Objective
The objective of the study was to determine whether the duration of membrane rupture of 4 or more hours is a significant risk factor for perinatal transmission of human immunodeficiency virus (HIV) in the era of combination antiretroviral therapy (ART).
Study Design
This was a prospective cohort study of 717 HIV-infected pregnant women-infant pairs with a delivery viral load available who received prenatal care and delivered at our institution during the interval 1996-2008.
Results
The cohort comprised 707 women receiving ART who delivered during this interval. The perinatal transmission rate was 1% in women with membranes ruptured for less than 4 hours and 1.9% when ruptured for 4 or more hours. For 493 women with a delivery viral load less than 1000 copies/mL receiving combination ART in pregnancy, there were no cases of perinatal transmission identified up to 25 hours of membrane rupture. Logistic regression demonstrated only a viral load above 10,000 copies/mL as an independent risk factor for perinatal transmission.
Conclusion
Duration of membrane rupture of 4 or more hours is not a risk factor for perinatal transmission of HIV in women with a viral load less than 1000 copies/mL receiving combination ART.
Scheduled cesarean delivery has increased among women with human immunodeficiency virus (HIV) infection since the demonstration that delivery prior to labor and membrane rupture can reduce the risk of intrapartum transmission of HIV to the neonate. An increased risk of perinatal transmission of HIV-1 has been reported to be associated with membrane rupture of 4 or more hours in HIV-infected women with low CD4 levels; however, less than 5% of the women in the study were receiving zidovudine. Data from a metaanalysis indicated that the risk of perinatal transmission of HIV-1 increased by 2% for every hour of ruptured membranes and an acquired immunodeficiency syndrome (AIDS) diagnosis may potentiate this effect.
With this evidence that an increasing duration of membrane rupture is associated with an increasing risk of perinatal transmission of HIV-1, the critical time of duration of membrane rupture for a woman with a low viral load receiving antiretroviral therapy planning a vaginal delivery to ensure maximum protection for her infant is still unknown. The current recommendation is that operative amniotomy should generally be avoided in laboring women with a nondetectable viral load and should be performed only for clear obstetric indications to avoid the small but potential increased risk of HIV transmission. Similarly for women presenting in labor desiring to proceed with a vaginal delivery despite a detectable viral load, artificial membrane rupture should be avoided and performed only for a clear obstetric indication.
The objective of this study was to investigate whether 4 or more hours of membrane rupture remains a significant risk factor for perinatal transmission of HIV in the era of combination antiretroviral therapy (ART).
Materials and Methods
This was a prospective study using data from an institutional review board–approved HIV perinatal database established in 1988. One of the specific objectives of the database was to investigate pregnancy outcome including the rate of perinatal transmission. Women diagnosed HIV positive prior to or during pregnancy, who received prenatal care and delivered at the University of Miami/Jackson Memorial Medical Center (UM/JMMC) from 1996 until 2008, were identified.
Inclusion criteria were a singleton pregnancy, attendance for at least 1 prenatal visit at our obstetric clinic dedicated to the care of HIV positive patients, delivery at or after 20 weeks’ gestation, an HIV-1 ribonucleic acid (RNA) viral load available at delivery (these were usually measured at 35 weeks), and confirmation of the infants HIV status. Women delivered by elective cesarean section were excluded.
Antiretroviral therapy was classified as none, monotherapy, or combination therapy with or without a protease inhibitor. Gestational age at birth was determined on the basis of the last menstrual period, ultrasound biometry, or both. Preterm delivery was defined as delivery at less than 37 completed weeks of gestation. Low birthweight was defined as less than 2500 g. Clinical chorioamnionitis was defined as maternal fever and tachycardia in the absence of other localizing signs of infection occurring in labor or prior to labor in the presence of ruptured membranes.
The lowest recorded antenatal CD4 cell count (categorized as less than 200, 200-499, or 500 or more cells per cubic millimeter) was used for analysis. Maternal HIV RNA viral loads were measured prior to delivery usually at 35 weeks’ gestation to guide decision making regarding mode of delivery and were categorized as 4 variables: less than 1000, 1000-9999, 10,000 or more, and 100,000 or more copies per milliliter. Duration of antiretroviral therapy was categorized as less than or more than 10 weeks.
Duration of membrane rupture was defined as the interval from membrane rupture until delivery measured in hours. The outcome was confirmed transmission or nontransmission of HIV to the infant as evidenced by a minimum of 2 consecutive deoxyribonucleic acid polymerase chain reaction tests performed within 6 months of delivery.
A prenatal clinic dedicated to the care of HIV-infected women in pregnancy has been in operation at the UM/JMMC since 1988. In contrast to several sites in the United States at which prenatal care is provided by an obstetric team, whereas HIV care is provided by an infectious diseases team, prenatal care at the UM/JMMC is provided by 4 nurse practitioners under the direct supervision of 3 maternal-fetal medicine specialists according to strict protocols. These protocols include obstetric guidelines specific to the UM/JMMC as well as the latest Public Health Service recommendations issued by the Perinatal HIV Guidelines Working Group.
Patients attend for care at least every 2 weeks but often have even closer surveillance when antiretroviral therapy is initiated. Implementation of these standards ensures that all patients are managed in a standardized manner, a factor we believe to be important when interpreting pregnancy outcomes of a large cohort of women.
All HIV-infected women admitted to the labor and delivery unit at our institution were managed according to our hospital-specific guidelines as well as the guidelines of the US Public Health Service Task Force. Any woman who planned to have a vaginal delivery, if admitted with ruptured membranes in early labor, was augmented with oxytocin and if admitted with ruptured membranes in active labor, was allowed to progress. Neither fetal scalp electrodes nor intrauterine pressure catheters were used. Intravenous zidovudine was infused throughout labor. Amniotomy was performed only if indicated for obstetric reasons, namely to determine the presence of meconium or blood if the fetal heart tracing was nonreassuring or to accelerate inadequate progress in the presence of efficient uterine activity. Labor progress was monitored on a partogram. Cesarean delivery was reserved for the usual obstetric indications.
Amniotomy was avoided in women undergoing an induction of labor or who were admitted in active labor with membranes intact. Women who were scheduled for an elective cesarean section because of a high viral load but who were admitted in labor with membranes ruptured or intact were assessed individually and counseled that the benefit of proceeding with a cesarean section might now be lost; hence, those in active labor and progressing well were allowed to progress if they so chose, whereas those still in the latent phase underwent cesarean delivery.
Women admitted with preterm rupture of membranes at or after 34 weeks’ gestation underwent induction of labor, and if less than 34 weeks’ gestation, were admitted to the antepartum floor on which they received antibiotics and antenatal corticosteroids and were observed for the development of chorioamnionitis until they went into spontaneous preterm labor, were delivered preterm for obstetric indications, or reached 34 weeks and then underwent induction of labor.
Data analysis
Univariate analyses were performed using either χ 2 or Fisher exact test where appropriate. A logistic regression model, which included any factor significant in the univariate analysis, was created to adjust odds ratios and confidence intervals for potential confounding variables. All of these variables were included in the model at once.
Using the effect size estimates for power analysis from the 24% relative increase in perinatal transmission rates observed by the International Perinatal HIV Group, our study with its sample size had 90% power to detect a relative increase in perinatal transmission of 24% when membrane rupture exceeded 4 hours. This was based on a 2-sided log-rank test with alpha = 0.05. Statistical analyses were performed using SPSS for Windows version 11.5 (SPSS Inc, Chicago, IL). All reported P values were two sided. A P ≤ .05 was considered to indicate statistical significance.
Results
There were 1000 mother-infant pairs, of whom 283 were delivered by elective cesarean delivery. Of these, 99 were performed for the prevention of perinatal transmission, and there were 7 HIV-infected infants in this group.
There were 717 mother-infant pairs who fulfilled inclusion criteria, of whom 707 received some type of antiretroviral therapy during pregnancy. Characteristics of the study participants stratified by transmission or nontransmission can be seen in Table 1 . The overall perinatal transmission rate of HIV in this labored population was 1.2%. Duration of membrane rupture was not significantly associated with perinatal transmission; however, the majority of patients delivered with membranes ruptured for less than 4 hours.
| Variable | Nontransmitters, n (%) | Transmitters, n (%) | P value |
|---|---|---|---|
| Maternal age at delivery, y | |||
| 12-17 | 24 (3.4) | 0 (0) | .730 |
| 18-34 | 577 (81.6) | 7 (77.8) | |
| >34 | 106 (15.0) | 2 (22.2) | |
| Race | |||
| Black | 327 (46.2) | 8 (88.9) | .244 |
| White | 23 (3.2) | 0 (0) | |
| Hispanic | 115 (16.2) | 0 (0) | |
| Haitian | 202 (28.5) | 1 (11.1) | |
| Caribbean | 39 (5.5) | 0 (0) | |
| Cigarette smoking in pregnancy | 40 (5.6) | 0 (0) | 1.000 |
| Alcohol use in pregnancy | 12 (1.7) | 0 (0) | 1.000 |
| STI in pregnancy | 262 (37.0) | 4 (44.4) | .733 |
| Illicit substance abuse | 75 (10.6) | 1 (11.1) | 1.000 |
| CD4+ cell count | |||
| <200/mL | 94 (13.4) | 0 (0) | .396 |
| 200-499/mL | 336 (47.7) | 4 (44.4) | |
| ≥500/mL | 274 (38.9) | 5 (55.6) | |
| Disease stage | |||
| HIV | 535 (76.5) | 9 (100.0) | .127 |
| AIDS | 164 (23.5) | 0 (0) | |
| Initiation of prenatal care | |||
| First trimester | 211 (30.1) | 2 (22.2) | .046 |
| Second trimester | 340 (48.4) | 2 (22.2) | |
| Third trimester | 151 (21.5) | 5 (55.6) | |
| Duration of ART | |||
| ≤10 wks | 155 (22.1) | 3 (42.9) | .190 |
| >10 wks | 545 (77.9) | 4 (57.1) |
There were 123 women who underwent induction of labor, of whom 2 delivered an infected infant. The overall perinatal transmission rate of HIV when membranes were ruptured for less than 4 hours was 1% as compared with 1.9% for women with membranes ruptured for 4 or more hours.
In the univariate analysis, late prenatal care, initiated in the third trimester, was significantly associated with perinatal transmission ( P = .046) as was a lack of antiretroviral therapy use in pregnancy ( P < .0001). Factors considered to increase the risk of perinatal transmission can be seen in Table 2 . A high delivery viral load (defined as a viral load of 1000 copies/mL or greater measured at 35 weeks’ gestation or if delivery prior to 35 weeks, then the last available result prior to delivery) was significantly associated with perinatal transmission ( P < .0001). Mode of delivery was not significantly associated with perinatal transmission of HIV.
| Variable | Nontransmitters, n (%) | Transmitters, n (%) | P value |
|---|---|---|---|
| Duration of membrane rupture, h | |||
| <4.0 | 496 (70.1) | 5 (55.6) | .447 |
| 4.0-8.9 | 90 (12.7) | 2 (22.2) | |
| 9.0-12.9 | 42 (5.9) | 0 (0) | |
| 13.0-24.9 | 59 (8.3) | 2 (22.2) | |
| ≥25.0 | 21 (3.0) | 0 (0) | |
| ART | |||
| None | 8 (1.1) | 2 (22.2) | < .0001 |
| AZT only | 67 (9.5) | 1 (11.1) | |
| Combination with a PI | 189 | 3 (33.3) | |
| Combination without a PI | 444 | 3 (33.3) | |
| Delivery viral load, copies/mL | |||
| <1000 | 539 (76.1) | 1 (11.1) | < .0001 |
| 1000-9999 | 101 (14.3) | 3 (33.3) | |
| 10,000-99,999 | 51 (7.2) | 5 (55.6) | |
| ≥100,000 | 17 (2.4) | 0 (0) | |
| Mode of delivery | |||
| Vaginal | 446 (63.0) | 7 (77.8) | .640 |
| Instrumental | 12 (1.7) | 0 (0) | |
| CS in labor | 250 (35.3) | 2 (22.2) | |
| Preterm delivery (<37 wks) | 214 (30.2) | 4 (44.4) | .466 |
| AZT in labor | 643 (90.8) | 7 (77.8) | .202 |
| Chorioamnionitis | 17 (2.4) | 0 (0) | 1.000 |
| Low birthweight (<2500 g) | 113 (16.0) | 2 (22.2) | .642 |
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