and organizational complexity of these studies will be great. Investigators with proven ability to recruit and retain high-risk women are needed for collaborative efforts, particularly when they can exploit existing clinical and social service infrastructures to improve the cost-efficiency of research.

PREGNANCY-ASSOCIATED

COMPLICATIONS

RELATED

TO HIV

Investigators have studied obstetric and neonatal outcomes in HIV-infected women from the United States, Europe, and developing countries, especially Africa and Haiti. Lack of appropriate control groups, small sample sizes, and incomplete assessments of drug use, nutrition, and coinfections are common problems in these challenging studies. A few studies, however, have included control populations with similar obstetric risks as the HIV-infected study subjects summarized in Table 3. Weak univariate associations and small sample sizes preclude adequate control of potentially confounding variables.

Selected Studies A study of 136 pregnant women in Edinburgh suggested no differences in low birth weight or prematurity between the HIV-seropositive and -seronegative groups (78). Differences in spontaneous abortion rates were not apparent in a study of 250 women in Nairobi (79). In a Bronx, NY, study of 125 pregnancies in 97 women (64), data collection varied somewhat across subgroups depending on the clinical recruitment site. In 67 live births, no major differences were noted in prematurity, intrauterine growth retardation, neonatal asphyxia, or other neonatal complications (64). Similarly, a study of 217 women in Brooklyn, NY, suggested few major differences in adverse obstetric outcomes between HIV-infected and -uninfected women (74). A trend for increased premature labor in the HIV-infected group was noted (OR: 2.3; 95% CI: 0.9 to 5.9). Spontaneous premature rupture of membranes was more common among HIV-infected women only in the drug-using subgroup (OR: 3.9; 95% CI: 1.4 to 11). (However, since a majority of nondrug users were of Haitian background, drug use was also a surrogate for non-Haitian background.) One of the largest studies to date, which followed nearly 200 HIV-infected and 2000 HIV-uninfected women in Port-au-Prince, Haiti, suggested increased prematurity and low birth weights in the HIV-infected group (77). Complications of pregnancy, and spontaneous abortions may be more common in HIV-infected persons, judging from a US Army study of 69 infected and 276 uninfected women (76). In Brazzaville,

Vermund et al. HIV/AIDS IN PREGNANT WOMEN

AEP Vol. 2. No. 6 November 1992: 773-803

781

Congo, increased low birth weight was noted in a study of 194 women, 64 of whom were HIV-infected (8 1). Findings of a study conducted in Kinshasa, Zaire, are difficult to interpret due to the exclusion of women in the HIV-uninfected control group whose newborns died in the first day or days after birth at one of two hospital sites [see Figure 2, Hospital A, HIV negative, in the article by Ryder and colleagues (82)]. Thus, the dramatic finding of a more than sevenfold increase in severe chorioamnionitis is likely to be an overestimate of the systematic exclusion of early neonatal deaths from the control (uninfected) group at the largest and most impoverished participating hospital site. Existence of an AIDS fetopathy or embryopathy manifested in abnormal facies was postulated from two case series in New York (83, 84). Controlled studies have not confirmed this finding (85-88). Resolution of this issue is important to facilitate clinical diagnosis, and to give insights into timing of transplacental HIV transmission. In summary, little consensus exists in the literature regarding the effect of HIV on obstetric outcomes. However, adverse effects may be greater in developing countries where cofactors such as malnutrition and coinfections may play an interactive role.

Drug Use as a Confounder of HIV-Related Outcomes In industrialized countries, cocaine, opiate, alcohol, and/or nicotine use will confound the relationship between HIV and obstetric and fetal outcomes. A number of review articles on drug use and reproductive outcomes are summarized in Table 4 in an attempt to introduce the often confusing published information. The articles generally indicate the strength of the evidence for a particular drug’s effect on obstetric and fetal outcome. The table suggests numerous contradictions in the literature; significant research challenges include describing the effects of cocaine, a current “drug of choice” in many HIV-endemic US communities (94).

DETERMINANTS

OF PERINATAL

TRANSMISSION

Children with AIDS are being reported to the CDC in increasing numbers as the number of women infected with HIV rises. Access to health care, foster care, and children orphaned as a result of parental HIV infection present major public health and social concerns. Boylan and Stein reviewed 29 prospective transmission studies in which the serostatus of mothers was known at the time of recruitment, and the cohort was established prior to or at delivery (103). Transmission rates of 22 to 36% in the United States, 22 to 30% in Europe, and 33 to 49% in Africa have been described in the most complete studies (Figure 1). Factors that may explain higher rates in Africa include poorer nutrition, higher STD rates, a greater proportion of women with advanced HIV disease compared to other regions, as well as the effect of other infectious diseases, and genetic susceptibility (103).

Socioeconomic Status The majority of US women with AIDS are of African-American and Hispanic origin, are of lower socioeconomic status, and live in inner cities. Many use illicit drugs or are sex partners of male drug users. In this setting, a fetus may experience multiple toxic exposures (e.g., to alcohol, nicotine, cocaine) even in the absence of HIV infection. Women with poor access to health services often receive prenatal care late, if at all (123-125). The extent to which factors associated with lower socioeconomic status facilitate perinatal HIV transmission is not yet known.

Brooklyn, NY

Brooklyn, NY

Study

TABLE

3

Yes

Yes

IDU

Premature labor PROM (excludes elective csections) Drug use No drug use

Maternal fever Chorioamnionitis Any medical Drug use No drug use

Mean gestational

Adverse obstetric outcome

Maternal medical complication

Fetal outcome

Maternal medical complications

Indicator

and -seronegative

age

5300 CD4 cells/mm3No. (%) with serious infections >300 CD4 cells/mm3No. (%) with serious infections

HIV-seropositive

Outcome

Studies comparing

0 (0) 74 (97)

0 (0) n varied 9178 (12) 21/109 (19)

(18) (21) (9) (5) (25) (32) (18)

8145 16/32 111119 61119 30020 16/50 12167

5116 (31)b 40 (71)

0 (0) n varied 13/56 (23) 25/80 (31)

16135 (46) 7139 (18)

38.8 wk

38.2 wk

2 (3)

16 (29)

(14) (2) (43) (41) (37)

n = 76

n = 56

12/84 2184 37186 16139 15/41

HIV mother

HIV + mother

1.6 0.5 2.3 1.5 2.6

(0.7-3.9) (0.1-2.3) (1.3-4.1) (0.6-3.5) (1.1-6.4)

3.9 (1.4-1.10) 0.2 (0.1-0.6)

2.3 (0.9-5.9) 1.9 (1.0-3.7)

7.9 (4.6-14.0)‘

Odds ratio

Mother’s serostatus was not associated with fetal outcomes.

HIV + nondrug-using mothers had elevated risk of any medical complications.

HIV + drug-using mothers had some Increased risk of obstetric complications.

HIV+ women with low CD4 counts had increased risk of serious infections during pregnancy.

Notes/conclusions

(74)

Minkoff et al.

(65)

Minkoff et al.

Reference

2&

Status or no. (%) with indicator

2 !-?

6

g

$2 E”

womena

pregnant

Female US Army soldiers

Bronx, NY

Yes

Yes

3 (12)

Adverse obstetric outcome

Complicated pregnancy Spontaneous abortion

Any antenatal complication Hospitalize for infectious disease Hospitalized for bacterial pneumonia Cbor~oamn~oni~is/ endometritis

5 (11)

17 (68) 3010 &

>37 wk gestation Mean birth weight Small-forgestational-age Apgar score