Abstract

BackgroundData on complications of pregnancy associated with antiretroviral therapy are limited. Some small studies have demonstrated an increased preterm delivery rate, but a recent retrospective United States multisite study did not concur with these findings. Our objective was to investigate whether antiretroviral therapy was associated with adverse pregnancy outcome at a single site

MethodsUsing prospectively gathered data, women were identified who were determined to be human immunodeficiency virus positive before or during pregnancy who sought care at our prenatal clinic and who gave birth at the University of Miami/Jackson Memorial Medical Center from 1990 through 2002. The outcome measures were preterm delivery, low birth weight, and stillbirth

ResultsThe cohort included 999 women who received antiretroviral therapy during pregnancy (monotherapy in 492, combination therapy without a protease inhibitor [PI] in 373, and combination therapy with a PI in 134) and 338 women who did not receive therapy. After adjustment for possible confounders, only combination therapy with a PI was associated with an increased risk of preterm delivery, compared with any other combination (odds ratio, 1.8 [95% confidence interval, 1.1–3.0]). There were no differences in rates of low birth weight and stillbirth, regardless of therapy

ConclusionCompared with monotherapy and combination therapy without a PI, only combination therapy with a PI was associated with an increased risk of preterm delivery

Antiretroviral therapy (ART) is recommended during pregnancy to decrease the risk of perinatal transmission of HIV-1 infection [1] and to improve maternal health [2]. The optimal antiretroviral regimen that provides the most protection with the least toxicity to mother and child has yet to be determined. Data about complications of pregnancy that are associated with ART are limited. A putative association with preterm birth was raised by a small retrospective Swiss study of 30 women who received combination therapy during pregnancy—with protease inhibitors (PIs) in 13 women and without PIs in 17—that demonstrated that this treatment was associated with a 33% risk of preterm delivery [3]. In the European Collaborative Study, prophylactic zidovudine monotherapy was associated with a decreased risk of low birth weight and prematurity in a cohort of 2300 HIV-infected women [4]. When the European and Swiss cohorts were combined, exposure to combination ART increased the risk of preterm delivery, independent of maternal CD4+ cell count and illicit drug use: infants exposed to a regimen containing a PI were 2.6 times more likely to be born prematurely [5]. However, in the largest assessment to date of the risks of adverse pregnancy outcomes associated with ART in the United States, Tuomala et al. [6] reported on 2123 HIV-infected women enrolled in 7 clinical studies who received some form of ART and 1143 women who did not receive any. Both groups had similar rates of low Apgar scores, preterm birth, and low-birth-weight infants. After adjustment for multiple risk factors, combination ART was not associated with an increased risk of preterm delivery or low birth weight, compared with monotherapy

The University of Miami was one of the collaborating sites for that study and provided data on pregnancies in HIV-infected women for 1 March 1994 through 31 July 1998. Data were provided for a total of 369 women. These were nonconsecutive patients and, for the purposes of that study, they were required to receive ART. However, women enrolled in the Pediatric AIDS Clinical Trial Group (PACTG) studies were excluded. Of the women included from the University of Miami, 244 received monotherapy, 106 received combination therapy without a PI, and 19 received combination therapy with a PI. Women not receiving therapy were excluded

Although data from such a multisite collaboration has the strength of a large sample size, a possible limitation is management by different physicians at different sites, especially given that these were retrospectively gathered data. The objective of the present study was to investigate whether ART was associated with adverse pregnancy outcome at a single site managed by maternal-fetal medicine subspecialists adhering to strict protocols and unified standards of care

Patients 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 using the outcome measures preterm delivery, low birth weight, and stillbirth. Women were identified who were determined to be HIV positive before or during pregnancy and received prenatal care and gave birth at the University of Miami/Jackson Memorial Medical Center (UM/JMMC) from January 1990 until December 2002. Inclusion criteria were a singleton pregnancy and attendance for at least 1 prenatal visit at our obstetric clinic dedicated to the care of HIV-positive patients

ART was classified as monotherapy, combination therapy with PIs, or combination therapy without PIs. If >1 regimen was used before delivery, ART was categorized hierarchically: combination therapy with PIs took precedence over combination therapy without PIs, which took precedence over monotherapy. The 12 years under study were divided into subcategories: 1990–1994, representing the era of zidovudine monotherapy; 1995–1997, representing the replacement of monotherapy with combination therapy; and 1998–2002, representing the current standard of care of combination therapy with or without a PI. Gestational age at birth was determined on the basis of the last menstrual period, ultrasound biometry, or both. Length of gestation was based on the last menstrual period—whether it was within 7 days of the ultrasonographic estimate during the first trimester, within 14 days of the ultrasonographic estimate during the second trimester, or within 21 days of the ultrasonographic estimate during the third trimester. Preterm delivery was defined as delivery at <37 completed weeks of gestation, and very preterm delivery was defined as delivery at <32 completed weeks of gestation. The denominator used for the analysis of risk of preterm delivery included all women, regardless of gestational age at entry into prenatal care. Low birth weight was defined as <2500 g, and very low birth weight was defined as <1500 g. Stillbirth was defined as a fetal death after 20 weeks of gestation. The lowest recorded antenatal CD4+ cell count (categorized as <200, 200–499, or ⩾500 cells/mm3) was used for analysis. The Centers for Disease Control and Prevention (CDC) stage of disease was recorded for each woman according to the 1993 classification (combining the 3 categories of CD4+ cell count with 3 symptom categories abstracted from patient’s histories) [7]. Maternal HIV RNA loads were measured from 1998 onward and were categorized as 4 variables: <1000, 1000–50,000, 50,000–100,000, and ⩾100,000 copies/mL. Duration of ART was categorized as ⩽10 or >10 weeks

To compare pregnancy outcomes of the study population with those reported in the multisite study [6], similar pairwise comparisons were performed to assess pregnancy outcome according to the type of ART: any antiretroviral agent versus none, monotherapy versus any combination therapy, and combination therapy with a PI versus combination therapy without a PI. The unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for preterm delivery and low birth weight were calculated according to the use or nonuse of ART. To ensure that the model for low birth weight reflected weight for age more accurately, gestational age was included in an additional unadjusted model for each outcome, as well as for the full models. A logistic-regression model was created to adjust ORs and CIs for potential confounding variables, which included any factor that was significant in the univariate analysis, in addition to a history of prior preterm delivery (although this is not significant, it is known to be the most powerful predictor of a future preterm delivery). The potential confounding variables were category of ART, race/ethnicity, lowest CD4+ cell count during pregnancy, CDC disease stage, use of illicit substances, cigarette smoking, the presence of a sexually transmitted disease (STD), history of a prior preterm delivery, time of initiation of prenatal care, duration of ART, ART use before pregnancy, and year of delivery. All of these variables were included in the model at once. To further isolate the effects of individual therapies, the model was repeated for each of the pairwise comparisons. Because the number of events was too small to repeat the multivariate analysis for very preterm delivery, Fisher’s exact test was used in the analysis, using the same set of variables. Statistical analyses were performed using SPSS for Windows (version 11.5; SPSS). All reported P values were 2-sided. P<.05 was considered to indicate statistical significance

Results

There were 1337 HIV-infected women who attended at least 1 prenatal visit, of whom 338 received no therapy. Of the 999 women who received ART, 492 received monotherapy, 373 received combination therapy without a PI, and 134 received combination therapy with a PI. Although therapy was categorized hierarchically, the median duration (±SD) of therapy was 13.3 (±9.6) weeks for zidovudine monotherapy, 18.3 (±12.7) weeks for combination therapy without a PI, and 24.3 (±16.4) weeks for combination therapy with a PI

Ninety-five percent of the women were of a minority race or ethnicity. Cigarette smoking during pregnancy was reported by 11.2% of women, alcohol use by 5.4%, and the use of illicit substances by 17.8%. Thirty-nine percent of women were diagnosed as having an STD during the pregnancy. Women who received combination therapy with PIs had given birth more recently, had lower CD4+ cell counts, and had a more advanced stage of disease (table 1). The rate of use of illicit substances, alcohol consumption, and cigarette smoking was higher in women who did not receive ART, compared with those who did. Women receiving combination therapy had a higher rate of STDs (which included gonorrhea, chlamydia, trichomonas, syphilis, herpes, and hepatitis B infections) during pregnancy, compared with those receiving monotherapy

Table 1

Characteristics of the 1337 study participants according to the use and nonuse of antiretroviral therapy (ART) during pregnancy

Table 1

Characteristics of the 1337 study participants according to the use and nonuse of antiretroviral therapy (ART) during pregnancy

The median gestational ages (interquartile ranges) at delivery of infants born to women receiving monotherapy, combination therapy without a PI, and combination therapy with a PI were 39 (2.0), 39 (3.0), and 38 (2.0) weeks, respectively. Women who received any combination therapy had a higher rate of preterm delivery than did women who received monotherapy. This increased rate of preterm delivery (at ⩽37 weeks) was most significant in the group who had a PI as part of their combination regimen (table 2). There was no increased risk of very preterm delivery (at ⩽32 weeks) in women who received any ART during pregnancy, but women who received no therapy had a higher rate of very preterm delivery. There was no significant difference in numbers of low-birth-weight infants across the categories of therapy. Numbers of very–low-birth-weight infants did not differ significantly according to whether or not combination therapy included a PI. The number of stillbirths was very small, and there was no significant difference. The preterm delivery rate for women receiving a PI, stratified by duration of therapy, demonstrated that women who received a PI for >10 weeks had a significantly higher preterm delivery rate of 33.6%, compared with 21.2% for those who received a regimen without a PI (P=.008)

Table 2

Outcomes of pregnancy according to the use or nonuse of antiretroviral therapy (ART), stratified by era

Table 2

Outcomes of pregnancy according to the use or nonuse of antiretroviral therapy (ART), stratified by era

Neither the unadjusted ORs for very preterm delivery, low birth weight, and very low birth weight nor the adjusted OR (AOR) for low birth weight varied significantly among the categories of antiretroviral regimens (table 3). However, when we adjusted for year of delivery, race, prior preterm delivery, lowest CD4+ cell count during pregnancy, CDC disease stage, number of weeks receiving therapy, treatment before pregnancy, use of illicit substances, cigarette smoking, alcohol consumption, and the presence of an STD during pregnancy, only combination therapy with a PI was associated with an increased risk of preterm delivery (AOR, 1.8 [95% CI, 1.1–3.0]), compared with any other combination (P=.03). Similarly, compared with no ART, monotherapy, or combination therapy without a PI, only combination therapy with a PI was associated with an increased risk of preterm delivery (P=.01; AOR, 2.3 [95% CI, 1.2–4.3]). The only other predictors of preterm delivery were a history of a prior preterm delivery (P=.0001; AOR, 3.4 [95% CI, 2.3–5.0]) and duration of ART for <10 weeks (P=.0001; AOR, 2.2 [95% CI, 1.6–3.0]). Because the cohort included women who initiated prenatal care during the third trimester, women who initiated care after 32 and after 37 weeks of gestation, respectively, were removed from the denominators used for the analysis of very preterm and preterm delivery. Again, combination therapy with a PI remained an independent risk factor for preterm delivery (P=.04; AOR, 1.6 [95% CI, 1.0–2.4]). All models were checked for collinearity, and there was none

Table 3

Risks of adverse pregnancy outcomes according to the antiretroviral (ART) regimen

Table 3

Risks of adverse pregnancy outcomes according to the antiretroviral (ART) regimen

Maternal HIV RNA load results were available for 582 women. Of these, 170 (29.2%) delivered preterm; however, the maternal HIV RNA load was not associated preterm delivery. The prematurity rate for each treatment group was further stratified by HIV RNA load; again, this was not statistically significant

Discussion

In a large cohort of HIV-infected women who received ART during pregnancy, only combination therapy with a PI was associated with an increased risk of preterm delivery. This is in contrast to the findings of Tuomala et al. [6], who did not demonstrate an increased risk of adverse pregnancy outcome associated with ART. Our findings that PIs may play a role in preterm delivery support the combined results of the European Collaborative Study and the Swiss Cohort Study in that infants exposed to ART with a PI were 2.6 times more likely to be born prematurely [5]. However, significant associations with the use of illicit substances, severe immunocompromise, and a lengthy duration of therapy in the European cohort were not significant in the present study. Even when we removed the duration of the use of ART and severity of illness from the logistic-regression model, to determine the confounding effect of these factors, combination therapy with a PI remained an independent predictor of preterm delivery. A history of prior preterm delivery was also a significant predictor, and this is consistent with the literature. A shorter duration of therapy most likely indicates women who entered prenatal care late during gestation

A prenatal clinic dedicated to the care of pregnant HIV-infected women has been in operation at the UM/JMMC since 1988. In contrast to several sites in the United States, where prenatal care is provided by an obstetric team and 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 in accordance with 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. Comprehensive obstetric care includes social services, mental health, and nutritional consultations. Patients report for care at least every 2 weeks but often have even closer surveillance when ART is initiated. The implementation of these standards ensures that all patients are managed in a standardized manner—a factor that we believe to be important when interpreting pregnancy outcomes of a large cohort of women

Although the multisite study of Tuomala et al. [6], which included the UM/JMMC as 1 of its 7 centers, had a larger cohort, in contrast to this single-site cohort of 1337 women, the numbers with respect to combination therapy are very similar (combination therapy without PIs in 396 vs. 373 women and combination therapy with PIs in 137 vs. 134 women). The larger sample size in the multisite study is driven by the fact that 75% of the 2123 women receiving therapy had a monotherapy regimen. In our study, there were no missing data on any of the variables of interest, especially a history of prior preterm delivery—the strongest predictor of a future preterm delivery—which was unavailable for 30% of subjects in the multisite study

A limitation of the present study was the inability to control for HIV RNA load, because these data were available only for the last 5 years of the study. A subanalysis demonstrated no significant association between HIV RNA load and prematurity, even when stratified for therapy. Indeed, maternal CD4+ cell count was a better predictor of prematurity than HIV RNA load in the European/Swiss cohort. It is essential to control for severity of immunocompromise, which, in some studies, has been associated with adverse pregnancy outcome [5]. This has been achieved in the present study with both CD4+ cell count and CDC disease stage, which suggests that the severity of immunocompromise does not influence pregnancy outcome

Associations between maternal use of illicit substances, cigarettes, and alcohol; poor fetal growth; and preterm birth have been well established in studies of women who are not HIV infected [8, 9]. These behavioral risk factors may be more prevalent in HIV-infected women than in the general population and may therefore spuriously increase the risk for adverse pregnancy outcome in HIV-infected women. The preterm delivery rate at the UM/JMMC is higher than that at other centers; however, after having considered all possible confounders, the present results appear to be real and to confirm reports from the European/Swiss cohort that ART during pregnancy, especially when it includes PIs, may increase the risk of preterm delivery [5]. The preterm delivery rate from that study of 29% in women receiving combination therapy with PIs was higher than the 19% rate reported in a review of 89 PI-exposed pregnancies in the United States [10], but it is closer to the rates in the present study. There was no significant increase in a rate of preterm delivery at ⩽32 weeks in women receiving combination therapy with a PI, possibly because of a decreased exposure time to the PI. The overall preterm delivery rate in our cohort was 29.9%. Of all preterm deliveries at ⩽37 weeks, spontaneous preterm labor occurred in 21.7% of women receiving no therapy, in 19.4% of women receiving monotherapy, and 19.3% of women receiving combination therapy without a PI. Of the women receiving combination therapy with a PI who gave birth at ⩽37 weeks, 78% had spontaneous preterm labor. Although the numbers were small (only 10 women), there was a high rate of preterm delivery during the period 1995–1997 among women receiving a PI, which could be attributable to the introduction of PI therapy during pregnancy for the most immunocompromised women. Tuomala et al. chose 27 weeks of gestation as the cutoff for the initiation of therapy; however, in the present study, there was no statistically significant difference. Of women receiving ART before 27 weeks of gestation, the preterm delivery rate was 27.3% in those receiving combination therapy without a PI and 36.1% in those receiving combination therapy with a PI; ART initiated after 27 weeks of gestation was associated with a preterm delivery rate of 26.2% in women receiving combination therapy without a PI and 41% in those receiving a PI

In a large cohort of mothers and infants who received zidovudine and enrolled in PACTG 185, rates of preterm delivery and low birth weight were comparable to those of uninfected women [11]. Although it is reassuring that there does not appear to be an increased risk of adverse pregnancy outcome associated with monotherapy or combination therapy without a PI, we believe that PIs should be used with caution. At our site, there are 3 categories of patients who receive PIs during pregnancy: those who become pregnant while already receiving a regimen that contains a PI, those with a low CD4+ cell count and/or a high HIV RNA load, and those who do not exhibit an appropriate decrease in HIV RNA load while receiving combination therapy without a PI. In the present study, nelfinavir was the most frequently used PI in combination regimens (n=86), followed by indinavir (n=37), saquinavir (n=27), ritonavir (n=16), and the combination of lopinavir with ritonavir (n=9)

Since 1994, the majority of pregnant women have received ART. Because the treated and untreated women delivered in different years, it is difficult to make a direct comparison, but we have adjusted for year of delivery. The increased experience gained during the past 12 years should result in near-optimal prenatal care for those women known to be HIV infected. In the presence of highly active ART aimed to improve maternal health, pregnancy outcomes should improve, and adverse outcomes, such as preterm delivery, should have been more likely during earlier years of the epidemic. Hence, the risk of preterm delivery posed by PIs since their introduction is significant

Despite adjustment for possible confounders, such as the severity of immunocompromise, there exists a possibility that women who receive a PI-based regimen during pregnancy are different. Nonetheless, our findings concur with those of the European study. Pathological examination of the placentas of these women appears to be promising for the determination of a possible mechanism of action [12]. Access to neonatal intensive care units in the United States ensures that perinatal morbidity is not significant for an infant born at ⩾32 weeks of gestation to an HIV-negative woman. This is also valid for an infant delivered at the same gestational age to an HIV-infected woman; however, despite the lack of morbidity secondary to prematurity, preterm delivery itself may increase the risk of perinatal transmission 2–3-fold [13–15]. To our knowledge, this is the largest single-site study and the only large study reported to date that can account for both the completeness of its data and its management protocols and is representative of HIV-infected pregnant women in the United States; the study is relatively unique because of the autonomous management by a maternal-fetal medicine team. It is reassuring to find that the risks of adverse pregnancy outcomes attributable to ART are small and likely to be outweighed by the known benefits of such therapy in pregnancy. However, the results of the present study suggest that a decision to initiate combination therapy with a PI during pregnancy should be made with caution and emphasize the importance of counseling patients about the risks of prematurity before the initiation of therapy

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Potential conflicts of interest: none reported
Presented in part: 24th Annual Meeting of the Society for Maternal Fetal Medicine, New Orleans, 7 February 2004. Am J Obstet Gynecol 2003; 189:S83