Introduction
Higher rates of preterm and low birth weight (LBW) deliveries in HIV-infected compared to uninfected women have been reported in some but not all studies. Most of the studies that have reported such associations are from developing countries [1–4] . For example, vitamin A deficiency, which has been associated with adverse pregnancy outcome (APO), is more common in pregnant women in developing countries. Conversely, antiretroviral therapy (ART), which has not been available in most developing countries, is now used during pregnancy by most HIV-infected women in developed countries [5–7] [8–15]
The extent to which HIV infection contributes to an excess risk for APO compared to non-HIV-related risk factors has not been well defined. Associations between maternal cigarette, alcohol and illicit drug use and poor fetal growth and preterm birth have been well established in studies in women who are not HIV-infected [16–18] [19] [20]
A delineation of risk factors for preterm birth, LBW, and intrauterine growth retardation (IUGR) in HIV-infected women receiving ART is needed to better characterize the HIV-related and unrelated risk factors for these outcomes and to develop interventions to reduce their incidence. Pediatric AIDS Clinical Trials Group Study 185 (PACTG 185) was a perinatal immunoprophylaxis study that enrolled HIV-infected pregnant women with CD4 lymphocyte counts ≤ 500 × 106 /l, who were all receiving ZDV prophylaxis for prevention of perinatal transmission. Detailed information on antenatal and obstetric variables and neonatal characteristics was collected during the trial, and laboratory assays to determine maternal plasma HIV RNA copy number, HIV quantitative peripheral blood mononuclear cell (PBMC) culture titer, and CD4 lymphocyte count were performed at several time points during pregnancy. This study thus provides an opportunity to evaluate the independent contribution of potential maternal virologic, immunologic, and therapeutic risk factors along with standard obstetrical factors, contributing to preterm birth, LBW, and IUGR in HIV-infected women receiving ZDV.
Materials and methods
Study design
PACTG 185 was a multicenter, randomized, double-blind, controlled phase III clinical trial conducted between October 1993 and March 1997 at 53 clinical sites in the mainland USA and Puerto Rico. The study evaluated whether ZDV prophylaxis combined with 200 mg/kg of human anti-HIV-1 hyperimmune immunoglobulin (HIVIG, North American Biologicals, Boca Raton, Florida, USA), administered intravenously at monthly intervals throughout pregnancy starting at 20–30 weeks gestation and once to the neonate at birth, would lower perinatal transmission compared to ZDV and infusions of intravenous immune globulin (IVIG) without HIV antibody (Gamimune N, Bayer, West Haven, Connecticut, USA) administered in an identical manner. The study protocol and informed consent forms were reviewed and approved by the Institutional Review Boards of each participating site. Each mother (and father of the child, when available) gave written informed consent for participation of herself and her child in this study. Results of the trial are reported elsewhere [21,22]
The study enrolled HIV-infected women who were 20–30 weeks pregnant, had baseline CD4 cell counts ≤ 500 × 106 /l, and who were receiving ZDV; women who were receiving other nucleoside analogue drugs or non-nucleoside reverse transcriptase inhibitors were allowed to enter the study with permission of the study chair. Women continued their physician-prescribed antepartum antiretroviral regimen and received intrapartum intravenous ZDV, and their infants received the standard 6-week course of ZDV prophylaxis [7]
In addition to standard obstetrical visits, women were seen monthly for study infusions and monitoring during pregnancy and at delivery. HIV quantitative PBMC culture was performed and blood specimens for HIV RNA assessments were obtained at baseline, just prior to the third infusion (third trimester) and at delivery. CD4 lymphocyte absolute number and percent were assessed at baseline and just prior to the third infusion.
Infants were seen at birth and weeks 1, 2, 6, and 12; every 4 weeks from week 16 through 24; every 12 weeks from week 24 through 60; and for a final evaluation at week 78 (18 months). HIV quantitative PBMC culture was obtained at birth and age 6, 24, and 48 weeks. All children who had any positive cultures had a second confirmatory culture performed. Results of all virologic and serologic assays were reviewed by a subgroup of the study team blinded to study treatment for final determination of infection status. Pregnancies that yielded multiple births were assessed as a single occurrence of HIV transmission if either of the infants were HIV-infected and as a single non-occurrence of transmission if neither was HIV-infected.
Detailed obstetric history was obtained at study entry, and screening was performed for Neisseria gonorrhoeae , Chlamydia trachomatis , and syphilis. Patients were interviewed at study entry and labor and delivery regarding any use of cigarettes, alcohol or illicit drugs during pregnancy (any versus none). Hard drug use was defined as use of cocaine, heroin or any illicit drug by injection. Data related to any new diagnoses, obstetric complications, and detailed information on antiretroviral drug use were recorded on standardized forms at each study visit and delivery. Pre-eclampsia was defined as new onset of hypertension with two readings at least 6 h apart of > 140 mm Hg systolic or > 90 mm Hg diastolic, or an increase from first trimester baseline blood pressure of at least 30 mm Hg systolic or 15 mm Hg diastolic, along with at least 1+ proteinuria (0.1 g/l) on dipstick or > 0.3 g/24 h urine collection, or with non-dependent edema or rapid weight gain.
Preterm birth was defined as birth at < 37 weeks gestation, and LBW was defined as an infant who weighed < 2500 g at delivery. Infant gestational age was determined by the best obstetric estimate, including clinical examination and ultrasound performed before 20 weeks gestation. If the birth weight of either member of a twin pair was < 2500 g, the birth was coded as low birth weight. IUGR, a measure that combines information on gestational age and birth weight, was defined on the basis of an infant's birth weight being below the 10th percentile for their gestational age, compared to distributions by gestational age derived from a large database [23] th percentile for gestational age, the birth was coded as displaying evidence of IUGR. As previously reported from this data, enrolment characteristics and rates of perinatal transmission were similar in the HIVIG and IVIG groups (4.1% in the HIVIG versus 6.0% in the IVIG group;P > 0.3) [21,22]
Laboratory methods
Syphilis was diagnosed by serology if both a non-treponemal test (RPR or VDRL) and a treponemal test (MHA-TP, FTA-ABS, HATS) were positive, without a history of adequate treatment. Neisseria gonorrhoeae and Chlamydia trachomatis were diagnosed by culture or federally approved antigen test. Genital herpes was diagnosed by clinical examination with confirmation by culture or antigen test, when available.
HIV quantitative PBMC microculture and lymphocyte phenotyping were performed in ACTG certified laboratories, according to standard methods [24,25]
Statistical methods
Categorical prognostic factors for preterm birth, LBW, and IUGR were evaluated with chi-square and Fisher's exact tests and logistic regression analysis. The association between continuous variables and APO was examined using the t test for assessing differences in means and non-parametric methods (median scores test) for assessing differences in medians. CD4 lymphocyte count, quantitative PBMC HIV culture titer, and HIV RNA copy number were evaluated as both categorical and continuous variables; quantitative PBMC HIV culture titer and HIV RNA copy number were log-transformed for analyses. HIV RNA assays with results below the level of quantification were set to the midpoint between zero and the quantification limit (e.g. 250 copies/ml). All variables significantly associated (P ≤ 0.10) with preterm birth, LBW, or IUGR in univariate analyses were included in the multivariate logistic regression models, along with the laboratory measures of maternal HIV infection [entry CD4 lymphocyte absolute count, entry HIV culture titer (log10 ), and entry HIV RNA (log10 )]. Beginning with this initial model, a stepwise backward elimination approach was used to exclude variables not contributing significantly to the model, and thereby assess the stability of the parameter estimates for the independent predictors of the outcomes. Differences between the initial and reduced model are noted. Investigation of the effect of multicollinearity due to correlations between these laboratory measures was not necessary as a prior investigation of such indicated that it did not significantly affect the multivariate analyses [22] [26]
Results
Study population
Five-hundred and one women were enrolled into the study; four were lost to follow-up prior to delivery, resulting in a final study population of 497 women. Data were evaluated for all 497 women for purposes of analysis of risk factors for preterm birth, LBW, and IUGR. There were 505 live-infants, including nine sets of twins and 487 singleton live births; one infant was stillborn. There were no significant differences between the HIVIG and IVIG study groups with respect to baseline maternal antenatal, obstetric or neonatal characteristics, including rates of preterm birth, LBW, and IUGR (data not shown). Overall, 24 (4.8%) infants were infected with HIV [95% confidence interval (CI), 2.9–6.7%].
Eighty-six percent of the women enrolled in the study were of minority race/ethnicity (Table 1 ). Cigarette smoking during pregnancy was reported by 31% of women; alcohol use by 18%; and hard drug use by 13%. Twenty-seven percent of women were diagnosed with a sexually transmitted disease (STD) during the current pregnancy. These STD included gonorrhea (3%), chlamydia (11%), syphilis (11%), and genital herpes (11%); women could be diagnosed with more than one STD during pregnancy. During pregnancy, 68 women (14%) received combination ART: 66 women received two-drug combination therapy, and two women received three drugs. One woman received delavirdine and one woman received a short course of ritonavir as part of combination therapy administered late in pregnancy. Six women (1.2%) received treatment initially with ZDV but were later switched to a single nucleoside analogue other than ZDV. ZDV was initiated before 14 weeks gestation (including before pregnancy) in 40% of study mothers, between 14 and 26 weeks gestation in 54%, and after 26 weeks gestation in only 6% of study mothers. At baseline, the median CD4 cell count was 315 × 106 /l (range, 3–911 × 106 /l); HIV culture titer was 8.1 IUPM (range, 0.32–5608 IUPM); and HIV RNA copy number was 8100 copies/ml (range < 500 to 1 100 000 copies/ml).
Table 1: Patients characteristics/potential antenatal risk factors.
Univariate analysis of risk factors for preterm birth, LBW and IUGR
Overall, 85 women (17%) delivered preterm, 67 (13%) had LBW infants, and 29 (6%) had infants with evidence of IUGR. A comparison of potential maternal antenatal and obstetric risk factors between those women who had adverse pregnancy outcomes, defined on the basis of the occurrence of preterm birth, LBW or IUGR, compared to those who did not is shown in Table 1 .
Women who had a preterm birth were significantly more likely than those without a preterm birth to have a prior history of preterm births (P < 0.001); current multiple gestation pregnancy (P = 0.009); and syphilis (P = 0.07), genital herpes (P = 0.04), or pre-eclampsia (P = 0.005) diagnosed during the current pregnancy (Table 1 ). Maternal age at entry and antenatal alcohol use had a borderline significant association (P ≤ 0.10). The rates of preterm births did not differ by race/ethnicity (P = 0.58); the rate among African–Americans, whites and Hispanics was 18.2%, 18.8%, and 14.6%, respectively. No significant association of preterm birth was observed with maternal baseline antenatal CD4 cell count [odds ratio (OR), 1.03 per 100 cell decrement in absolute CD4 count; 95% CI, 0.88–1.21], HIV culture titer (OR, 1.19 per 1 log10 increment in HIV culture titer; 95% CI, 0.94–1.52), or HIV RNA copy number (OR, 1.09 per 1 log10 increment in HIV RNA copy number; 95% CI, 0.84–1.41) (Table 2 ).
Table 2: Preterm birth risk factors.
Women who had a LBW infant were significantly more likely than those who did not to have a prior history of preterm births (P = 0.006); a current multiple gestation pregnancy (P < 0.001); antenatal use of cigarettes (P = 0.005), alcohol (P = 0.023), and/or hard drugs (P < 0.001); syphilis (P = 0.05), genital herpes (P = 0.02), or pre-eclampsia (P = 0.014) diagnosed during the current pregnancy; and a higher baseline mean and median HIV culture titer (P < 0.05) (Table 1 ). The rates of LBW differed by race/ethnicity, but not significantly so (P = 0.23); the rate was 15.9% among African–Americans, 10.9% for whites, and 10.5% among Hispanics. A significant association of LBW with maternal age at study entry (OR, 1.79; 95% CI, 1.06–3.00) and baseline antenatal HIV culture titer (OR, 1.43; 95% CI, 1.09–1.87) was observed in univariate logistic regression analyses (Table 3 ). No significant association of LBW was observed with maternal baseline antenatal CD4 cell count (OR, 1.02; 95% CI, 0.85–1.21) or HIV RNA copy number (OR, 1.26; 95% CI, 0.94–1.69).
Table 3: Low birth weight risk factors.
Women who had an infant with evidence of IUGR were significantly more likely than those who did not to have a current multiple gestation pregnancy (P = 0.01); antenatal use of cigarettes (P = 0.001) and/or hard drugs (P = 0.006); pre-eclampsia diagnosed during the current pregnancy (P = 0.008); and a higher baseline mean HIV culture titer (P = 0.08) (Table 1 ). The rates of IUGR did not differ by race/ethnicity (P = 0.60); the rate among African–Americans, whites and Hispanics was 6.2%, 3.1%, and 6.4%, respectively. In univariate logistic regression analyses, no significant association of IUGR was observed with maternal baseline antenatal CD4 cell count (OR, 0.98; 95% CI, 0.76–1.27), HIV culture titer (OR, 1.41; 95% CI, 0.96–2.06) or HIV RNA copy number (OR, 1.43; 95% CI, 0.92–2.21) (Table 4 ).
Table 4: Intrauterine growth retardation risk factors.
Factors that were not related to preterm birth, LBW, or IUGR included gestational age of the woman at entry into the trial; the diagnosis of a urinary tract infection or gestational diabetes during the current pregnancy; receipt of ART during pregnancy (monotherapy versus combination therapy and timing of initiation of ZDV therapy); and the HIV infection status of the infant.
Multivariate analysis of risk factors for preterm birth, LBW and IUGR
A multivariate model containing variables significantly (P ≤ 0.10) associated with risk for preterm delivery in univariate analyses and the laboratory measures of maternal HIV infection (entry CD4 cell count, HIV culture titer, and HIV RNA copy number) was developed. On multivariate analysis, each of the factors associated with preterm birth in the univariate analyses remained independently associated with risk in the multivariate model (Table 2 ). The fitted model included prior history of preterm births (OR, 3.34; 95% CI, 1.70–6.55); current multiple gestation (OR, 6.02; 95% CI, 1.50–24.13); antenatal alcohol use (OR, 1.91; 95% CI, 1.04–3.53); and the diagnosis of genital herpes (OR, 0.24; 95% CI, 0.07–0.82), and pre-eclampsia during the current pregnancy (OR, 6.36; 95% CI, 1.26–32.04). Neither maternal age at entry, the diagnosis of syphilis during pregnancy, antenatal immune status, HIV culture titer nor viral load was significantly associated with preterm birth when included in the multivariate model. The reduced model fit to the data included prior history of preterm births, current multiple gestation, antenatal alcohol use, and the diagnosis of genital herpes and pre-eclampsia during the current pregnancy; the OR associated with these variables were not appreciably altered from the fuller model.
Similarly, a multivariate model was developed containing variables significantly associated with risk for LBW in univariate analyses. Since all of the birth weights assigned to twin births were < 2500 g, the OR for the association of multiple gestation with LBW could not be calculated. Variables analyzed in the multivariate model included maternal age at baseline as a categorical variable [> median versus ≤ median (26 years of age)]; prior history of preterm births; antenatal cigarette, alcohol and hard drug use; the diagnosis of syphilis, genital herpes, and pre-eclampsia during the current pregnancy; and laboratory measures of maternal HIV infection (baseline CD4 cell count, HIV culture titer, and HIV RNA copy number). On multivariate analysis, the diagnosis of genital herpes (OR, 0.08; 95% CI, 0.01–0.60) and pre-eclampsia during the current pregnancy (OR, 6.48; 95% CI, 1.29–32.57) remained significantly associated with the risk of having a LBW infant, as did maternal HIV culture titer (OR, 1.41; 95% CI, 1.02–1.95). The reduced model identifying the best predictors for LBW included: antenatal cigarette use (OR, 2.57; 95% CI, 1.45–4.56); the diagnosis of syphilis (OR, 2.76; 95% CI, 1.08–7.06), genital herpes (OR, 0.08; 95% CI, 0.01–0.63), and pre-eclampsia during the current pregnancy (OR, 6.29; 95% CI, 1.30–30.42); and HIV culture titer (OR, 1.59; 95% CI, 1.20–2.09).
Lastly, a multivariate model was developed containing variables significantly associated in univariate analyses with risk for IUGR. On multivariate analysis, current multiple gestation (OR, 8.20; 95% CI 1.67–40.39); antenatal cigarette use (OR, 3.60; 95% CI 1.41–9.24); and the diagnosis of pre-eclampsia during the current pregnancy (OR, 12.90; 95% CI 2.03–81.88) were significantly associated with the risk of having an infant with IUGR. Maternal antenatal hard drug use, antenatal immune status, HIV culture titer, and viral load were not associated with IUGR when included in the multivariate model. The reduced model fit to the data included current multiple gestation, antenatal cigarette smoking, and the diagnosis of pre-eclampsia during the current pregnancy; the OR associated with these variables did not vary appreciably from those of the fuller model.
Discussion
Women infected with HIV may have other behaviors that place them at risk for adverse pregnancy outcome, making it difficult to separate the independent roles of non-HIV associated factors and those more directly related to HIV, such as uncontrolled viral replication and immunosuppression. The rate of preterm and LBW births in the HIV-infected women in our study (17% and 13%, respectively), is in a similar range as that reported for many other HIV-uninfected minority obstetric populations [27,28] [27]
The rates of APO in our study are actually lower than those reported in many published studies describing cohorts of HIV-infected pregnant women in the USA. In a report on pregnancy outcome in HIV-infected women from the Women and Infants Transmission Study (WITS), the rate of preterm birth was 21% and LBW was 19%[12] [29]
Use of ART may be associated with lower rates of adverse pregnancy outcome than that observed in HIV-infected women not receiving such therapy. Lower rates of preterm birth and LBW infants have been reported in women receiving ZDV compared to those not receiving ZDV in the European Collaborative Study [19]
However, the safety of most individual antiretroviral agents and of combination regimens for the pregnant woman and her fetus continues to be under scrutiny and there are questions about their effect on pregnancy outcome. A retrospective study from Switzerland found that 33% of 30 women who received combination therapy had preterm deliveries [20]
Some published studies have implicated low CD4 cell counts and advanced HIV disease as risk factors for APO among HIV-infected women [12,30,31] [19]
In contrast to data from other studies, we did not find an association between race/ethnicity and preterm birth, LBW, or IUGR. However, the vast majority of women in our study were of minority race/ethnicity, and only a small proportion were Caucasian, reflective of the epidemiology of HIV infection in women in the USA. Therefore, there was very limited power to detect a difference in adverse outcomes by race/ethnicity in our study.
A number of early natural history studies have reported an association between prematurity and a higher risk of HIV infection in the infant [32–35] [32] [12,35–38] [39] et al have speculated that ART during pregnancy may have an indirect effect on perinatal transmission by reducing elevated rates of preterm delivery and LBW seen in untreated women [31]
In summary, in this large cohort of ZDV-receiving mothers and infants enrolled in PACTG 185, rates of preterm delivery, LBW, and IUGR and risk factors for these adverse outcomes, were comparable with those to uninfected women of similar race/ethnicity who received adequate prenatal care. This finding is in contrast to studies from untreated HIV-infected women, in whom high rates of adverse pregnancy outcome have been described and these outcomes have been associated with HIV disease stage. Although a temporal trend of reduced preterm birth and low birth weight unrelated to specific HIV care or ART cannot be ruled out, this effect is unlikely since an increasing rate of preterm birth has been observed in the USA and Canada in recent years [27,40]
Acknowledgements
The authors thank M. Luby and N. Daigle for secretarial assistance, J. Read and M.-L. Newell for review and critique of the manuscript.
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Appendix
PACTG 185 participating sites, principal investigators, and protocol team members
Case Western University Hospital, Cleveland, OH: P. Toltzis and S. Gillinou; University of Medicine & Dentistry of New Jersey, Newark, NJ: J. Oleske, A. Bardequez; Children's Hospital and Brigham and Women's Hospital, Boston, MA: S. Burchett, K. McIntosh and R. Tuomala; Boston Medical Center, Boston, MA: S. Pelton and M. Mirochnick; University of California Medical Center at Los Angeles, Los Angeles, CA: E.R. Stiehm, Y. Bryson and P. Boyer; Harbor University of California Medical Center, Los Angeles, CA: M. Keller and M. Beall; Johns Hopkins University School of Medicine, Baltimore, MD: J. Lambert, A. Ruff and J. Anderson; University of Maryland, Baltimore, MD: P. Vink and L. Alger; Baylor College of Medicine and University of Texas Medical School, Houston, TX: W. Shearer and H. Hammill, Houston: Columbia Presbyterian Medical Center, New York, NY: A. Gershon, J. Pitt and G. Brown; University of Miami School of Medicine, Miami, FL: G. Scott and M.J. O'Sullivan; Mount Sinai School of Medicine, New York, NY: H. Sacks and R. Sperling; New York University Medical Center, New York, NY: W. Borkowsky and M. Allen; University of California at San Francisco and San Francisco General Hospital, San Francisco, CA: D. Wara, S. Kilpatrick; and D. Landers; University of California at San Diego, La Jolla, CA: S. Spector, M. Besser, M. Caffery; University of North Carolina, Chapel Hill, NC: W. Lim and M. McMahon; University of Illinois, Chicago, IL: K. Rich and M. Vajaranant; San Juan City Hospital, San Juan, PR: E. Jimenez and J. Gandia; Ramon Ruiz Arnau University Hospital, Bayamon, PR: R. Aguayo and H. Cintron-Principe; State University of New York at Stony Brook, Stony Brook, NY: S. Nachman and D. Baker; Children's Hospital Michigan and Hutzel Hospital, Detroit, MI: E. Moore and T. Jones; Albany Medical Center, Albany, NY: M. Lepow, N. Wade and R. Samelson; University of Texas Southwestern Medical Center, Dallas, TX: J. Squires and G. Wendel; Howard University Hospital, Washington, D.C.: S. Rana and B. Wesley; University of Southern California/Los Angeles County Medical Center, Los Angeles, CA: A. Kovacs and A. Stek; University of Florida Health Science Center, Jacksonville, FL: M. Rathore and I. Delke; University of Colorado Health Science Center, Denver, CO: M. Levin, E. McFarland, and J. McGregor; Virginia Commonwealth University, Richmond, VI: S. Lavoie and M. Dinsmoor; St Jude Children's Research Hospital, Regional Medical Center of Memphis, Methodist Hospital, Memphis, TN: P. Flynn and R. Lewis; University of Puerto Rico School of Medicine, San Juan, PR: C. Diaz and C. Zorrilla; Children's Hospital of Philadelphia and Hospital of University of Pennsylvania, Philadelphia, PA: S. Starr, J. Merrill and N. Rose; Thomas Jefferson University Hospital, Philadelphia, PA: S. Adeniyi-Jones and N. Silverman; St. Christopher's Hospital for Children and Temple University, Philadelphia, PA: H. Lischner and V. Whiteman; Children's Hospital and Medical Center, Seattle, WA: L. Frankel and D.H. Watts; Bronx Lebanon Hospital, Bronx, NY: A. Wiznia and L. Solomon; Children's National Medical Center and Washington Hospital Center, Washington, D.C.: T. Rakusan and P. Goldstein; Children's Hospital of the King's Daughter and Sentara Norfolk General, Norfolk, VI: T. Rubio and B. Dattel; Tulane University and Louisiana State University, New Orleans, LA: M. Silio, Russell Van Dyke, and R. Maupin; Medical Center of Central Massachusetts, Worcester, MA: W. Durbin and K. Green; Baystate Medical Center, Springfield, MA: B. Stechenberg and L. Bayer-Zwerillo; University of Connecticut Health Center and Connecticut Children's Medical Center, Farmington, CT: P. Krause and W. Campbell; University of Alabama at Birmingham, Birmingham, AL: R. Pass and J. Hauth; State University of New York Health Science Center, Brooklyn, NY: H. Minkoff; George Washington University Medical Center, Washington, D.C.: H. Fox University of Minnesota, Minneapolis, MN: C. Fletcher; Community Representatives: B. Finley, J. Davids; PACTG Statistical and Data Analysis Center, Harvard University School of Public Health, Boston, MA: D. Shapiro; National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD: G. Nemo, L. Barbosa, E. Sloand, N.L. Geller, D. Follman; National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD: L. Mofenson, J. Moye, R. Nugent, A. Willoughby; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD: M.G. Fowler, P. Reichelderfer, L. Purdue, B. Mathieson; Westat, Rockville, MD: J. Whitehouse, J. Bethel, J. Korelitz, D.R. Harris, W. Owen, E. Yu, R. Mitchell, D. Butler, D. DeRycke; Wanda Upole; NABI, Boca Raton, FL: C.V. Sapan; Glaxo Wellcome, Research Triangle Park, NC: S. Hetherington; Quest Diagnostics, Baltimore, MD: W.A. Meyer, III, H. Suter, M. Bradley.
