www.elsevier.com/locate/ajog

American Journal of Obstetrics and Gynecology (2004) 190, 506e16

Maternal toxicity and pregnancy complications in humanimmunodeficiency viruseinfected women receivingantiretroviral therapy: PACTG 316

D. Heather Watts, MD,a,* Rajalakshmi Balasubramanian, DSc,b

Robert T. Maupin Jr, MD,c Isaac Delke, MD,d Alejandro Dorenbaum, MD,e

Simone Fiore, MD,f Marie-Louise Newell,f Jean-Francois Delfraissy, MD,g

Richard D. Gelber, PhD,b Lynne M. Mofenson, MD,a Mary Culnane, MS, CRNP,h

Coleen K. Cunningham, MD,i for the PACTG 316 Study Team

National Institute of Child Health and Human Development, Bethesda, Md,a the Statistical and Data Analysis Center,Harvard School of Public Health, Boston, Mass,b Louisiana State University, New Orleans, La,c the University ofFlorida, Jacksonville, Fla,d BioMarin Pharmaceutical, Inc, Novato, Calif,e the Institute of Child Health, London,United Kingdom,f Agence Nationale de Rescherches sur le SIDA, APHP, Biatze Hospital,g Centers for DiseaseControl,h Bangkok, Thailand, and the State University of New York, Upstate Medical University, Syracuse, NY i

Received for publication May 20, 2003; revised July 24, 2003; accepted July 29, 2003

––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––Objective: The purpose of this study was to evaluate rates of maternal toxicity, pregnancy com-plications, and peripartum morbidity by type and duration of antiretroviral therapy (ART) dur-

ing pregnancy.Study design: The Pediatric AIDS Clinical Trials Group (PACTG) Protocol 316 (PACTG 316)study evaluated the addition of intrapartum/neonatal nevirapine to background ART to reduce

perinatal transmission of human immunodeficiency virus-1 (HIV-1). For this secondary analysis,women were categorized into one of six groups on the basis of ART during pregnancy (monother-apy [monoRx], combination without protease inhibitor [PI], combination with PI), and start time(early: before or during first trimester; late: second or third trimester).

Results: One thousand four hundred seven women were included: 288 monoRx late, 34 monoRxearly, 327 combo, no PI late, 175 combo, no PI early, 320 combo, PI late, and 263 combo, PI

KEY WORDSHuman

immunodeficiencyvirus infection

PregnancyAntiretroviral therapy

Supported by the Pediatric AIDS Clinical Trials Group of the

National Institute of Allergy and Infectious Diseases and the Pediatric/

Perinatal HIV Clinical Trials Network of the National Institute of

Child Health and Human Development, National Institutes of Health,

the Agence Nationale de Recherches sur le SIDA (ANRS 083) and

Boehringer Ingelheim (France); and the European Commission (PL

962005 and QLRT-1999-30002) and the Medical Research Council (UK).

This analysis was supported by the Statistical and Data Analysis Center

of the AIDS Clinical Trials Group, under the National Institute of

Allergy and Infectious Diseases cooperative agreement No. U01 AI41110.

0002-9378/$ - see front matter � 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.ajog.2003.07.018

Study sites in the United States and other countries with the

corresponding investigators are listed in the Appendix.

Presented in part as a poster session at the Tenth Conference on

Retroviruses and Opportunistic Infections, Boston, Mass, February

2003.

*Reprint requests: D. Heather Watts, MD, Pediatric, Adolescent

and Maternal AIDS Branch, CRMC/NICHD/NIH, 6100 Executive

Blvd, Room 4B11, MSC 7510, Bethesda, MD 20892-7510.E-mail: hw59I@nih.gov

Watts et al 507

early. Symptoms and laboratory abnormalities of moderate grade or more occurred in less than5% of women. Only gestational diabetes (highest in combo PI early) varied significantly by ther-

apy group.Conclusion: In HIV-infected women receiving prenatal care and ART, adverse events were un-common.

� 2004 Elsevier Inc. All rights reserved.

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Pregnant women are increasingly being treated withmultiple antiretroviral drugs during pregnancy, eitherfor their own care or for prevention of perinatal transmis-sion of human immunodeficiency virus-1 (HIV-1).1-3

Although rates of perinatal transmission of less than2% have been reported with use of combination antire-troviral regimens,1,4 the potential for complicationsmay increase with the number of drugs used during preg-nancy.5 Data are conflicting as to whether the use ofcombination therapy including protease inhibitors (PI)during pregnancy increases the risk of preterm deliv-ery.5,6 Maternal complications such as lactic acidosisand hepatic failure have been reported with the use ofseveral combination regimens during pregnancy, andthe risk may increase with duration of therapy.7,8 Inaddition, pregnancy may increase the risk of otherside effects of antiretroviral agents, such as anemia orvomiting, which may have an impact on adherence andefficacy. Further study of the impact of combinationantiretroviral therapy (ART) on pregnancy out-come and on the rates of toxicity during pregnancy isneeded.

The Pediatric AIDS Clinical Trials Group (PACTG)Protocol 316, a trial of peripartum nevirapine versusplacebo in addition to standard ART to prevent perina-tal transmission of HIV-1,4 provided an opportunity toexamine the effect of combination therapy on pregnancyoutcome. In particular, the impact of ART on maternaltoxicity, pregnancy complications and maternal peripar-tum morbidity according to the type and duration ofART during pregnancy was examined.

Material and methods

PACTG 316 was a phase III, randomized, double-blindtrial designed to evaluate whether adding a two-dose ne-virapine regimen (one dose intrapartum to the womanand one dose 48 hours after birth to the infant) to estab-lished ART would decrease the rate of perinatal trans-mission of HIV-1 compared with placebo. ART, chosenon the basis of established treatment guidelines andlocal standard of care, was prescribed by the woman’sprimary provider. The primary results of the trial havebeen reported previously.4 At the third planned interimanalysis, the Data and Safety Monitoring Board recom-mended early closure of the study because the overall

transmission rate of 1.5% was significantly less thanthe 5% rate used for sample size estimation, and thelarge sample size required to detect a difference in trans-mission rates at this level was impractical. Enrollmentoccurred at sites in the United States, Europe, Brazil,and the Bahamas. The study protocol and informedconsent were reviewed and approved by the institutionalreview board at each study site. Written informed con-sent was obtained from each woman and the father ofthe baby, if available.

Eligible subjects were HIV-infected women who wereaged 13 years or older (or of legal age to give consent)and at least 20 weeks of gestation. Enrollment was initi-ated in May 1997. Gestational age was estimated withuse of either reliable menstrual history that corre-sponded with uterine size or sonogram performed at lessthan 20 weeks’ gestation. Women were excluded fromthe study if they were enrolled in other perinatal treat-ment trials, had previously received non-nucleoside re-verse transcriptase inhibitors, were hypersensitive tobenzodiazepines, or had elevated serum alanine amino-transferase (ALT) 10 times higher than the upper limitof normal (ULN). Women who intended to breast-feedand whose pregnancies were identified with a fetalanomaly incompatible with life were also excluded.

A total of 1506 women were enrolled into PACTG316. Of these women, 84 were taken out of the study be-fore delivery: 54 because of study closure by the Dataand Safety Monitoring Board, 16 voluntarily withdrew,and 14 were lost to follow-up, leaving a total of 1422 forinclusion in this analysis. Of these women, 15 were ex-cluded, 8 because they received no ART and 7 becausethey had missing dates of initiation of ART, resultingin a total of 1407 women.

Women underwent clinical and laboratory evalua-tions at enrollment, during labor, between 48 and 72hours after delivery, and at 4 to 6 weeks’ post partum.Evaluations at each visit included history and physicalexamination, complete blood cell count, CD4+ lympho-cyte count, blood chemistry levels, and HIV-1 RNAquantification. At enrollment, detailed information re-garding obstetric history, antiretroviral use before andduring pregnancy, clinical events, screening for genitalinfections, and other laboratory and sonographic testingduring pregnancy, was collected with use of standard-ized forms, and source documentation was obtained forall testing and events. Toxicities were graded according

508 Watts et al

to the National Institute of Allergy and InfectiousDiseases Division of AIDS Toxicity Tables (http://pactg:cure@roc.s-3.com/members/download/adulttox.doc). Signs and symptoms were graded as mild, moder-ate, severe, or life threatening, with mild symptoms(grade 1) causing transient or mild discomfort and re-quiring no therapy; moderate symptoms (grade 2) caus-ing mild-to-moderate limitation in activity but requiringno therapy or only outpatient treatment; and severesymptoms (grade 3) causing marked limitation in activ-ity requiring medical intervention and possible hospital-ization. Grade 4 signs or symptoms were considered lifethreatening, requiring significant medical interventionand probable hospitalization. For example, vomitingwould be coded as grade 1 if two to three episodes oc-curred daily for less than 1 week; as grade 2 if four to fiveepisodes occurred daily or mild vomiting lasted for morethan 1 week; as grade 3 if all food and fluids had beenvomited in the past 24 hours or orthostatic hypotensionwas present or intravenous hydration was required; andgrade 4 if hypotensive shock was present or hospitaliza-tion for continued intravenous hydration was required.

Hematology and chemistry studies were performedwith use of local institutional standard procedures.The following laboratory criteria met the definition formoderate or greater toxicity and were used in the anal-ysis: hemoglobin below 8 g/dL, absolute neutrophilcount below 1000/mm3, platelet count below 75,000/mm3, amylase 1.5 times greater than ULN, aspartameaminotransferase (AST) greater than 2.5 times ULN,ALT 2.5 times greater than ULN, or creatinine 1.5 timeshigher than ULN.

Pregnancy and peripartum complications were diag-nosed on the basis of standard criteria adopted by thePACTG. Gestational diabetes was diagnosed based onthe presence of two abnormal values on a standard100-g, 3-hour glucose tolerance test,9 fasting hyperglyce-mia (glucose O95 mg/dL) on at least two separate occa-sions, or oral serum glucose O200 mg/dL 1 hour aftera 50-g glucose load. Gestational hypertension withoutproteinuria and preeclampsia were defined accordingto standard criteria and considered together as hyper-tensive disorders.10 Preterm labor was diagnosed ifpreterm contractions occurred with cervical changesufficient to warrant administration of oral or parenteraltocolytic agents or with delivery. Because only 4% of thewomen enrolled by 28 weeks of gestation and 26% by 32weeks, rates of preterm birth were not assessed by treat-ment group. Oligohydramnios was defined as an amni-otic fluid index under 5 cm or largest vertical pocketunder 2 cm, and polyhydramnios was defined as an am-niotic fluid index above 24 cm or largest vertical pocketabove 8 cm. Cesarean deliveries performed before theonset of labor and rupture of membranes were classifiedas scheduled, regardless of indication, and all otherswere categorized as urgent.

Pneumonia was diagnosed if fever and clinical find-ings, such as cough or dyspnea with an abnormal chestx-ray film consistent with pneumonia, were present. Spe-cific pathogen was recorded when available. The Centersfor Disease Control and Prevention 1993 criteria foracquired immunodeficiency syndrome (AIDS)edefiningconditions were used to categorize diagnoses as AIDSdefining.11 Urinary tract infection, pyelonephritis, post-partum febrile morbidity, endometritis, wound in-fection, and septic pelvic thrombophlebitis were diag-nosed with use of standard criteria.12 Hemorrhage wasdefined as estimated blood loss of more than 750 mLafter vaginal delivery and 1200 mL after cesareandelivery. Severity was graded according to the presenceor absence of hemodynamic instability (blood pres-sure !90/60 mm Hg, or pulse O120 beats/min), needfor treatment with volume expanders alone or transfu-sion, and need for surgical procedures such as uterinecurettage or uterine artery ligation for treatment.

To assess the impact of both type and duration ofARTon outcomes of interest, each subject was assigned toa mutually exclusive category. Women were assigned tothe category according to the most complex therapy re-ceived during pregnancy. ART was categorized as mono-therapy if a single nucleoside agent was administered ata time. If two or more nucleoside agents were received to-gether without a PI, therapy was coded as combinationtherapy without PI. If PI therapy was received with twoor more nucleoside agents, therapy was coded as combi-nation therapy with PI. Therapy was coded as early if itwas begun before pregnancy or during the first trimester,up to 12 completedweeks of gestation. Therapybeginningafter the first trimester was categorized as late. Becauserandomization to the study treatment arms resulted ingroups with similar characteristics,4 and study treatment(nevirapine or placebo) was not begun until labor, studytreatment was not considered in the analyses.

Rates of selected symptoms, toxicities, and pregnancycomplications were assessed by category and timing oftherapy. Rate differences according to therapy groupwere evaluated by a Fisher-Freeman-Halton exact testfor categorical variables and by Kruskal-Wallis test forcontinuous variables.13 Outcomes found to differ bytherapy group were evaluated by multivariate logistic re-gression models. Clinical variables previously associatedwith the outcome, as well as potential confounders suchas age, race, site of enrollment, HIV RNA level, andCD4+ lymphocyte count that varied among therapygroups, were considered for inclusion in the models.Variables associated with the outcome at P!.05 levelwere retained in the final models.

Results

The characteristics of the subjects included in this studyaccording to therapy group are summarized in Table I.

Watts et al 509

Table I Enrollment characteristics according to antiretroviral therapy category during pregnancy

Characteristic

Latemonotherapy(n = 288)(%)

Earlymonotherapy(n = 34)(%)

Latecombo, noPI (n = 327)(%)

Earlycombo, noPI (n = 175)(%)

Late combowith PI(n = 320)(%)

Early combowith PI(n = 263)(%)

Total(n = 1,407)(No. [%]) P value*

Study groupPACTG (US) 51.7 91.2 73.1 66.9 86.9 68.4 70.6 (994) !.001ANRS (France) 28.1 0 20.5 24.0 7.2 21.3 19.1 (269)ECS 11.5 8.8 4.6 8.0 4.7 9.9 7.5 (106)Brazil 2.8 0 1.8 1.1 1.3 0.4 1.5 (21)Bahamas 5.9 0 0 0 0 0 1.2 (17)

Age at entry (y)Median 27.3 29.0 27.0 28.7 27.4 30.6 28.1 .002

RaceWhite 17.7 11.8 22.6 33.7 13.1 31.9 22.4 (315) !.001African, not Hispanic 64.6 76.5 57.8 46.9 62.8 53.2 58.6 (825)Hispanic 17.7 8.8 18.7 16.6 22.5 13.7 17.9 (252)

Other 0 2.9 0.9 2.9 1.6 1.1 1.2 (17)Gestational age

at entry (wk)Median 33.9 34.0 35.0 33.1 35.0 33.4 34.0 .20Range 28.0-42 22.0-39 26.0-42 18.4-39.7 20.0-40 21.7-40.3 18.4-42.4

AIDS-defining illnessbefore pregnancy

0 2.9 1.2 4.6 2.5 18.3 4.9 !.001

CD4 cell countat entry (cells/mL)y

(n = 286) (n = 34) (n = 326) (n = 175) (n = 319) (n = 263) (n = 1403)

Mediany 486.0 452.0 463.5 436.0 375.0 363.0 426.0 !.001%200 4.2 8.8 7.4 6.9 21.9 20.9 12.5 (176)201e500 50.4 44.1 49.1 48.6 50.8 51.3 50.1 (703)O500 45.5 47.1 43.4 44.6 27.3 27.8 37.5 (526)

HIV RNA levelat entry (copies/mL)

(n = 276) (n = 34) (n = 321) (n = 172) (n = 311) (n = 257) (n = 1371)

Medianz 1357.0 946.0 400.0 644.5 400.0 400.0 570.0 !.001%400 24.3 38.2 50.5 37.8 52.7 51.4 44.0 (603)401e2,500 37.7 20.6 22.7 37.8 20.3 17.9 26.1 (358)2,501e5,000 12.7 5.9 7.5 8.7 8.0 7.4 8.8 (121)5,001e10,000 9.1 8.8 4.4 5.8 5.8 7.8 6.6 (91)O10,000 16.3 26.5 15.0 9.9 13.2 15.6 14.6 (200)

Receiving OI prophylaxis 2.1 5.9 5.5 5.7 18.4 16.7 9.9 (139) !.001

PI, Protease inhibitor; PACTG, Pediatric AIDS Clinical Trials Group; ANRS, Agence Nationale de Rescherches sur le SIDA; ECS, European Collaborative Study

group; OI, opportunistic infection.

* P values by Kruskal-Wallis and Fisher-Freeman-Halton exact tests for continuous and categorical variables, respectively.y Earliest CD4 specimen for each individual.z Earliest measurement or specimen obtained at most 1 week after randomization.

Of the 1407 women, 23% received monotherapy, 36%combination therapy without PI, and 41% combinationtherapy including a PI during pregnancy. In the UnitedStates, combination therapy with PI predominated,whereas at French sites combination therapy withoutPI was most common. In the other European and Bra-zilian sites, women were fairly evenly distributed be-tween the three classes of therapy, whereas womenfrom the Bahamas received monotherapy. The racialgroups were representative of the HIV-infected womenof each participating country. The median gestationalage at enrollment was 34 weeks. Therapy groups dif-

fered with respect to CD4+ cell count and HIV RNAlevel at entry. Overall, 2.8% of women had gonococcal,8.2% had chlamydial infections, and 19.4% had bacte-rial vaginosis diagnosed during pregnancy. Only womenenrolled at US sites had detailed information on smok-ing and alcohol use during pregnancy. Of these, 24.2%reported smoking and 9.0% reported alcohol use, andrates did not differ by therapy group. Among allwomen, 8.5% reported injection drug use at enrollment.

Rates of selected symptoms, laboratory abnormali-ties, and pregnancy outcomes are shown in Table II. Themost common symptoms were nausea and vomiting,

510 Watts et al

Table II Maternal signs and symptoms of at least moderate intensity, laboratory abnormalities, and pregnancy outcomes according totreatment during pregnancy

Finding

Latemonotherapy(n = 288)(%)

Earlymonotherapy(n = 34)(%)

Latecombo,no PI(n = 327)(%)

Earlycombo,no PI(n = 175)(%)

Latecombowith PI (%)(n = 320)(%)

Earlycombowith PI(n = 263)(%)

Total(n = 1407)(% [No.])

Signs, symptoms, diagnosesNausea and vomiting 1.7 2.9 4.0 4.6 2.2 3.8 3.1 (44)Rash 1.4 0 1.8 1.7 1.9 2.3 1.8 (25)Headache 1.7 5.9 2.5 3.4 2.2 3.0 2.6 (36)Abdominal pain 2.8 5.9 3.4 2.3 3.4 2.7 3.1 (43)Vaginal bleeding 0 2.9 2.1 1.1 0.9 2.3 1.4 (19)

Laboratory abnormalitiesHemoglobin !8g/dL 1.4 5.9 1.2 1.7 3.8 2.3 2.2 (31)Absolute neutrophilcount !1000/mL

0.7 0 0.3 0 0.3 1.1 0.5 (7)

Platelets !75,000/mL 0 0 0.6 0.6 1.3 0 0.5 (7)Amylase O1.5 ! ULN 0 2.9 0 0 0 0.4 0.1 (2)ASTO2.5 ! ULN 0.7 0 0.6 0.6 0.6 1.9 0.9 (12)ALTO2.5 ! ULN 0.7 0 1.2 0.6 0.6 2.7 1.1 (16)

Obstetric outcomesGestational diabetesa 1.4 0 2.4 1.7 0.6 4.6 2.1 (29)Hypertensive disorders 4.5 5.8 6.2 6.9 5.0 6.0 5.6 (79)Preterm laborrequiring tocolysis

4.9 2.9 2.1 4.6 3.8 6.1 4.1 (58)

Oligohydramnios 3.8 2.9 3.4 3.4 2.5 1.9 3.0 (42)Polyhydramnios 0.4 0 0.6 0 1.6 0 0.6 (8)Median gestational ageat delivery (wk [range])

38.1(29.1-47.1)

38.1(23.9-41.3)

38.7(30.3-43.3)

38.0(25.0-42.1)

38.4(23.4-42.9)

38.1(21.9-43.6)

38.3(21.9-47.1)

Median birth weight (g)* 3071.0 3140.0 3112.0 3050.1 3030.3 3050.0 3070.0Stillbirth 0 0 0.9 0.6 0.6 0 0.4 (6)Mode of deliverya

Vaginal, spontaneous,or forceps

41.6 61.8 56.9 51.5 53.5 46.8 50.5 (711)

Urgent cesarean 16.3 14.7 15.9 16.0 21.3 18.3 17.6 (248)Scheduled cesarean 42.1 23.5 27.2 32.6 25.3 35.0 31.8 (448)

Multiple pregnancy 2.4 0 1.5 1.7 3.4 1.5 2.1 (30)a P values by Fisher-Freeman-Halton exact tests, unadjusted for multiple comparisons. Gestational diabetes: P = .038; mode of delivery: P!.001. PI,

Protease inhibitor; ULN, upper limit of normal; AST, aspartate aminotransferase; ALT, alanine aminotransferase.

* If multiple birth, birth weight for twin A only included.

reported by 3.1% of women, headache in 2.6%, andabdominal pain in 3.1%. Vaginal bleeding differedslightly between groups but had a maximum frequencyof 2.9%. Likewise, rates of laboratory abnormalitieswere low, occurring in less than 3% of subjects, withthe exception of hemoglobin values below 8 g/dL, whichoccurred in 5.9% of women in the early monotherapygroup and 3.8% in the combination with PI starting lategroup. Abnormal liver enzyme tests occurred in a totalof 20 (1.4%) women, including both AST and ALT in8, AST in 4 only, and ALT in 8 only. No creatinine orlipase elevations were reported.

Rates of pregnancy complications and selected out-comes were not significantly different between treatmentgroups with the exception of gestational diabetes (Table

II). Univariate and multivariate analyses for factors as-sociated with gestational diabetes are shown in TableIII. Late monotherapy was used as the reference groupbecause this group had the least antiretroviral exposure.The association between maternal therapy group andthe development of gestational diabetes was assessedwhile controlling for site of enrollment, age, race,CD4+ cell count, and HIV RNA level at entry. Therapygroup (P=.03), site of enrollment (P!.001), and ma-ternal age (P=.01) were significantly associated withgestational diabetes in multivariate analysis. The highestevent rate of 4.6% was seen in the early combo with PIgroup and the lowest of 0% in the early monotherapygroup. Limiting the analysis to 1314 women for whommaternal weight at entry was available yielded similar

Watts et al 511

Table III Univariate and multivariate analyses of factors related to gestational diabetes

Total

Univariateanalysis results

Multivariateanalysis results

Risk factor subjects Events % (95% CI) P value OR (95% CI) P value OR (95% CI)

Total 1407 29 2.1% (1.0-3.0)

Maternal antiretroviral group .023 .03Late monotherapy 288 4 1.4% (0.4-3.5) Reference ReferenceEarly monotherapy 34 0 0% (0.0-10.0) NA NALate combo, no PI 327 8 2.4% (1.1-4.8) 1.78 (0.53-5.98) 1.28 (0.38-4.34)Early combo, no PI 175 3 1.7% (0.4-4.9) 1.24 (0.27-5.60) 0.87 (0.19-4.00)Late combo with PI 320 2 0.6% (0.1-2.2) 0.45 (0.08-2.46) 0.25 (0.05-1.38)Early combo with PI 263 12 4.6% (2.4-7.8) 3.39 (1.08-10.66) 1.94 (0.60-6.28)

Site of enrollment .003 !.001PACTG 994 28 2.8% (1.9-4.1) Reference ReferenceFrance 269 0 0% (0-1.4) d dECS 106 1 0.9% (0-5.2) 0.33 (0.04-2.44) 0.23 (0.03-1.74)Bahamas 17 0 0% (0-19.5) d dBrazil 21 0 0% (0-16.1) d d

Maternal age(per 1 year increase)

.012 1.09 (1.02-1.16) .01 1.09 (1.02-1.17)

Race/ethnicity .344White 314 4 1.3% (0.4-3.2) ReferenceAfrican American 824 16 1.9% (1.1-3.1) 1.54 (0.51-4.63)Hispanic 252 8 3.2% (1.4-6.2) 2.54 (0.76-8.54)Other 17 1 5.9% (0.2-28.7) 4.84 (0.51-45.87)

CD4 at entryy .27Log10CD4 3.23 (0.66-15.94)

RNA at entry* .80Log10RNA 0.85 (0.48-1.49)

NA, Not applicable because no events were observed.

* RNA at entry: 36 mothers were missing RNA at entry. One out of 36 had gestational diabetes. RNA is modeled as follows: If HIV RNA =missing: RNA

missing = 1, Log10RNA = 0; else if HIV RNA %400: Log10RNA = Log10(400), RNA missing = 0; else if HIV RNAO400: Log10RNA = Log10(copy/mL), RNA

miss = 0.y CD4 at entry: 5 mothers were missing CD4 count at entry. None (out of 5) had gestational diabetes. CD4 is modeled as follows: If CD4 =missing: CD4

missing = 1, Log10CD4 = 0; else: CD4 missing = 0, Log10CD4 = Log10(CD4�count).

results, with therapy group adjusting for site of enroll-ment and age associated with gestational diabetes;maternal weight was not associated with gestationaldiabetes (data not shown).

The median gestational age at delivery was 38 weeksor more in all therapy groups and did not differ signifi-cantly among groups. A total of 6 (0.4%) stillbirths oc-curred. Of note, the median gestational age varied bymode of delivery, with women delivered vaginally hav-ing a median gestational age of 38.9 weeks comparedwith 38.0 weeks for women undergoing urgent cesareanand 38.1 weeks for those undergoing scheduled cesareansection (P!.001). Although the rate of urgent cesareandelivery did not vary by therapy group, the rate ofscheduled cesarean section did, with the highest rate oc-curring among women initiating monotherapy later inpregnancy (42.1%).

Among 179 women, 243 hospitalizations occurred atany time during the study pregnancy, not including de-

livery hospitalization, for a rate of 17.3 nondelivery hos-pitalizations/100 delivery hospitalizations (Table IV).The largest group (97, 40%) of nondelivery hospitaliza-tions were related to obstetric indications such as pre-term labor, hypertensive disorders of pregnancy, andglucose control. Bacterial infections, predominantlypneumonia and pyelonephritis, accounted for 20% ofantepartum admissions. Management of intercurrentmedical illnesses such as asthma and sickle cell crisis ac-counted for 10% of admissions. Hospitalizations fortreatment of substance abuse or major depression ac-counted for 9% of admissions. Evaluation and treat-ment of gastrointestinal symptoms accounted for 8%,AIDS-associated conditions for 4%, viral infections,predominantly upper respiratory infections, accountedfor 5%, and miscellaneous conditions accounted for4%.

Additional selected complications assessed are sum-marized in Table V. Bacterial pneumonia was common,

512 Watts et al

Table IV Indications for hospitalizations during pregnancy,excluding delivery hospitalization, among enrolled women

Condition% of totaladmissions

Rate ofnondeliveryhospitalizations/100 deliveries

Total 243admissions

1407 deliveries

Obstetric indications 39.8 6.9Preterm labor 19.3 3.3Hypertensive disorders 6.1 1.1Glucosecontrol in diabetics

5.7 1.0

Fetal distressor growth restriction

2.0 0.4

Pretermrupture of membranes

2.0 0.4

Cerclage placement 2.0 0.4Vaginal bleeding 1.2 0.2Other obstetricconditions

1.2 0.2

Bacterial infections 19.7 3.4Pneumonia 9.0 1.6Pyelonephritis 7.0 1.2Tonsillitis/bronchitis 1.6 0.3Other infections 2.0 0.4

Medical conditions 9.8 1.6Asthma 2.9 0.5Sickle cell crisis 2.5 0.4Anemia 1.2 0.2Thrombophlebitis 0.8 0.1Kidney stones 0.8 0.1Other medical conditions 1.6 0.3

Psychosocial issues 9.0 1.6Substance abuse treatment 5.7 1.0Major depression 3.3 0.6

Gastointestinal symptoms 7.8 1.4Nausea/vomiting 2.9 0.5Diarrhea 1.6 0.3Gastroenteritis 1.2 0.2Pancreatitis 0.8 0.1Dehydration 1.2 0.2

HIV-associated conditions 4.0 0.7P carinii pneumonia 2.0 0.4Esophageal candidiasis 0.4 0.07Lymphoma 0.4 0.07Cervical cancer 0.8 0.1Histoplasmosis 0.4 0.07

Viral infections 4.9 0.9Herpes simplex virus 0.4 0.07Varicella 0.4 0.07Upper respiratoryinfection/unspecifiedviral syndrome

4.1 0.7

Miscellaneous conditions 4.5 0.8Trauma 2.0 0.4Rash 0.8 0.1Desensitization 0.4 0.07No diagnosis 1.2 0.2

occurring in at least 2.1% of all groups except the smallearly monotherapy group. AIDS-related pneumonia,primarily Pneumocystis carinii, occurred in only 5(0.4%) women during pregnancy or through 6 weeks’post partum. Any AIDS-defining illness occurred in2.7% of women during pregnancy or the postpartum pe-riod, with the lowest rates among women on monother-apy, suggesting that women on combination regimenswere receiving therapy for their own health as well asprophylaxis of transmission. Urinary tract infectionoccurred among 12.8% of women, with no significantdifferences by therapy group. Peripartum infectiouscomplications and hemorrhage did not differ by therapygroup.

Complication rates were also assessed by mode of de-livery to describe rates among women receiving ART.As expected, rates of endometritis were highest amongwomen undergoing urgent cesarean delivery (18/248,7.3%), intermediate among those with scheduled ce-sarean delivery (16/448, 3.6%), and lowest among thosewith spontaneous vaginal delivery (9/671, 1.3%).Wound complications occurred at similar rates amongwomen with urgent (15/248, 6.1%) or scheduled (25/448, 5.6%) cesarean section. Rates of hemorrhage didnot differ significantly by mode of delivery.

Comment

Overall, the rate of symptoms and laboratory abnormal-ities in women enrolled in PACTG 316 were low and didnot differ significantly by treatment group. The low rateof symptoms and laboratory abnormalities is unlikely tobe related to the inclusion criteria because they were de-signed to allow broad enrollment. The only exclusionbased on laboratory results was an ALT level 10 timeshigher than the ULN, well over 400 U/L in most labo-ratories, and the only exclusion related to obstetric fac-tors was a known fetal congenital anomaly incompatiblewith extrauterine life. Although exclusion criteria likelydo not account for the low rate of symptoms, theremay be some selection bias in that women who havemore symptoms may be less likely to enroll into a clinicaltrial, even one with a minimal intervention. However,the rates of symptoms and laboratory abnormalitiesdid not differ by therapy group, suggesting that morecomplex therapies were well tolerated.

Although the overall rate of gestational diabetes of2.1% was within the 2% to 3% range expected,9 the ratevaried significantly by therapy group and was 4.6% inthe group on long-term PI therapy. An increased riskof gestational diabetes among women on long-term PItherapy is consistent with studies in nonpregnant adults,indicating an increased risk of diabetes or glucose intol-erance among PI users. The incidence of new-onset dia-betes after initiation of PI therapy in nonpregnant adults

Watts et al 513

Table V Maternal infections and peripartum morbidity according to treatment during pregnancy

Finding

Latemonotherapy(n = 288)(%)

Earlymonotherapy(n = 34)(%)

Latecombo,no PI(n = 327)(%)

Earlycombo,no PI(n = 175)(%)

Latecombowith PI (%)(n = 320)(%)

Earlycombowith PI(n = 263)(%)

Total(n = 1,407)(No. [%])

Febrile morbidity 5.6 0 7.0 4.6 9.1 7.6 6.8 (96)Endomyometritis 3.1 0 1.8 1.1 4.1 4.9 3.1 (43)UTI 12.9 14.7 13.5 9.1 14.7 11.8 12.8 (180)Maternal hemorrhage 5.9 8.8 9.5 6.9 11.6 8.4 8.7 (122)Wound complications 4.2 2.9 2.5 5.7 2.2 3.8 3.4 (48)Septic pelvic thrombophlebitis 0 0 0 0.6 1.3 0 0.4 (5)Pneumonia, not AIDS related 2.1 0 2.5 2.3 4.1 2.3 2.6 (37)Pneumonia, AIDS related 0 0 0.3 0 0.9 0.4 0.4 (5)Pulmonary embolism 0 0 0.3 0.6 0 0 0.1 (2)AIDS defining illnessa 0.7 0 3.1 2.3 5.3 1.9 2.7 (38)

UTI, pneumonia, pulmonary embolism, and AIDS-defining illness include occurrences during pregnancy and through 6 weeks’ postpartum. Other events

occurred at or after delivery through 6 weeks’ post partum. UTI, Urinary tract infection; AIDS, acquired immune deficiency syndrome.a P values by Fisher-Freeman-Halton exact tests, unadjusted for multiple comparisons. AIDS defining illness: P = .02.

ranged from 1% to 7%, and an additional 16% to 61%had impaired glucose tolerance without frank diabe-tes.14 In another study of subjects initiating indinavirtherapy, insulin sensitivity decreased by 30.5% after 8weeks on therapy, with a resultant increase in fastingglucose levels but without a compensatory increase in in-sulin release, suggesting indinavir-induced defects inboth glucose utilization and beta cell function.15 A largecohort study of nonpregnant women with similar racialdistribution of subjects in the current study found anadjusted hazard ratio of 2.9 (95% CI, 1.5-5.6) for thedevelopment of diabetes among women on PI therapycompared with HIV-infected women on nucleosideagents or no therapy.16

Data on PI therapy and gestational diabetes are lim-ited. Two small studies, including 34 and 39 women onPI therapy, did not find an increased rate of gestationaldiabetes in women on PIs compared with HIV-infectedwomen on zidovudine.17,18 One cohort study noted 3(3.3%) cases of gestational diabetes among 89 womenon PI therapy.19 In our study, the rate of gestational di-abetes was actually lower (0.6%) among women startingPI therapy in the second or third trimester. This lowerrate could be due to the lower age of this group or con-founding by indication (ie, women perceived to be athigher risk of gestational diabetes were preferentiallynot placed on PI therapy) or to some other unmeasuredconfounders. Our results suggest an association betweenlong-term PI use and an increased risk of gestational di-abetes, which is plausible based on the observed effectsof PI therapy on glucose metabolism in nonpregnantadults, laboratory studies, and the known anti-insulineffects of pregnancy hormones.9,14 However, confirma-tion in other studies is required.

Median gestational age did not differ significantly be-tween the therapy groups, but this cohort did not allowfor accurate assessment of absolute rates of pretermbirth, especially preterm birth before 32 weeks of gesta-tion, because only 26% of the cohort enrolled before 32weeks. Data remain conflicting regarding a potential in-creased risk of preterm delivery overall among womenon PI-containing therapy. The European CollaborativeStudy/Swiss collaborative study joint analysis, including108 women on PI therapy, found an increased risk ofpreterm birth among women on PI therapy, with thehighest risk occurring among women on therapy beforepregnancy or beginning in the first trimester.5 A US col-laborative study, including 137 women on PI therapy,did not find an increased risk of preterm birth or lowbirth weight with PI therapy, although an increased riskof delivery of an infant with birth weight under 1500 gwas found.6 In our study, CD4+ cell counts were lowerfor women who were on PI therapy, suggesting that dis-ease stage may confound inferences regarding the influ-ence of antiretroviral treatment on pregnancy outcome.

A reassuring finding in our study is that the rate ofnondelivery hospitalizations per 100 births amongHIV-infected women on ART was similar to that re-ported in the literature for the general population ofpregnant women.20-22 Bennett et al,20 with use of na-tional hospital discharge data, found a rate of 18.0 totalpregnancy-associated hospitalizations per 100 births, in-cluding rates of 17.2 per 100 births for whites and 28.1per 100 births for African American women. Althoughthese figures include a rate of 4.4 hospitalizations per100 births for pregnancy loss that would not be includedin our population, rates for other conditions were simi-lar to our data. For example, Bennett et al found a rate

514 Watts et al

of hospitalization for hypertensive disorders of 0.8 com-pared with 1.1 in our study, diabetes 1.2 in AfricanAmerican women compared with 1.0, pyelonephritis1.2 compared with 1.2, and 1.1 overall and 1.7 per 100in African American women for vomiting comparedwith 1.4 for all gastrointestinal symptoms currently.Categories that are increased in the current study rela-tive to population numbers include other infections,0.3 compared with 2.4, and substance abuse 0.1 totalcompared with 1.0. The rate of bacterial pneumoniaduring pregnancy or in the early postpartum period inour cohort was 2.6% overall, much higher than the rateof 0.8% among 32,179 deliveries reported by Mad-inger.23 An increased risk of bacterial pneumoniaamong HIV-infected compared with uninfected preg-nant and early postpartum women has been suggestedin earlier studies.24,25 The increased rate of admissionsfor substance abuse is not surprising given that sub-stance abuse is a risk factor for HIV infection. Althoughthese data are generally reassuring, women enrolledwere fairly healthy, with only 12% having CD4+ lym-phocyte counts below 200 cells/UL, and all women werereceiving ART and prenatal care.

The results of our study merit several limitations. Be-cause of the study design, no nonnucleoside reversetranscriptase inhibitor therapy was allowed before en-rollment, so side effects of these drugs could not be as-sessed. However, this study has reported toxicity dataon the largest group (583) of women on PI therapy dur-ing pregnancy to date. No untreated group was in-cluded, but because ART is now recommended for allpregnant women,25 it is important to have data on out-comes among treated women. Women were not ran-domly assigned to their background antiretroviralregimen, leading to some significant differences betweengroups in risk factors for adverse outcomes. However,we attempted to control for important confounders inregression analyses of outcomes. The assessment of theeffects of ART on gestational age at delivery, one ofthe key unanswered questions in this area, was pre-vented by the small proportion of women enrolled be-fore 28 weeks of gestation.

The strength of this study is the large number ofwomen included, all with detailed data on the typeand timing of ART and ongoing, systematic collectionof data regarding symptoms, toxicity, and pregnancyoutcomes. These data are, for the most part, reassuringbut do suggest areas for further surveillance. The poten-tial for an increased risk of gestational diabetes amongwomen on long-term PI therapy and the unresolvedquestion of the effect of PI therapy on the risk of earlypreterm birth require further study. In addition, as preg-nant women are treated with increasingly complex anti-retroviral regimens and with new agents less studied inpregnancy, they must be monitored for potential toxicityat both the individual and population level.

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12. Watts DH, Lambert JS, Stiehm ER, Bethel J, Whitehouse J,

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13. Freeman GH, Halton JH. Note on an exact treatment of

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15. DubeMP, Edmondson-Melancon H, Qian D, Aqeel R, JohnsonD,

Buchanan TA. Prospective evaluation of the effect of initiating

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HIV-infected patients. J Acquir ImmuneDefic Syndr 2001;27:130-4.

16. Justman JE, Benning L, Danoff A, Minkoff H, Levine A,

Greenblatt RM, et al. Protease inhibitor use and the incidence of

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Acquir Immune Defic Syndr 2003;32:298-302.17. Fassett M, Kramer F, Stek A. Treatment with protease inhibitors

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Appendix

In addition to those listed at the beginning of the article,the International PACTG 316 team includes Brigitte Ba-zin, MD (ANRS, Villejuif, France), Paula Britto, MS(Statistical and Data Analysis Center, Harvard Schoolof Public Health, Boston, Mass), Yvonne Bryson, MD(UCLA School of Medicine, Los Angeles, Calif), NinaSublette, ACRN, MSN (Regional Medical Center,Memphis, Tenn), Bethann Cunningham-Schrader andKathleen A. Kaiser, AAS, COTA, MS (Frontier Scienceand Technology Research Foundation, Buffalo, NY),Mobeen Rathore, MD (University of Florida, Jackson-ville, Fla), Scharla Estep, MS, RPh (NIAID, Bethesda,Md), Maria Gigliotti, MS (Boehringer Ingelheim),Adolfo Gonzalez-Garcia, MD (University of Miami),Mark Mirochnick, MD (Boston University, Boston,Mass), Claire Rekacewicz, MD (ARNS, Villejuif, France),Maureen Shannon, MS, FNP (San Francisco GeneralHospital, San Francisco, Calif), and John L. Sullivan,MD (University of Massachusetts, Worcester, Mass).The European Collaborative Study (ECS) includes inves-tigators and study sites throughout Europe (listed be-low). Collaborating investigators include PACTG: DrHeather Watts and Dr Lynne Mofenson (NICHD), DrBeverly E. Sha and Ruth M. Davis, RN (Rush-Presbyte-rian/St Lukes, Chicago, Ill), Dr Arlene D. Bardeguez andJocelyn Grandchamp, RN (University of Medicine andDentistry of NJ), Lisa Melton and Audra Deveikis(Long Beach Memorial), Dr William T. Shearer andDr Hunter A. Hammill (Baylor College of Medicine),Dr Ram Yogev and Donna Stanislawski (Children’s Me-morial and Prentice Women’s Hospital), Dr Charles D.Mitchell and Patricia Bryan, RN (University of Miami),DrWilliam Borkowsky andMaryannMinter, RN (Belle-

vue Hospital), Dr Diane Wara and Maureen Shannon,RN, MS FNP, CNM (UCSF Moffitt Hospital), Dr Di-ane Wara and Dr Karen Beckerman (San FranciscoGeneral), Dr Ana Puga and DrWinston Bliss (Children’sDiagnostic and Treatment Center), Dr Jane Pitt and DrGina Brown (Columbia University), Dr Gary Kaufmanand Laureen Katz, RN (Boston Medical Center), An-drew D. Hull and Stephen A. Spector (UCSD MedicalCenter), Dr Elizabeth Livingston and Lori Ferguson,RN (Duke University), Dr Mobeen Rathore and DrIsaac Delke (University of Florida Health Sciences Cen-ter), Dr Wilma Lim and Betsy Pitkin, RN (University ofNorth Carolina at Chapel Hill), Dr Jorge Gandia and DrEleanor Jimenez (San Juan City Hospital), Dr SohailRana and Marilyn Dennis (Howard University Hospi-tal), Dr Alice Stek and Dr Andrea Kovacs (Universityof Southern California), Dr Elizabeth J. McFarlandand Carol Salbenblatt, RN (Children’s Hospital), DrMyron J. Levin and Dr Adriana Weinberg (DenverMedical Center), Susan Laverty, RN, and Dr GeoffreyA. Weinberg (University of Rochester), Dr Hannah Gayand Netta Boudreaux, RN (University of MississippiMedical Center), Dr Susanne R. Lavoie and Tima Y.Smith, RN (Medical College of Virginia), Dr EdwinThorpe and Ms Nina Sublette (Regional Medical Cen-ter), Dr Dan Lancaster and Dr Debra Terry (MethodistHospital Central), Dr Gregory J. Wilson and PeggyBender, FNP (Vanderbilt University Medical Center),I. Heyer, RN, BSN, and Dr L. Lugo (University ofPuerto Rico), Harold W. Lischner, MSN, and Kelly R.Hassey, MSN, CRNP (St Christopher’s Hospital forChildren), Deb Goldman, ARNP, and Dr Jane Hitti(Children’s Hospital and Medical Center), Dr RobertMaupin and Dr Thomas Alchediak (Tulane UniversityHospital), Dr Katherine Luzuriaga and Sheila Noone,RN, PhD (University of Massachusetts Medical School),Dr Juan C. Salazar and Dr Winston Campbell (Univer-sity of Connecticut), Gail Karas, RN, and Dr Juan C.Salazar (Connecticut Children’s Medical Center), DrGeorge Wendel and Dr Janet Squires (Children’s Medi-cal Center), Dr Theodore Jones and Dr Ellen Moore(Children’s Hospital of Michigan), Dr Mobeen Rathoreand Dr Isaac Delke (University of Florida Health Sci-ences Center), Dr Jaime Deville and Maryanne Dillon,BSN (University of California Medical Center), Dr RuthTuomala (Brigham and Women’s Hospital), Dr SandraBurchett (Children’s Hospital), Dr John Farley and Bar-bara Davis, RN, MEd (University of Maryland), DrKenneth Rich and Dr Mark Vajaranant (University ofIllinois), Dr Indu Pathak and Dr Hamida Khakoo (Met-ropolitan Hospital Center), Dr Nancy Wade and Dr Re-nee Samelson (Children’s Hospital at Albany MedicalCenter), Emily Barr and Dr John Nosovitch (State Uni-versity of New York Upstate Medical University), PamDaniel and Patty Kohler, RN (University of Cincinnati),Dr Margaret Keller and Marie Beall (Harbor University

516 Watts et al

of California Medical Center), Angela Ranzini and Mar-ian Lake (St Peter’s Medical Center), Dr Robert Passand Dr Marilyn Crain (University of Alabama), Dr Val-erie Whiteman and Dr Ellen Tidaldi (Temple UniversitySchool of Medicine), Carla Duff, RN and Dr JohnSleaseman (University of Florida, Gainesville), Dr Hec-tor Cintron and Wanda Figueroa (Ramon Ruiz), DrGeorge Johnson and Moya Clarken, RN (Medical Uni-versity of South Carolina), Dr Savita Pahwa (NorthShore LIJ Research Institute), Dr Sunanda Gaur andPatricia Whitley Williams (Robert Wood Johnson AIDSProgram), Dr Michael Hughes and Dr David Shapiro(Statistical and Data Analysis Center, Harvard Schoolof Public Health). European Collaborative Study: Dr I.Grosch-Worner, Dr K. Seel, (Charite Virchow-Klini-kum, Berlin, Germany), Dr J. Jimenez (Hospital 12 DeOctubre, Madrid, Spain); Dr A.B. Bohlin, Dr S. Lindg-ren, (Huddinge and Karolinska Hospitals, Sweden), DrA. Mur, Dr A. Paya, (Hospital del Mar, Barcelona,Spain), Dr O. Coll, Dr C. Fortuny (Hospital Clinic, Bar-celona, Spain), Dr M. Casellas Caro (Hospital VallD’Hebron, Barcelona, Spain), Dr M. Leyes, Dr L.Ciria(Hospital Son Dureta, Mallorca), Prof P. Martinelli,Dr W. Buffolano, Dr M. Sansone (II Policlinico, Naples,Italy), Dr C. Tibaldi, Dr N. Ziarati (S Anna Hospital,Torino, Italy), Dr S. Alberico, Dr C. Salvatore (BurloGarofolo Hospital, Trieste, Italy), Prof M. Temmerman(University of Ghent), Dr I. Hoesli, Dr C. Rudin (Uni-versity of Basel), Dr X. Carnet, Dr J. Pich (Clinical Phar-macology Unit, University of Barcelona), Dr M.Ravizza, Prof G. Pardi, Dr L. Mangiarotti (San PaoloHospital, Milan, Italy), Dr V. Savasi, Dr A.E. Semprini,Prof E. Ferrazzi (Sacco Hospital, Milan, Italy), Dr M.Sharland, Ms T. Chester, (St George’s Hospital, Lon-don, UK), Dr A. Fakoya (Newham General Hospital,London, UK), Dr G. Scaravelli (PUI, Rome, Italy), DrW. Coroleou, Dr Cavalle Gelabret (H Germans TrialsI pujol, Badalona, Spain), Prof C. Loveday (UniversityCollege London, UK); France: Scientific Committee:

Annie Metro (ANRS), Marie-Jeanne Mayaux, StephaneBlanche, Christine Rouzioux, Marc Tardieu (EnquetePediatrique Francaise (EPF)); Jean-Pierre Aboulker(Service Commun 10, INSERM); Bertrand Baumelou(Boehringer Ingelheim, France); Clinicians: VeroniqueChambrin, Hassina Razafimahefa (Hopital Antoine Be-clere, Clamart), Laurent Mandelbrot, Guislaine Firtion(Hopital Cochin-Port Royal, Paris), Nicole Ciraru-Vi-gneron, Claudine Bruner (Hopital Lariboisiere, Paris),Alain Berrebi, Joelle Tricoire (Hopital Purpan, Tou-louse), Claude Hocke, Daniele Douard (Hopital Pelle-grin, Bordeaux), Catherine Crenn-Hebert, CorinneFloch-Tulal (Hopital Louis-Mourier, Colombes), Eti-enne Wilmer, Annick Ottenvalter (Hopital RobertDebre, Paris), Marie-Aude Khuong, Jean-Marc Retbi(Hopital Delafontaine, Saint-Denis), Vincent Jeantils,Eric Lachassine (Hopital Jean-Verdier, Bondy), SophieMatheron, Jean-Louis Benifla (Hopital Bichat-Claude-Bernard, Paris), Cristianne Huraux-Rendu, Joelle Te-boul (Hopital Henri-Mondor, Creteil), Deborah Fried,Brigitte Heller-Roussin (Hopital Intercommunal Mon-treuil), Brigitte Clavier, Veronique Brossard (HopitalCharles Nicolle, Rouen), Andre Bongain, Fabrice Mon-poux (Hopital de l’Archet, Nice), Michel Levardon,Fabienne Mazy (Hopital Beaujon, Clichy), VeroniqueCayol, Catherine Dolfus (Hopital Saint-Antoine-Trous-seau, Paris), Paul Benos, Joelle Nicolas (Hopital ArnaudDe Villeneuve, Montpellier), Daniel Raudrant, LaurentCotte (Hopital de l’Hotel Dieu, Lyon), Cecile Francois,FrancoiseMechinaud (Hopital de l’Hotel-Dieu, Nantes),Rose Nguyen, Adrien May (Hopital Louise Michel,Evry), Benedicte Mougeon, Alain Devidas (HopitalGilles de Corbeil, Corbeil); Brazil: Dr Susie Andries No-gueira, Dr Marcia Bondarowisky (Federal University ofRio de Janeiro, Brazil), Esau Custodio Joao Filho, MD,Marcos Machado D’Ippolito, MD (Hospital dos Servi-dores in Rio de Janiero, Brazil); Bahamas: Dr M. PerryGomez, Dr P. McNeil (Princess Margaret Hospital,Bahamas).