- Email: [email protected]
Obstetric factors and mother-to-child transmission of human immunodeficiency virus type 1: The French perinatal cohorts
Obstetrics Obstetric factors and mother-to-child transmission of human immunodeficiency virus type 1: The French perinatal cohorts Laurent Mandelbrot, MD, a Marie-Jeanne Mayaux, BA, Andr6 Bongain, MD,e Alain Berrebi, MD,' Yasmine Moudoub-Jeanpetit, MD,dJean-Louis B6nifla, MD, b Nicole Ciraru-Vigneron, MD, c Jer6me Le Chenadec, MS, d St6phane Blanche, MD,d Jean-Francois Delfraissy, MD,d SEROGEST, and The French Pediatric HIV Infection Study Group Paris,Nice, and Toulouse, France OBJECTIVE: We attempted to determine whether the risk of mother-to-child transmission of human immunodeficiency virus type 1 is related to events in pregnancy, labor, and delivery. STUDY DESIGN: In a prospective multicenter cohort study of human immunodeficiency virus type 1-infected mothers and their children, we studied pregnancy histories, labor (including gestational age, induction, membrane rupture, length of labor, intrapartum procedures, bleeding, infection, antiseptic technique, and antiretroviral therapy), and conditions of delivery. RESULTS: Among 1632 singleton infants, 310 were confirmed infected with human immunodeficiency virus type 1 at age 18 months (19.0% + 1.9%). Procedures (in particular, amniocentesis and amnioscopy) and sexually transmitted diseases during pregnancy, preterm delivery, premature membrane rupture, hemorrhage in labor, and bloody amniotic fluid were associated with increased transmission. Transmission was not related to mode of delivery or to the conditions of labor and delivery. CONCLUSIONS: Transmission was not decreased after emergency or elective cesarean section. Most risk factors either were rare or appeared poorly amenable to obstetric management, with the exception of invasive procedures, which should be avoided. (Am J Obstet Gynecol 1996;175:661-7.) Key words: Human immunodeficiency virus, acquired immunodeficiency syndrome, mother-to-child transmission, obstetric factors
To target interventions to decrease mother-to-child transmission of human immunodeficiency virus (HIV), it is crucial to understand its timing and mechanisms. Substantial data are now available on timing, most of which point to the late in utero and intrapartum periods. In a study of 100 second-trimester abortuses, early in utero HIV infection was rare.' Postnatal cohorts offer further evidence for late transmission. HIV is undetectable in the
From INSERM (Institut National de la Sante et de la Recherche Medicale) U149 and H6pital Cochin-Port Royal,' H6pital Bichat,' and H6pital Lariboisire,' Paris; INSERM U292, H6pitalde Bictre,' and H6pital Saint Roch,' Nice; and HopitalLa Grave, Toulouse. A complete list of the participants in SEROGEST and The French PediatricHIV Infection Study Group appears at the end of the article. Supported by grants from Sidaction and the Agence Nationale de Recherche contre le Sida. Received for publicationFebruary 2, 1996; revised May 1, 1996; accepted May 31, 1996. Reprint requests: L. Mandelbrot, MD, H6pital Cochin-Port Royal, Service de Gyndcologie-Obstetrique, 123 Boulevard de Port Royal, 75014 Paris, France. Copyright © 1996 by Mosby-Year Book, Inc. 0002-9378/96 $5.00+ 0 6/1/75478
majority of infected infants during the first days after birth, according to highly sensitive polymerase chain reaction or viral cultures."-5 With a mathematic model that takes into account the time from birth to p2 4 antigen and virus detection, as well as antibody production, Rouzioux et al. 6 concluded that one third of transmission occurs over the last weeks of pregnancy and two thirds at the time of delivery. In contrast, little is known about the actual mechanisms of mother-to-child transmission, which may involve placental transfer,7 maternal-fetal hemorrhage,' ascending route infection, direct mucocutaneous contact, and absorption in the fetal-neonatal digestive tract. Because intrapartum transmission appears to be important, a relation between obstetric management and transmission might be expected. Recently, the European Collaborative Study reported a significantly lower transmission rate in children born by cesarean section versus vaginal delivery, 9 whereas the French perinatal cohort study showed no difference in transmission according to the mode of delivery." This discordance between the two largest cohort studies indicates that there may be differ661
662
Mandelbrot et al.
ences in patient characteristics or peripartum management. We focused our attention on the pregnancy history and a detailed analysis of the circumstances of labor and delivery in the French perinatal cohorts. Patients and methods Two prospective multicenter cohorts have been established in France to study perinatal HIV transmission. The French Pediatric Cohort, established in September 1985, involves follow-up of all infants born to HIV-infected mothers in 69 obstetric services throughout the country. The protocol for follow-up and anonymous data transmission has been reported previously. ° ' 1 Perinatal data recorded include maternal age, geographic origin, suspected route of HIV acquisition, clinical status, lymphocyte subpopulations, gestational age at birth (based on last menstrual period and/or first-trimester ultrasonography), birth weight, mode of delivery, and breast-feeding. The SEROGEST cohort, established in 1989, involves 24 centers. It enrolls HIV-infected women, with written consent, during the first or second trimester of pregnancy or at the time of pregnancy termination or delivery. Follow-up is every 3 months during the first year and every 6 months for another 9 years. When pregnancy is continued to delivery, the child is enrolled in the French Pediatric Cohort. At each trimester, clinical and biologic data are recorded by the obstetric team and by an infectious diseases specialist or internist. These data are reported on obstetric and HIV case report forms and transmitted on an anonymous basis to the coordinating center. All gestational complications are recorded, including specifically defined entries for premature labor (requiring hospitalization), bleeding, cervicovaginal infections (confirmed by microbiologic testing), documented sexually transmitted diseases, and invasive procedures. Information on labor and delivery includes mode of delivery, mode of induction, duration of labor, duration of membrane rupture, procedures performed, perineal status (episiotomy, tear), complications (fetal distress indicated by abnormal cardiotocograms, neonatal pH <7.20 or Apgar score <7), fever >37 ° C, bleeding, maternal or fetal infection (i.e., fetal tachycardia, positive bacterial cultures from amniotic fluid, or neonatal bacterial sepsis), and measures such as disinfection of the genital tract and antiretroviral therapy. The coordinators of the two French cohorts decided to ask centers involved in the Pediatric Cohort to participate in the study of obstetric factors. All obstetric data had been recorded prospectively on-site and were collected by an obstetric investigator on supplementary, anonymous case report forms and included in the SEROGEST database. Data from 45 centers were thus added, so the total number of centers participating in the study was 69. Infants' HIV infection status was determined according to international consensus definitions. 2 A child was con-
September 1996 AmJ Obstet Gynecol
sidered infected if HIV type 1 antibodies persisted beyond 18 months or if the child died of HIV-related disease before this age; a child was considered uninfected if at least two HIV antibody test results were negative by the age of 18 months. Testing for HIV antibodies was carried out with two commercial enzyme-linked immunosorbent assays (ELISA), and positive results were confirmed by Immunoblot (Diagnostics Pasteur or Dupont de Nemours, Paris) assay. Immunoblot assay was considered negative when no HIV antibody of any type was present. Transmission rates were compared for each factor by univariate analysis. Proportions were compared with the 2 test or Fisher's exact test for cell counts <5. Relative risks and their 95% confidence intervals were estimated according to the Mantel-Haenszel method for prospective cohort studies. The Mantel-Haenszel x2 test was also used for adjusted comparisons. Quantitative variables were expressed as mean ± 1 SD. Means were compared by Student's t test or the nonparametric Wilcoxon test for numbers <30. Selected continuous variables were categorized into two classes, according to thresholds established a priori by the clinicians. Logistic regression was performed to estimate the independent effects of each selected risk factor in transmission. All variables found to be significant at a threshold of 0.05 in the univariate analysis were included in the final model, exept rare events, for which the proportion of women at risk was <3%. Odds ratios, adjusted for all the other factors, were calculated in the logistic regression model. We also entered the variable mode of delivery into the model, to check that it did not influence the results. Analysis was performed with SAS (SAS Institute, Cary, N.C.) software. %
Results Between September 1985 and December 1993, 2167 HIV-seropositive mothers were delivered in the participating obstetric services. After mothers with type HIV 2 infection (n = 96), twin pairs (n = 34), and repeat pregnancies (n= 160) were excluded, so that the same mothers would not be included more than once, 1842 motherchild pairs were eligible for study. Among these infants 28 died before HIV status could be determined, 54 could not be enrolled because of lack of parental consent, and 111 were not available for follow-up (including 50 who returned to their country of origin). The nonevaluable children did not differ significantly from the study group for any of the pregnancy or labor and delivery variables investigated. The study group comprised 1632 children fulfilling the inclusion criteria, with known HIV status at 18 months. The proportion of HIV-infected children in the population under study was 310 of 1632 (19.0%; 95% confidence interval 17.1% to 20.9%). Maternal characteristics were comparable to those previously described for the French Pediatric Cohort.' o Among the 1632 mothers in the study group, all those
Mandelbrot et al. 663
Volume 175, Number 3, Part 1 AmJ Obstet Gynecol
Table I. Mother-to-child HIV type 1 transmission rate according to events during pregnancy Event Bleeding No (n= 1154) Yes (n = 122) Cervicovaginal infection No (n = 803) Yes (n= 477) Sexually transmitted diseases No (n= 1060) Yes (n=212) Procedures* No (n= 1185) Yes (n = 68)
Children infected (%)
Relative risk
95% Confidence interval
Significance
18.5 20.5
1.1
0.7-1.6
NS
16.7 22.2
1.3
1.1-1.7
p= 0.018
17.3 26.4
1.5
1.1-2.0
p=0.003
18.0 33.8
1.9
1.3-2.7
p= 0.003
*Amniocentesis and other needling procedures, cerclage, laser therapy, or amnioscopy.
delivered through 1990 (n= 944) were included in the previous publication. Mean age was 27 years (SD ± 4.5), 36.5% were previous or current intravenous drug users, and 34.1% were born in sub-Saharan Africa or the Caribbean. Evaluation for undissociated p24 antigenemia at delivery was available in 1366 women; the result was positive in 7.1%. CD4+ lymphocyte counts were distributed as follows: 134 women (14.7%) had <200 cells/mm', 361 (37.3%) had between 200 and 500 cells/mm 3 , and 468 mothers (48.0%) had 500 CD4+ cells/mm3 . Only 2.1% of the infants were breast-fed. Complications during pregnancy (Table I). Bleeding, at any time in pregnancy before labor, was observed in 122 cases (9.6% of pregnancies), and cervicovaginal infections were recorded in 477 cases (37.3%). Neither bleeding nor cervicovaginal infection was associated with an increase in transmission. Sexually transmitted diseases (STD) occurred in 212 pregnancies (16.7%), mainly genital herpes, papillomavirus infection (genital warts or cervical dysplasia), trichomoniasis, gonococcal or chlamydia infection, or confirmed syphilis. Transmission was significantly higher in cases of STD (26.4% vs 17.3%, p < 0.003). Only 100 women (5.5%) received zidovudine during pregnancy, the main indication during the study period (through 1993) being advanced immune deficiency. Transmission occurred in 24.7% of cases, but this was not significantly higher than for untreated women. Procedures were performed in 68 cases (5.4% of pregnancies) and were associated with a transmission rate of 33.8% versus 18.5% (p < 0.003). These included invasive procedures (i.e., amniocentesis and other needling procedures, n= 13; amnioscopy, n = 26), as well as cerclage (n = 8), external cephalic version (n = 2) and laser therapy (n = 19). The transmission rate remained significantly increased (36%) when only needling procedures and amnioscopy were considered. Circumstances of labor (Table II). The overall rate of preterm birth before 37 weeks from the last menstrual period was 10.2%. The transmission rate was significantly
higher in preterm deliveries than in term ones (25.5% and 17.9%, respectively; p < 0.02). The relation between prematurity and mother-to-child transmission was also observed when pregnancies that were terminated for medical indications were excluded and only spontaneous preterm deliveries were considered. In cases of severe prematurity, up to 34 weeks (n = 67 cases) the transmission rate was 26.9%. The mean gestational age of infected infants was 38.5 weeks, significantly less than for uninfected infants (38.9 weeks, p < 0.02). This difference persisted when only spontaneous preterm deliveries were considered. Labor was induced in 17.8% of deliveries, with the use of prostaglandins, amniotomy, and/or oxytocin; transmission was not more frequent than after spontaneous labor. The transmission rate did not differ according to the duration of active labor. The mean duration of labor was the same for infected children and for uninfected children (6 + 3 hours). Rupture of membranes before the onset of labor occurred in 26.9% of cases. Transmission was higher in cases with premature rupture of membranes (23.8% vs 17.1%, p < 0.009). Premature membrane rupture was related to preterm delivery, occurring in 53.3% of deliveries before 34 weeks, 37.0% at 35 to 36 weeks, 26.3% at 37 to 41 weeks, and 15.8% beyond 41 weeks. The mean duration between membrane rupture and birth appeared longer for infected infants than for uninfected ones (14 hours and 10 hours, respectively), but the difference was not statistically significant. The transmission rate was higher when membranes ruptured >12 hours before delivery (23.9% vs 17.8%, p < 0.05). However, the transmission rate did not increase significantly in proportion to the duration of membrane rupture (21.1% vs 17.2%, p < 0.08, at a 4-hour cutoff; 25.5% vs 18.2%, p < 0.07, at a 24-hour cutoff). Fever during labor or delivery was noted in 88 deliveries (7.3%), and evidence of chorioamnionitis was noted in 6.3% of deliveries. Fetal distress occurred in 21.9% of
664 Mandelbrot et al.
September 1996 AmJ Obstet Gynecol
Table II. Mother-to-child HIV type 1 transmission rate according to events during labor Event Gestational age >37 wk (n= 1455) <37 wk (n = 165) Onset of labor Spontaneous (n= 1018) Induced (n = 220) Premature membrane rupture No (n = 890) Yes (n= 327) Fever (>37.8 ° C) during labor No (n= 1123) Yes (n= 88) Maternal-fetal sepsis No (n= 1105) Yes (n= 74) Hemorrhage in labor No (n = 1179) Yes (n= 32) Color of amniotic fluid Clear (n = 886) Meconium-stained (n = 308) Bloody (n = 30)
Fetal distress No (n = 988) Yes (n= 277) Fetal skin lesions (scalp electrode, pH) No (n= 1014) Yes (n = 79) Vaginal lavage No (n = 783) Yes (n=217)
Children infected (%)
Relative risk
95% Confidence interval
17.9 25.5
1.4
1.1-1.9
p = 0.02
20.9 18.6
1.1
0.8-1.5
NS
17.1 23.8
1.4
1.1-1.8
p=0.009
18.4 25.0
1.4
0.9-2.0
NS
18.8 17.6
0.9
0.5-1.5
NS
18.1 34.4
1.9
1.1-3.2
17.2 19.2
1.1
0.8-1.5
60.0
3.5
2.3-5.3
18.5 18.8
1.0
0.7-1.3
NS
18.2 21.5
1.2
0.7-1.8
NS
18.9 19.3
1.0
0.9-1.1
NS
Significance
p=0.03
p < 10-
Table III. Mother-to-child HIV type 1 transmission rate according to events during delivery Event Mode of delivery Vaginal (n= 1360) Emergency cesarean section (n= 162) Elective cesarean section (n= 108) Instrumental vaginal delivery No (n = 915) Yes (n= 182) Assisted vaginal delivery No (n= 994) Yes (n=96) Perineum Intact (n = 288) Episiotomy-tear (n= 729) Neonatal antiseptic bath No (n = 1053) Yes (n= 149)
Children infected (%)
Relative risk
95% Confidence interval
Significance
19.1 19.1 15.7
1.0 0.8
0.9-1.1 0.5-1.3
NS NS
19.5 16.5
0.8
0.6-1.2
NS
18.7 21.9
1.1
0.7-1.8
NS
18.8 19.2
1.0
0.7-1.3
NS
18.7 16.7
1.1
0.7-1.6
NS
cases. None of these events was associated with an increase in transmission. Hemorrhage during labor (including abruptio placentae and placenta previa) was observed in 32 cases (2.6% of deliveries) and was associated with a significant increase in transmission (34.4% vs 18.1%, p< 0.03). Amniotic fluid was bloody in 2.5% of deliveries and meconium stained in 25.2%. Transmission rates were higher in cases
of bloody fluid or meconium staining than for clear fluid (60.0%, 19.2%, and 17.2%, respectively; p< 10-5). The
95% confidence interval of the relative risk was >1 for bloody fluid but not for meconium-stained fluid. Fetal skin lesions from scalp pH determination or electrode placement were reported in 7.2% of cases. These were not associated with a significant increase in transmission. Vaginal lavage with antiseptic solutions (povidone-
Mandelbrot et al. 665
Volume 175, Number 3, Part I AmJ Obstet Gynecol
iodine, chlorhexidine, or benzalkonium chloride) was performed during labor in 217 cases (21.7%); the transmission rate was not lower than without vaginal lavage. Circumstances of delivery (Table III). Cesarean sections were performed in 270 cases (16.6% of deliveries), 60% of which were on an emergency basis and 40% of which were planned. No difference in transmission was observed between infants delivered vaginally and those delivered by cesarean section. The transmission rate was 15.7% after elective cesarean sections versus 19.1% after emergency cesarean sections, which was not significantly different. Similarly, there was no significant difference in transmission after cesarean delivery according to whether membranes were intact or ruptured. The proportion of infants who were breast-fed did not differ, significantly between those delivered by cesarean section and those delivered vaginally. Because cesarean section rates varied between centers, from 0% to 40%, we looked for a relation between cesarean rates and mother-to-child transmission rates in each center; there was no correlation (r=-0.02). Because the cesarean rate was higher in women with more advanced disease (24.4% when CD4* counts were <200 cells/mm3 ), we also looked for differences in transmission rates according to mode of delivery when stratifying for CD4 + counts <200, 200 to 500, or >500 cells/mm 3 . No difference in mother-to-child transmission according to mode of delivery was observed when CD4 + cell levels were taken into account. Forceps or vacuum extractors were used in 9.4% of vaginal deliveries. Episiotomies and/or perineal tears were reported in 71.7% of vaginal deliveries. Neither instrumental delivery nor other procedures during delivery, such as breech extraction or episiotomies or tears, were associated with increased transmission. At birth, 149 neonates (12.4%) were bathed in antiseptic solutions (benzalkonium chloride, sodium hypochlorite, chlorhexidine, or povidone-iodine). A neonatal antiseptic bath was not associated with a decrease in HIV transmission. Maternal HIV status. The proportion of H1V-infected children was inversely proportional to maternal CD4 + lymphocyte count (27.6% <200 cells/mm 3 , 22.2% between 200 and 500 cells/mm3 , and 16.9% >500 cells/mm 3 ; p < 0.02). Transmission was significantly higher in case of a positive result for p24 antigenemia (39.1% versus 17.6% for antigen-negative women, p< 10-). The relation with transmission was stronger for antigenemia than for CD4 + cell count. Multivariate analysis of obstetric factors. Variables that were significantly related to mother-to-child transmission (p < 0.05) were further analyzed in a stepwise logistic regression model. We excluded from the model those risk factors that were infrequent (i.e., hemorrhage in labor, 32/1632; bloody amniotic fluid, 30/1632). Because these events were rare, they were not potential confounding factors but could make the model unreliable. Conversely,
because maternal disease status was an important potential confounder, the presence of p24 antigenemia at delivery was entered into the model. Three of the variables tested remained significantly related to mother-to-child transmission in the multivariate analysis: p24 antigenemia (odds ratio 3.49, 95% confidence interval 1.93 to 6.30; p < 10-3), premature rupture of membranes (odds ratio 1.55, 95% confidence interval 1.06 to 2.25; p < 0.03), and procedures during pregnancy (odds ratio 2.08, 95% confidence interval 1.02 to 4.25; p < 0.05). We chose p24 antigen rather than CD4 cell count as a marker for maternal infection status because it was the variable most strongly related to mother-to-child transmission in the univariate analysis and allowed for analysis of more cases (n = 860). Sexually transmitted disease during pregnancy and premature delivery did not achieve statistical significance in the multivariate analysis. We also checked that mode of delivery, which was not included in the final model because it was not related to mother-to-child transmission in univariate analysis, did not change the results. Comment A number of factors have been reported to favor mother-to-child transmission of HIV type 1, among which breast-feeding and, above all, maternal immune deficiency stand out.'t 1'5" Although much of transmission is thought to occur around the time of birth, this is the first large cohort study to evaluate the impact on mother-to-child transmission of a wide spectrum of obstetric events. Our data concern a period before the introduction of zidovudine to decrease mother-to-child transmission,"6 therefore they represent the "natural history" of transmission. Procedures during pregnancy were associated with a twofold increase in transmission, which is significant even when only "invasive" procedures are considered (i.e., needling procedures or amnioscopy). Such procedures have previously been considered in only one, small study, which failed to detect a relation to mother-to-child transmission. These procedures are known to favor rhesus isoimmunization and may similarly predispose to motherto-fetus transmission because of subclinical bleeding in the placenta, the outer membranes, or the amniotic cavity. We also found bloody amniotic fluid to be associated with a fourfold increase in transmission. In a small cohort from San Francisco,' 8 a sanguineous neonatal gastric aspirate was associated with increased mother-to-child transmission. Prepartum and intrapartum bleeding may be a cause of exposure by the fetus to maternal blood but also a consequence of placental disruption, favoring transplacental transmission. There was a relation between premature rupture of membranes and mother-to-child transmission. Previous studies have also observed a relation between prolonged
666
Mandelbrot et al.
September 1996
AmJ Obstet Gynecol
membrane rupture and transmission.' 9 In a registry of twin pregnancies2" the first twin, who is in more prolonged contact with the maternal genital tract, is at increased risk of HIV transmission. These findings may be suggestive of ascending route HIV infection. Interestingly, we did not find that mother-to-child transmission increased proportionately to the duration of membrane rupture. A possible explanation is that HIV infection may precede, or be concomitant with, membrane rupture rather than be a consequence of more prolonged rupture. The relation between premature membrane rupture and transmission may also involve viral, parasitic, or bacterial coinfections. Transfer of HIV may be favored not only by an ascending route but also through the placenta. Chorioamnionitis has been found to be associated with HIV transmission in several studies.' 1' 21. 22 We also observed an association between sexually transmitted diseases during pregnancy and mother-to-child transmission, as has been previously reported, 2 as well as a trend toward increased transmission in case of fever during labor, although we did not demonstrate a relation between cervicovaginal infection or maternal-fetal sepsis and transmission. However, placental pathologic findings were not available in this multicenter cohort study. Premature delivery was associated with an increase in transmission. However, our multivariate analysis may suggest that premature rupture of the membranes, rather than prematurity, accounted for the increase in motherto-child transmission. An association between preterm delivery and mother-to-child transmission has already been reported," 23 but the causal relationship is not known. Preterm labor may favor viral transmission; fetal HIV infection may lead to premature delivery and may favor both preterm labor and mother-to-child transmission. Subclinical bacterial infection is known to play an important role in preterm delivery, through cytokinemediated mechanisms,2 4 and may be involved in premature rupture of the membranes, both at term and before term. We found no relation between the management of labor and delivery and mother-to-child transmission. Protracted labor, instrumental delivery, fetal skin abrasions, and episiotomy or perineal tears, all of which increase direct exposure of the fetus to maternal blood, were not related to transmission. Data from the European Collaborative Study have also failed to show a consistent relation between transmission and perineal status or instrumental delivery.9 We also found no decrease in transmission when vaginal lavage with virucidal agents was performed during labor or when the neonate was promptly bathed with such antiseptics. Mode of delivery, the only obstetric factor that has been widely studied with regard to mother-to-child transmission, remains a topic of controversy. We observed no protective effect of cesarean section, whereas in the Eu-
ropean Collaborative Study9 transmission was 12% after cesarean section versus 18% for vaginal delivery. Surprisingly, the European Collaborative Study found a lower transmission rate after planned versus emergency cesarean sections, whereas one would expect cesarean delivery before labor and with intact membranes to be more protective than emergency cesarean delivery for fetal distress and/or dystocia during labor. Although women with more advanced HIV infection were more likely to undergo cesarean section in our study, mother-to-child transmission did not differ according to mode of delivery, even when stratified by maternal CD4 + counts. In short, we failed to identify differences in mother-tochild transmission of HIV type 1 according to variables related to routine obstetric management, such as mode and conditions of delivery, duration of labor, or perineal status. These findings are puzzling, given the available evidence suggesting that the majority of mother-to-child transmission occurs during delivery. A possible explanation is that intrapartum transmission is less frequent than previously thought. An alternate hypothesis is that intrapartum transmission may be related to events occurring before labor, independently of obstetric management. A major objective of this study was to target risk factors related to gestation and delivery for intervention. However, few recommendations for mode of delivery or intrapartum management can be made at present. Invasive procedures during pregnancy, such as needling procedures and amnioscopy, can be avoided. Prevention of premature membrane rupture, as well as premature delivery, is difficult, but diagnosis and treatment of vaginal infections can be stressed. When premature rupture of the membranes does occur, rapid delivery may be an option; however, it is not known whether the risk of HIV transmission follows or precedes premature membrane rupture. Wide use of antibiotics may be considered, but their impact on transmission has not yet been evaluated. Intraamniotic bleeding usually precedes active labor, and it is essentially unpredictable and unpreventable. Zidovudine to decrease mother-to-child HV transmission'6 is changing clinical practice in industrialized countries. However, because its efficacy is incomplete, further measures to decrease intrapartum transmission are needed. 5 Because the cohort approach has so far been inconclusive to determine the efficacy of obstetric interventions, randomized, controlled trials have been started with local disinfection with virucides, as well as elective cesarean delivery. Persons participating in the study group and their institutions are as follows: J.C. Boulanger, B. Pautard, Amiens; P.M. Piquet,J.C. Smolarski, Argenteuil; P. Eloy, A. Mamou, M.A. Rozan, Aubervilliers; P. Caubel, M. Dandine, Aulnay; L. Benoist, V. Jeantils, E. Lachassine, M. Uzan, Bondy; P. Barjot, C. Bazin, G. Muller, Caen; V. Chambrin, J.F. Delfraissy, J.C. Pons, Clamart;
Volume 175, Number 3, Part 1 Am J Obstet Gynecol
G. Faucher, M. Levardon, F. Mazy, Clichy; C. Crenn, P. Engelman, C. Floch, F. Mazy, F. Meier, Colombes; C. Huraux-Rendu, J.B. Paniel, C. Touboul, Crdteil; R.J6ny, M. Robin, Esquirol; S. Elhaik, M. Nardou, Evreux; D. Galli-Douani, A. May, Evry; C. Dallot, P. Lhuillier, Fontainebleau; R. Bronstein, H. Seaume, Longjumeau; J.C. Berardi, A. de Lanette, Mantes la Jolie; C. Chau, P. Deboisse, M. Gamerre, Marseille Belle de Mai; J. Haddad, B. Robichez, Meulan; V. Clmencet, T. Kleitz, Melun; J.F. Ropert, C. Talon, Monffermeil; P. Benos, E Laffargue, Montpellier; J.M. Bourgeais, J.A. Cacault, B. Kazemi, Nanterre; D. Berterottidre,J.N. Botto, Neuilly; A. Bongain, J.Y Gillet, Nice; I. Nisand, E. Rousset, Poissy; G. Mouchnino, J.M. Muray, Pontoise; F. Borsa-Lebas, B. Clavier, C. Duval, Rouen; M.C. Allemon, C. Bazin, N. Ghibaudo, Saint Denis; J. Belaisch-Allart, F. Labbe, Sevres; A.M. Boulley, J.C. Colau, Suresnes; A. Berrebi, G. Pontonnier, Toulouse; A. Fignon, J. Lansac, Tours; A. Lacroix Coutry, V. Piat, Vitry; F. Guillot, F. Grasland, B. Maria, Villeneuve-St. Georges; H. Bastian,J.L. Btnifla, P. Madelenat, S. Matheron, H6pital Bichat, Paris; S. Parat, R. Taurelle, H6pital Boucicaut, Paris; C. Carlus, H. Cohen, Cit6 Universitaire, Paris; C. Aufrant, S. de Kervadec, Notre Dame de Bon Secours, Paris; P. Poitout, F. Rigaux, M. Ronzier, H6tel Dieu, Paris; N. Ciraru-Vigneron, R. Colonna, V. Lefevre, Hpital Lariboisiere, Paris; J.M. Cheynier, G. Hatem, B. Heller-Roussin, H6pital des Mtallurgistes, Paris; B. Bianco, P. Darbois, C. Katlama, Hopital Pitid-Salpetriere, Paris; F. Artiguebieille, N. Moudoub, L. Mandelbrot, E. Papiernik, D. Sdrdni, Port Royal, Paris; P. Blot, L. Mandelbrot, F. Schaller, H6pital Robert Debr&, Paris; G. Barau, M.G. Lebrette, A. Pign6, H6pital Rothschild, Paris; L. Marpeau, M.C. Meyohas, J. Milliez, Hopital Saint-Antoine, Paris; J. Chavinid, P. Landowski, D. Sicard, H6pital Saint-Vincent de Paul, Paris; G. Delzant, M. Dupuis, S. Uzan, H6pital Tenon, Paris. We acknowledge Dr. Maris-Louise Newell for her thoughtful comments. REFERENCES
1. Brossard Y,AubinJT, Mandelbrot L, et al. Frequency of early in utero HIV1 infection: a blind DNA polymerase chain reaction study on 100 fetal thymuses. AIDS 1995;9:359-66. 2. Burgard M, Mayaux MJ, Blanche S, et al. The use of viral culture and p2 4 antigen testing to diagnose human immunodeficiency virus infection in neonates. N EnglJ Med 1992; 327:1192-7. 3. Bryson YY, Luzuriaga K, Sullivan JL, Wara DW. Proposed definitions for in utero versus intrapartum transmission of HIV-1. N EnglJ Med 1992;327:1246-7. 4. De Rossi A, Ometto L, Mammano F, et al. Vertical transmission of HIV-1: lack of detectable virus in peripheral blood cells of infected children at birth. AIDS 1992;6:1117-20. 5. Krivine A, Firtion G, Cao L, Francoual C, Henrion R, Lebon P. HIV replication during the first weeks of life. Lancet 1992;339:1187-9. 6. Rouzioux C, Costagliola D, Burgard M, et al. Estimated timing of mother-to-child human immunodeficiency virus type I transmission by use of a Markov model. AmJ Epidemiol 1995;142:1330-7.
Mandelbrot et al.
667
7. Amirhessami-Aghila N, Spector SA. Human immunodeficiency virus type 1 infection of human placenta: potential route for fetal infection. J Virol 1991;65:2231-6. 8. Pons JC, Brossard Y, Jrad I, et al. Transplacental microtransfusions of maternal blood toward the fetus: is there a relation with HIV vertical transmission? In: Proceedings of the second international symposium on AIDS and reproduction. Montpellier: Sauramps Medical, 1994. 9. European Collaborative Study. Caesarean section and risk of vertical transmission of HIV-l infection. Lancet 1994;343: 1464-7. 10. Mayaux MJ, Blanche S, Rouzioux C, et al. Maternal factors associated with perinatal HIV-1 transmission: The French cohort study-7 years of follow-up observation. J Acquir Immune Defic Syndr Hum Retrovirol 1995;8:188-94. 11. Blanche S, Rouzioux C, Guilhard Moscato ML, et al. A prospective study of infants born to women seropositive for human immunodeficiency virus type 1. N EnglJ Med 1989; 320:1643-8. 12. Cadwell MB, Oxtoby MJ; Simonds RJ, Lindegren ML, Rogers ME. 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR Morb Mortal Wkly Rep 1994;43:1-10. 13. Ryder RW, NsaW, Hassing SE, et al. Perinatal transmission of the human immunodeficiency virus type 1 to infants of seropositive women in Zaire. N EnglJ Med 1988;320:163742. 14. European Collaborative Study. Risk factors for mother-tochild transmission of HIV-1. Lancet 1992;339:1007-12. 15. St. Louis ME, Kamenga M, Brown C, et al. Risk for perinatal HIV-1 transmission according to maternal, immunologic, virologic and placental factors. JAMA 1993;269: 2853-9. 16. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N EnglJ Med 1994; 331:1173-80. 17. Viscarello RR, DeGennaro NJ, Griffith SM, Andiman W, Hobbins JC. Does an antepartum invasive procedure increase the risk of perinatal transmission of HIV-1? [Ab-
stract]. AmJ Obstet Gynecol 1992;166:384. 18. William-Herman D, Wara D, Levy J, Benson M, Dattel B, Landers D. Risk factors for perinatal HIV1 transmission. In: Proceedings of the Ninth International Conference on AIDS, 1993; Berlin. PO-B05-1064. 19. Minkoff H, Burns DN, Landesman S, et al. The relationship of the duration of ruptured membranes to vertical transmission of human immunodeficiency virus. Am J Obstet Gynecol 1995;173:585-9. 20. Duliege AM, Amos CI, Felton S, Biggar RJ, International Registry of HIV-exposed Twins, Goedert JJ. Birth order,
delivery route and concordance in the transmission of human immunodeficiency virus type I from mothers to twins. J Pediatr 1995;126:625-32. 21. Nair P, Alger L, Hines S, et al. Maternal and neonatal characteristics associated with HIV infection in infants of seropositive women. J Acquir Immune Defic Syndr Hum Retrovirol 1993;6:298-302. 22. Temmerman M, N'Yong'o AO, BwayoJ, et al. Risk factors for mother-to-child transmission of human immunodeficiency
virus-1 infection. AmJ Obstet Gynecol 1995;172:700-5. 23. European Collaborative Study. Risk factors for mother-tochild transmission of HIV-1. Lancet 1992;339:1007-12. 24. Romero R, Mazor M. Infection and preterm labor. Clin Obstet Gynecol 1988;31:553-61. 25. Siena Consensus Workshop II. Strategies for prevention of perinatal transmission of HIV infection. J Acquir Immune Defic Syndr Hum Retrovirol 1995;8:161-75.
To target interventions to decrease mother-to-child transmission of human immunodeficiency virus (HIV), it is crucial to understand its timing and mechanisms. Substantial data are now available on timing, most of which point to the late in utero and intrapartum periods. In a study of 100 second-trimester abortuses, early in utero HIV infection was rare.' Postnatal cohorts offer further evidence for late transmission. HIV is undetectable in the
From INSERM (Institut National de la Sante et de la Recherche Medicale) U149 and H6pital Cochin-Port Royal,' H6pital Bichat,' and H6pital Lariboisire,' Paris; INSERM U292, H6pitalde Bictre,' and H6pital Saint Roch,' Nice; and HopitalLa Grave, Toulouse. A complete list of the participants in SEROGEST and The French PediatricHIV Infection Study Group appears at the end of the article. Supported by grants from Sidaction and the Agence Nationale de Recherche contre le Sida. Received for publicationFebruary 2, 1996; revised May 1, 1996; accepted May 31, 1996. Reprint requests: L. Mandelbrot, MD, H6pital Cochin-Port Royal, Service de Gyndcologie-Obstetrique, 123 Boulevard de Port Royal, 75014 Paris, France. Copyright © 1996 by Mosby-Year Book, Inc. 0002-9378/96 $5.00+ 0 6/1/75478
majority of infected infants during the first days after birth, according to highly sensitive polymerase chain reaction or viral cultures."-5 With a mathematic model that takes into account the time from birth to p2 4 antigen and virus detection, as well as antibody production, Rouzioux et al. 6 concluded that one third of transmission occurs over the last weeks of pregnancy and two thirds at the time of delivery. In contrast, little is known about the actual mechanisms of mother-to-child transmission, which may involve placental transfer,7 maternal-fetal hemorrhage,' ascending route infection, direct mucocutaneous contact, and absorption in the fetal-neonatal digestive tract. Because intrapartum transmission appears to be important, a relation between obstetric management and transmission might be expected. Recently, the European Collaborative Study reported a significantly lower transmission rate in children born by cesarean section versus vaginal delivery, 9 whereas the French perinatal cohort study showed no difference in transmission according to the mode of delivery." This discordance between the two largest cohort studies indicates that there may be differ661
662
Mandelbrot et al.
ences in patient characteristics or peripartum management. We focused our attention on the pregnancy history and a detailed analysis of the circumstances of labor and delivery in the French perinatal cohorts. Patients and methods Two prospective multicenter cohorts have been established in France to study perinatal HIV transmission. The French Pediatric Cohort, established in September 1985, involves follow-up of all infants born to HIV-infected mothers in 69 obstetric services throughout the country. The protocol for follow-up and anonymous data transmission has been reported previously. ° ' 1 Perinatal data recorded include maternal age, geographic origin, suspected route of HIV acquisition, clinical status, lymphocyte subpopulations, gestational age at birth (based on last menstrual period and/or first-trimester ultrasonography), birth weight, mode of delivery, and breast-feeding. The SEROGEST cohort, established in 1989, involves 24 centers. It enrolls HIV-infected women, with written consent, during the first or second trimester of pregnancy or at the time of pregnancy termination or delivery. Follow-up is every 3 months during the first year and every 6 months for another 9 years. When pregnancy is continued to delivery, the child is enrolled in the French Pediatric Cohort. At each trimester, clinical and biologic data are recorded by the obstetric team and by an infectious diseases specialist or internist. These data are reported on obstetric and HIV case report forms and transmitted on an anonymous basis to the coordinating center. All gestational complications are recorded, including specifically defined entries for premature labor (requiring hospitalization), bleeding, cervicovaginal infections (confirmed by microbiologic testing), documented sexually transmitted diseases, and invasive procedures. Information on labor and delivery includes mode of delivery, mode of induction, duration of labor, duration of membrane rupture, procedures performed, perineal status (episiotomy, tear), complications (fetal distress indicated by abnormal cardiotocograms, neonatal pH <7.20 or Apgar score <7), fever >37 ° C, bleeding, maternal or fetal infection (i.e., fetal tachycardia, positive bacterial cultures from amniotic fluid, or neonatal bacterial sepsis), and measures such as disinfection of the genital tract and antiretroviral therapy. The coordinators of the two French cohorts decided to ask centers involved in the Pediatric Cohort to participate in the study of obstetric factors. All obstetric data had been recorded prospectively on-site and were collected by an obstetric investigator on supplementary, anonymous case report forms and included in the SEROGEST database. Data from 45 centers were thus added, so the total number of centers participating in the study was 69. Infants' HIV infection status was determined according to international consensus definitions. 2 A child was con-
September 1996 AmJ Obstet Gynecol
sidered infected if HIV type 1 antibodies persisted beyond 18 months or if the child died of HIV-related disease before this age; a child was considered uninfected if at least two HIV antibody test results were negative by the age of 18 months. Testing for HIV antibodies was carried out with two commercial enzyme-linked immunosorbent assays (ELISA), and positive results were confirmed by Immunoblot (Diagnostics Pasteur or Dupont de Nemours, Paris) assay. Immunoblot assay was considered negative when no HIV antibody of any type was present. Transmission rates were compared for each factor by univariate analysis. Proportions were compared with the 2 test or Fisher's exact test for cell counts <5. Relative risks and their 95% confidence intervals were estimated according to the Mantel-Haenszel method for prospective cohort studies. The Mantel-Haenszel x2 test was also used for adjusted comparisons. Quantitative variables were expressed as mean ± 1 SD. Means were compared by Student's t test or the nonparametric Wilcoxon test for numbers <30. Selected continuous variables were categorized into two classes, according to thresholds established a priori by the clinicians. Logistic regression was performed to estimate the independent effects of each selected risk factor in transmission. All variables found to be significant at a threshold of 0.05 in the univariate analysis were included in the final model, exept rare events, for which the proportion of women at risk was <3%. Odds ratios, adjusted for all the other factors, were calculated in the logistic regression model. We also entered the variable mode of delivery into the model, to check that it did not influence the results. Analysis was performed with SAS (SAS Institute, Cary, N.C.) software. %
Results Between September 1985 and December 1993, 2167 HIV-seropositive mothers were delivered in the participating obstetric services. After mothers with type HIV 2 infection (n = 96), twin pairs (n = 34), and repeat pregnancies (n= 160) were excluded, so that the same mothers would not be included more than once, 1842 motherchild pairs were eligible for study. Among these infants 28 died before HIV status could be determined, 54 could not be enrolled because of lack of parental consent, and 111 were not available for follow-up (including 50 who returned to their country of origin). The nonevaluable children did not differ significantly from the study group for any of the pregnancy or labor and delivery variables investigated. The study group comprised 1632 children fulfilling the inclusion criteria, with known HIV status at 18 months. The proportion of HIV-infected children in the population under study was 310 of 1632 (19.0%; 95% confidence interval 17.1% to 20.9%). Maternal characteristics were comparable to those previously described for the French Pediatric Cohort.' o Among the 1632 mothers in the study group, all those
Mandelbrot et al. 663
Volume 175, Number 3, Part 1 AmJ Obstet Gynecol
Table I. Mother-to-child HIV type 1 transmission rate according to events during pregnancy Event Bleeding No (n= 1154) Yes (n = 122) Cervicovaginal infection No (n = 803) Yes (n= 477) Sexually transmitted diseases No (n= 1060) Yes (n=212) Procedures* No (n= 1185) Yes (n = 68)
Children infected (%)
Relative risk
95% Confidence interval
Significance
18.5 20.5
1.1
0.7-1.6
NS
16.7 22.2
1.3
1.1-1.7
p= 0.018
17.3 26.4
1.5
1.1-2.0
p=0.003
18.0 33.8
1.9
1.3-2.7
p= 0.003
*Amniocentesis and other needling procedures, cerclage, laser therapy, or amnioscopy.
delivered through 1990 (n= 944) were included in the previous publication. Mean age was 27 years (SD ± 4.5), 36.5% were previous or current intravenous drug users, and 34.1% were born in sub-Saharan Africa or the Caribbean. Evaluation for undissociated p24 antigenemia at delivery was available in 1366 women; the result was positive in 7.1%. CD4+ lymphocyte counts were distributed as follows: 134 women (14.7%) had <200 cells/mm', 361 (37.3%) had between 200 and 500 cells/mm 3 , and 468 mothers (48.0%) had 500 CD4+ cells/mm3 . Only 2.1% of the infants were breast-fed. Complications during pregnancy (Table I). Bleeding, at any time in pregnancy before labor, was observed in 122 cases (9.6% of pregnancies), and cervicovaginal infections were recorded in 477 cases (37.3%). Neither bleeding nor cervicovaginal infection was associated with an increase in transmission. Sexually transmitted diseases (STD) occurred in 212 pregnancies (16.7%), mainly genital herpes, papillomavirus infection (genital warts or cervical dysplasia), trichomoniasis, gonococcal or chlamydia infection, or confirmed syphilis. Transmission was significantly higher in cases of STD (26.4% vs 17.3%, p < 0.003). Only 100 women (5.5%) received zidovudine during pregnancy, the main indication during the study period (through 1993) being advanced immune deficiency. Transmission occurred in 24.7% of cases, but this was not significantly higher than for untreated women. Procedures were performed in 68 cases (5.4% of pregnancies) and were associated with a transmission rate of 33.8% versus 18.5% (p < 0.003). These included invasive procedures (i.e., amniocentesis and other needling procedures, n= 13; amnioscopy, n = 26), as well as cerclage (n = 8), external cephalic version (n = 2) and laser therapy (n = 19). The transmission rate remained significantly increased (36%) when only needling procedures and amnioscopy were considered. Circumstances of labor (Table II). The overall rate of preterm birth before 37 weeks from the last menstrual period was 10.2%. The transmission rate was significantly
higher in preterm deliveries than in term ones (25.5% and 17.9%, respectively; p < 0.02). The relation between prematurity and mother-to-child transmission was also observed when pregnancies that were terminated for medical indications were excluded and only spontaneous preterm deliveries were considered. In cases of severe prematurity, up to 34 weeks (n = 67 cases) the transmission rate was 26.9%. The mean gestational age of infected infants was 38.5 weeks, significantly less than for uninfected infants (38.9 weeks, p < 0.02). This difference persisted when only spontaneous preterm deliveries were considered. Labor was induced in 17.8% of deliveries, with the use of prostaglandins, amniotomy, and/or oxytocin; transmission was not more frequent than after spontaneous labor. The transmission rate did not differ according to the duration of active labor. The mean duration of labor was the same for infected children and for uninfected children (6 + 3 hours). Rupture of membranes before the onset of labor occurred in 26.9% of cases. Transmission was higher in cases with premature rupture of membranes (23.8% vs 17.1%, p < 0.009). Premature membrane rupture was related to preterm delivery, occurring in 53.3% of deliveries before 34 weeks, 37.0% at 35 to 36 weeks, 26.3% at 37 to 41 weeks, and 15.8% beyond 41 weeks. The mean duration between membrane rupture and birth appeared longer for infected infants than for uninfected ones (14 hours and 10 hours, respectively), but the difference was not statistically significant. The transmission rate was higher when membranes ruptured >12 hours before delivery (23.9% vs 17.8%, p < 0.05). However, the transmission rate did not increase significantly in proportion to the duration of membrane rupture (21.1% vs 17.2%, p < 0.08, at a 4-hour cutoff; 25.5% vs 18.2%, p < 0.07, at a 24-hour cutoff). Fever during labor or delivery was noted in 88 deliveries (7.3%), and evidence of chorioamnionitis was noted in 6.3% of deliveries. Fetal distress occurred in 21.9% of
664 Mandelbrot et al.
September 1996 AmJ Obstet Gynecol
Table II. Mother-to-child HIV type 1 transmission rate according to events during labor Event Gestational age >37 wk (n= 1455) <37 wk (n = 165) Onset of labor Spontaneous (n= 1018) Induced (n = 220) Premature membrane rupture No (n = 890) Yes (n= 327) Fever (>37.8 ° C) during labor No (n= 1123) Yes (n= 88) Maternal-fetal sepsis No (n= 1105) Yes (n= 74) Hemorrhage in labor No (n = 1179) Yes (n= 32) Color of amniotic fluid Clear (n = 886) Meconium-stained (n = 308) Bloody (n = 30)
Fetal distress No (n = 988) Yes (n= 277) Fetal skin lesions (scalp electrode, pH) No (n= 1014) Yes (n = 79) Vaginal lavage No (n = 783) Yes (n=217)
Children infected (%)
Relative risk
95% Confidence interval
17.9 25.5
1.4
1.1-1.9
p = 0.02
20.9 18.6
1.1
0.8-1.5
NS
17.1 23.8
1.4
1.1-1.8
p=0.009
18.4 25.0
1.4
0.9-2.0
NS
18.8 17.6
0.9
0.5-1.5
NS
18.1 34.4
1.9
1.1-3.2
17.2 19.2
1.1
0.8-1.5
60.0
3.5
2.3-5.3
18.5 18.8
1.0
0.7-1.3
NS
18.2 21.5
1.2
0.7-1.8
NS
18.9 19.3
1.0
0.9-1.1
NS
Significance
p=0.03
p < 10-
Table III. Mother-to-child HIV type 1 transmission rate according to events during delivery Event Mode of delivery Vaginal (n= 1360) Emergency cesarean section (n= 162) Elective cesarean section (n= 108) Instrumental vaginal delivery No (n = 915) Yes (n= 182) Assisted vaginal delivery No (n= 994) Yes (n=96) Perineum Intact (n = 288) Episiotomy-tear (n= 729) Neonatal antiseptic bath No (n = 1053) Yes (n= 149)
Children infected (%)
Relative risk
95% Confidence interval
Significance
19.1 19.1 15.7
1.0 0.8
0.9-1.1 0.5-1.3
NS NS
19.5 16.5
0.8
0.6-1.2
NS
18.7 21.9
1.1
0.7-1.8
NS
18.8 19.2
1.0
0.7-1.3
NS
18.7 16.7
1.1
0.7-1.6
NS
cases. None of these events was associated with an increase in transmission. Hemorrhage during labor (including abruptio placentae and placenta previa) was observed in 32 cases (2.6% of deliveries) and was associated with a significant increase in transmission (34.4% vs 18.1%, p< 0.03). Amniotic fluid was bloody in 2.5% of deliveries and meconium stained in 25.2%. Transmission rates were higher in cases
of bloody fluid or meconium staining than for clear fluid (60.0%, 19.2%, and 17.2%, respectively; p< 10-5). The
95% confidence interval of the relative risk was >1 for bloody fluid but not for meconium-stained fluid. Fetal skin lesions from scalp pH determination or electrode placement were reported in 7.2% of cases. These were not associated with a significant increase in transmission. Vaginal lavage with antiseptic solutions (povidone-
Mandelbrot et al. 665
Volume 175, Number 3, Part I AmJ Obstet Gynecol
iodine, chlorhexidine, or benzalkonium chloride) was performed during labor in 217 cases (21.7%); the transmission rate was not lower than without vaginal lavage. Circumstances of delivery (Table III). Cesarean sections were performed in 270 cases (16.6% of deliveries), 60% of which were on an emergency basis and 40% of which were planned. No difference in transmission was observed between infants delivered vaginally and those delivered by cesarean section. The transmission rate was 15.7% after elective cesarean sections versus 19.1% after emergency cesarean sections, which was not significantly different. Similarly, there was no significant difference in transmission after cesarean delivery according to whether membranes were intact or ruptured. The proportion of infants who were breast-fed did not differ, significantly between those delivered by cesarean section and those delivered vaginally. Because cesarean section rates varied between centers, from 0% to 40%, we looked for a relation between cesarean rates and mother-to-child transmission rates in each center; there was no correlation (r=-0.02). Because the cesarean rate was higher in women with more advanced disease (24.4% when CD4* counts were <200 cells/mm3 ), we also looked for differences in transmission rates according to mode of delivery when stratifying for CD4 + counts <200, 200 to 500, or >500 cells/mm 3 . No difference in mother-to-child transmission according to mode of delivery was observed when CD4 + cell levels were taken into account. Forceps or vacuum extractors were used in 9.4% of vaginal deliveries. Episiotomies and/or perineal tears were reported in 71.7% of vaginal deliveries. Neither instrumental delivery nor other procedures during delivery, such as breech extraction or episiotomies or tears, were associated with increased transmission. At birth, 149 neonates (12.4%) were bathed in antiseptic solutions (benzalkonium chloride, sodium hypochlorite, chlorhexidine, or povidone-iodine). A neonatal antiseptic bath was not associated with a decrease in HIV transmission. Maternal HIV status. The proportion of H1V-infected children was inversely proportional to maternal CD4 + lymphocyte count (27.6% <200 cells/mm 3 , 22.2% between 200 and 500 cells/mm3 , and 16.9% >500 cells/mm 3 ; p < 0.02). Transmission was significantly higher in case of a positive result for p24 antigenemia (39.1% versus 17.6% for antigen-negative women, p< 10-). The relation with transmission was stronger for antigenemia than for CD4 + cell count. Multivariate analysis of obstetric factors. Variables that were significantly related to mother-to-child transmission (p < 0.05) were further analyzed in a stepwise logistic regression model. We excluded from the model those risk factors that were infrequent (i.e., hemorrhage in labor, 32/1632; bloody amniotic fluid, 30/1632). Because these events were rare, they were not potential confounding factors but could make the model unreliable. Conversely,
because maternal disease status was an important potential confounder, the presence of p24 antigenemia at delivery was entered into the model. Three of the variables tested remained significantly related to mother-to-child transmission in the multivariate analysis: p24 antigenemia (odds ratio 3.49, 95% confidence interval 1.93 to 6.30; p < 10-3), premature rupture of membranes (odds ratio 1.55, 95% confidence interval 1.06 to 2.25; p < 0.03), and procedures during pregnancy (odds ratio 2.08, 95% confidence interval 1.02 to 4.25; p < 0.05). We chose p24 antigen rather than CD4 cell count as a marker for maternal infection status because it was the variable most strongly related to mother-to-child transmission in the univariate analysis and allowed for analysis of more cases (n = 860). Sexually transmitted disease during pregnancy and premature delivery did not achieve statistical significance in the multivariate analysis. We also checked that mode of delivery, which was not included in the final model because it was not related to mother-to-child transmission in univariate analysis, did not change the results. Comment A number of factors have been reported to favor mother-to-child transmission of HIV type 1, among which breast-feeding and, above all, maternal immune deficiency stand out.'t 1'5" Although much of transmission is thought to occur around the time of birth, this is the first large cohort study to evaluate the impact on mother-to-child transmission of a wide spectrum of obstetric events. Our data concern a period before the introduction of zidovudine to decrease mother-to-child transmission,"6 therefore they represent the "natural history" of transmission. Procedures during pregnancy were associated with a twofold increase in transmission, which is significant even when only "invasive" procedures are considered (i.e., needling procedures or amnioscopy). Such procedures have previously been considered in only one, small study, which failed to detect a relation to mother-to-child transmission. These procedures are known to favor rhesus isoimmunization and may similarly predispose to motherto-fetus transmission because of subclinical bleeding in the placenta, the outer membranes, or the amniotic cavity. We also found bloody amniotic fluid to be associated with a fourfold increase in transmission. In a small cohort from San Francisco,' 8 a sanguineous neonatal gastric aspirate was associated with increased mother-to-child transmission. Prepartum and intrapartum bleeding may be a cause of exposure by the fetus to maternal blood but also a consequence of placental disruption, favoring transplacental transmission. There was a relation between premature rupture of membranes and mother-to-child transmission. Previous studies have also observed a relation between prolonged
666
Mandelbrot et al.
September 1996
AmJ Obstet Gynecol
membrane rupture and transmission.' 9 In a registry of twin pregnancies2" the first twin, who is in more prolonged contact with the maternal genital tract, is at increased risk of HIV transmission. These findings may be suggestive of ascending route HIV infection. Interestingly, we did not find that mother-to-child transmission increased proportionately to the duration of membrane rupture. A possible explanation is that HIV infection may precede, or be concomitant with, membrane rupture rather than be a consequence of more prolonged rupture. The relation between premature membrane rupture and transmission may also involve viral, parasitic, or bacterial coinfections. Transfer of HIV may be favored not only by an ascending route but also through the placenta. Chorioamnionitis has been found to be associated with HIV transmission in several studies.' 1' 21. 22 We also observed an association between sexually transmitted diseases during pregnancy and mother-to-child transmission, as has been previously reported, 2 as well as a trend toward increased transmission in case of fever during labor, although we did not demonstrate a relation between cervicovaginal infection or maternal-fetal sepsis and transmission. However, placental pathologic findings were not available in this multicenter cohort study. Premature delivery was associated with an increase in transmission. However, our multivariate analysis may suggest that premature rupture of the membranes, rather than prematurity, accounted for the increase in motherto-child transmission. An association between preterm delivery and mother-to-child transmission has already been reported," 23 but the causal relationship is not known. Preterm labor may favor viral transmission; fetal HIV infection may lead to premature delivery and may favor both preterm labor and mother-to-child transmission. Subclinical bacterial infection is known to play an important role in preterm delivery, through cytokinemediated mechanisms,2 4 and may be involved in premature rupture of the membranes, both at term and before term. We found no relation between the management of labor and delivery and mother-to-child transmission. Protracted labor, instrumental delivery, fetal skin abrasions, and episiotomy or perineal tears, all of which increase direct exposure of the fetus to maternal blood, were not related to transmission. Data from the European Collaborative Study have also failed to show a consistent relation between transmission and perineal status or instrumental delivery.9 We also found no decrease in transmission when vaginal lavage with virucidal agents was performed during labor or when the neonate was promptly bathed with such antiseptics. Mode of delivery, the only obstetric factor that has been widely studied with regard to mother-to-child transmission, remains a topic of controversy. We observed no protective effect of cesarean section, whereas in the Eu-
ropean Collaborative Study9 transmission was 12% after cesarean section versus 18% for vaginal delivery. Surprisingly, the European Collaborative Study found a lower transmission rate after planned versus emergency cesarean sections, whereas one would expect cesarean delivery before labor and with intact membranes to be more protective than emergency cesarean delivery for fetal distress and/or dystocia during labor. Although women with more advanced HIV infection were more likely to undergo cesarean section in our study, mother-to-child transmission did not differ according to mode of delivery, even when stratified by maternal CD4 + counts. In short, we failed to identify differences in mother-tochild transmission of HIV type 1 according to variables related to routine obstetric management, such as mode and conditions of delivery, duration of labor, or perineal status. These findings are puzzling, given the available evidence suggesting that the majority of mother-to-child transmission occurs during delivery. A possible explanation is that intrapartum transmission is less frequent than previously thought. An alternate hypothesis is that intrapartum transmission may be related to events occurring before labor, independently of obstetric management. A major objective of this study was to target risk factors related to gestation and delivery for intervention. However, few recommendations for mode of delivery or intrapartum management can be made at present. Invasive procedures during pregnancy, such as needling procedures and amnioscopy, can be avoided. Prevention of premature membrane rupture, as well as premature delivery, is difficult, but diagnosis and treatment of vaginal infections can be stressed. When premature rupture of the membranes does occur, rapid delivery may be an option; however, it is not known whether the risk of HIV transmission follows or precedes premature membrane rupture. Wide use of antibiotics may be considered, but their impact on transmission has not yet been evaluated. Intraamniotic bleeding usually precedes active labor, and it is essentially unpredictable and unpreventable. Zidovudine to decrease mother-to-child HV transmission'6 is changing clinical practice in industrialized countries. However, because its efficacy is incomplete, further measures to decrease intrapartum transmission are needed. 5 Because the cohort approach has so far been inconclusive to determine the efficacy of obstetric interventions, randomized, controlled trials have been started with local disinfection with virucides, as well as elective cesarean delivery. Persons participating in the study group and their institutions are as follows: J.C. Boulanger, B. Pautard, Amiens; P.M. Piquet,J.C. Smolarski, Argenteuil; P. Eloy, A. Mamou, M.A. Rozan, Aubervilliers; P. Caubel, M. Dandine, Aulnay; L. Benoist, V. Jeantils, E. Lachassine, M. Uzan, Bondy; P. Barjot, C. Bazin, G. Muller, Caen; V. Chambrin, J.F. Delfraissy, J.C. Pons, Clamart;
Volume 175, Number 3, Part 1 Am J Obstet Gynecol
G. Faucher, M. Levardon, F. Mazy, Clichy; C. Crenn, P. Engelman, C. Floch, F. Mazy, F. Meier, Colombes; C. Huraux-Rendu, J.B. Paniel, C. Touboul, Crdteil; R.J6ny, M. Robin, Esquirol; S. Elhaik, M. Nardou, Evreux; D. Galli-Douani, A. May, Evry; C. Dallot, P. Lhuillier, Fontainebleau; R. Bronstein, H. Seaume, Longjumeau; J.C. Berardi, A. de Lanette, Mantes la Jolie; C. Chau, P. Deboisse, M. Gamerre, Marseille Belle de Mai; J. Haddad, B. Robichez, Meulan; V. Clmencet, T. Kleitz, Melun; J.F. Ropert, C. Talon, Monffermeil; P. Benos, E Laffargue, Montpellier; J.M. Bourgeais, J.A. Cacault, B. Kazemi, Nanterre; D. Berterottidre,J.N. Botto, Neuilly; A. Bongain, J.Y Gillet, Nice; I. Nisand, E. Rousset, Poissy; G. Mouchnino, J.M. Muray, Pontoise; F. Borsa-Lebas, B. Clavier, C. Duval, Rouen; M.C. Allemon, C. Bazin, N. Ghibaudo, Saint Denis; J. Belaisch-Allart, F. Labbe, Sevres; A.M. Boulley, J.C. Colau, Suresnes; A. Berrebi, G. Pontonnier, Toulouse; A. Fignon, J. Lansac, Tours; A. Lacroix Coutry, V. Piat, Vitry; F. Guillot, F. Grasland, B. Maria, Villeneuve-St. Georges; H. Bastian,J.L. Btnifla, P. Madelenat, S. Matheron, H6pital Bichat, Paris; S. Parat, R. Taurelle, H6pital Boucicaut, Paris; C. Carlus, H. Cohen, Cit6 Universitaire, Paris; C. Aufrant, S. de Kervadec, Notre Dame de Bon Secours, Paris; P. Poitout, F. Rigaux, M. Ronzier, H6tel Dieu, Paris; N. Ciraru-Vigneron, R. Colonna, V. Lefevre, Hpital Lariboisiere, Paris; J.M. Cheynier, G. Hatem, B. Heller-Roussin, H6pital des Mtallurgistes, Paris; B. Bianco, P. Darbois, C. Katlama, Hopital Pitid-Salpetriere, Paris; F. Artiguebieille, N. Moudoub, L. Mandelbrot, E. Papiernik, D. Sdrdni, Port Royal, Paris; P. Blot, L. Mandelbrot, F. Schaller, H6pital Robert Debr&, Paris; G. Barau, M.G. Lebrette, A. Pign6, H6pital Rothschild, Paris; L. Marpeau, M.C. Meyohas, J. Milliez, Hopital Saint-Antoine, Paris; J. Chavinid, P. Landowski, D. Sicard, H6pital Saint-Vincent de Paul, Paris; G. Delzant, M. Dupuis, S. Uzan, H6pital Tenon, Paris. We acknowledge Dr. Maris-Louise Newell for her thoughtful comments. REFERENCES
1. Brossard Y,AubinJT, Mandelbrot L, et al. Frequency of early in utero HIV1 infection: a blind DNA polymerase chain reaction study on 100 fetal thymuses. AIDS 1995;9:359-66. 2. Burgard M, Mayaux MJ, Blanche S, et al. The use of viral culture and p2 4 antigen testing to diagnose human immunodeficiency virus infection in neonates. N EnglJ Med 1992; 327:1192-7. 3. Bryson YY, Luzuriaga K, Sullivan JL, Wara DW. Proposed definitions for in utero versus intrapartum transmission of HIV-1. N EnglJ Med 1992;327:1246-7. 4. De Rossi A, Ometto L, Mammano F, et al. Vertical transmission of HIV-1: lack of detectable virus in peripheral blood cells of infected children at birth. AIDS 1992;6:1117-20. 5. Krivine A, Firtion G, Cao L, Francoual C, Henrion R, Lebon P. HIV replication during the first weeks of life. Lancet 1992;339:1187-9. 6. Rouzioux C, Costagliola D, Burgard M, et al. Estimated timing of mother-to-child human immunodeficiency virus type I transmission by use of a Markov model. AmJ Epidemiol 1995;142:1330-7.
Mandelbrot et al.
667
7. Amirhessami-Aghila N, Spector SA. Human immunodeficiency virus type 1 infection of human placenta: potential route for fetal infection. J Virol 1991;65:2231-6. 8. Pons JC, Brossard Y, Jrad I, et al. Transplacental microtransfusions of maternal blood toward the fetus: is there a relation with HIV vertical transmission? In: Proceedings of the second international symposium on AIDS and reproduction. Montpellier: Sauramps Medical, 1994. 9. European Collaborative Study. Caesarean section and risk of vertical transmission of HIV-l infection. Lancet 1994;343: 1464-7. 10. Mayaux MJ, Blanche S, Rouzioux C, et al. Maternal factors associated with perinatal HIV-1 transmission: The French cohort study-7 years of follow-up observation. J Acquir Immune Defic Syndr Hum Retrovirol 1995;8:188-94. 11. Blanche S, Rouzioux C, Guilhard Moscato ML, et al. A prospective study of infants born to women seropositive for human immunodeficiency virus type 1. N EnglJ Med 1989; 320:1643-8. 12. Cadwell MB, Oxtoby MJ; Simonds RJ, Lindegren ML, Rogers ME. 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR Morb Mortal Wkly Rep 1994;43:1-10. 13. Ryder RW, NsaW, Hassing SE, et al. Perinatal transmission of the human immunodeficiency virus type 1 to infants of seropositive women in Zaire. N EnglJ Med 1988;320:163742. 14. European Collaborative Study. Risk factors for mother-tochild transmission of HIV-1. Lancet 1992;339:1007-12. 15. St. Louis ME, Kamenga M, Brown C, et al. Risk for perinatal HIV-1 transmission according to maternal, immunologic, virologic and placental factors. JAMA 1993;269: 2853-9. 16. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N EnglJ Med 1994; 331:1173-80. 17. Viscarello RR, DeGennaro NJ, Griffith SM, Andiman W, Hobbins JC. Does an antepartum invasive procedure increase the risk of perinatal transmission of HIV-1? [Ab-
stract]. AmJ Obstet Gynecol 1992;166:384. 18. William-Herman D, Wara D, Levy J, Benson M, Dattel B, Landers D. Risk factors for perinatal HIV1 transmission. In: Proceedings of the Ninth International Conference on AIDS, 1993; Berlin. PO-B05-1064. 19. Minkoff H, Burns DN, Landesman S, et al. The relationship of the duration of ruptured membranes to vertical transmission of human immunodeficiency virus. Am J Obstet Gynecol 1995;173:585-9. 20. Duliege AM, Amos CI, Felton S, Biggar RJ, International Registry of HIV-exposed Twins, Goedert JJ. Birth order,
delivery route and concordance in the transmission of human immunodeficiency virus type I from mothers to twins. J Pediatr 1995;126:625-32. 21. Nair P, Alger L, Hines S, et al. Maternal and neonatal characteristics associated with HIV infection in infants of seropositive women. J Acquir Immune Defic Syndr Hum Retrovirol 1993;6:298-302. 22. Temmerman M, N'Yong'o AO, BwayoJ, et al. Risk factors for mother-to-child transmission of human immunodeficiency
virus-1 infection. AmJ Obstet Gynecol 1995;172:700-5. 23. European Collaborative Study. Risk factors for mother-tochild transmission of HIV-1. Lancet 1992;339:1007-12. 24. Romero R, Mazor M. Infection and preterm labor. Clin Obstet Gynecol 1988;31:553-61. 25. Siena Consensus Workshop II. Strategies for prevention of perinatal transmission of HIV infection. J Acquir Immune Defic Syndr Hum Retrovirol 1995;8:161-75.