In the developed world, highly active antiretroviral therapy (HAART) is now the standard of care for treatment of HIV infection in adults. In pregnancy this strategy is also employed to meet 2 goals: optimal treatment of the health of the woman and prevention of perinatal HIV transmission. Data demonstrate an association between lower perinatal transmission rates and lower maternal viral loads at the time of delivery.1,2 In the United States, most HAART regimens used during pregnancy include a protease inhibitor (PI) and this is the basis for investigating the effects of PIs specifically rather than all HAART regimens. Prospective trials employing PIs during pregnancy are ongoing. It has long been known that antiretroviral treatment with zidovudine significantly lowers HIV perinatal transmission.3 In PACTG 367, transmission rates were significantly lower with more intensive antiretroviral therapy and lower plasma HIV RNA level (<1000 copies/mL) but did not differ according to delivery mode.4 Recent data and meta-analyses have demonstrated further significant benefit in decreasing perinatal transmission with the use of highly active regimens.5,6 Conflicting data have been reported regarding a possible increase in premature births in women on HAART regimens containing PIs.5-7 Concern has also existed regarding adverse events in infants including low birth weight and stillbirth, and here again data have been conflicting.8,9 Because larger prospective trials using PIs in pregnancy are not yet available, data from retrospective and observational cohorts serve to inform the field and provide direction for clinicians treating HIV-infected pregnant women.
The medical records of all women treated with PIs during pregnancy at 5 sites in the United States and Puerto Rico between December 1997 and December 2001 were reviewed. Sites known to treat HIV-infected pregnant women were invited to participate in this ad hoc collaboration. Institutional review board waivers or reviews were obtained according to individual site requirements for retrospective chart reviews. Demographics, risk factors for prematurity and adverse pregnancy outcomes, maternal immunologic and virologic data, prematurity, infant infection status, infant weight and length, and maternal and infant adverse events were recorded. Factors in prematurity and low birth weight were tested using multiple logistic regression. A forward stepwise procedure was used. A maximum likelihood procedure was used to calculate the regression coefficients. The likelihood ratio criterion was used to determine the significance of individual factors in the regression model.
Case report forms were designed to elicit available information on demographics, maternal immunologic and virologic data, maternal and infant adverse events and concomitant diagnoses, birth weight, length, prematurity rates defined as infants born at less than 37 weeks' gestation, and infant HIV infection status. Data were not requested or collected on women not treated with PIs and participating sites were asked to provide all available data on all women treated with PIs. Not all information was available on each woman, which is reflected in the denominator of the tables.
Known risk factors for prematurity were tested using multiple logistic regression.10 A forward stepwise procedure was used with maximum likelihood estimation of the regression coefficients. The likelihood ratio criterion11 was used to determine significance of individual factors in the regression model.
The records of 233 pregnancies were reviewed (11-91 records per site). A total of 233 women delivered a total of 231 live infants including 4 sets of twins and 1 set of triplets. Other infant outcomes included 2 spontaneous abortions, 3 fetal demise, 1 stillbirth, and 3 unknown outcomes due to loss to follow-up.
The majority of women were Latina (47%) or African American (31%) with the remainder being white (15%) or other (7%). The median age was 27 years (16-43) and most (87%) acquired HIV through heterosexual contact, a rate that is higher than in many cohorts.
Most women (85%) had prior pregnancies. Most women (53%) were antiretroviral naive; the majority (70%) were PI naive. Women were classified as having asymptomatic HIV infection in 73%; symptomatic HIV, but not AIDS, in 7%; and AIDS based on CD4 cells lower than 200 cells/mm3 or AIDS based on the history of an AIDS indicator condition in 13%.
Antiretroviral Regimens and Other Medications Used During Pregnancy
Most women were treated with single PIs (96.5%). Ritonavir-boosted regimens were used in 8 women (3.4%). Nelfinavir was part of the regimen in 215 women (92%). A few received sequential or double PIs. PIs were already part of an antiretroviral regimen at the time of conception in 44 women (19%). PIs were started during the 1st trimester in 41 women, during the 2nd trimester in 97 women, and during the 3rd trimester in 51 women. The majority of women (93%) received the dual nucleoside combination of zidovudine and lamivudine as part of their antiretroviral regimen. The combination of stavudine and didanosine was used in 5 women. Two women were on efavirenz at the time of conception and were then changed to PI-containing regimens.
Overall, from the first available CD4 cell counts and viral load measurements in pregnancy to the last available results, women experienced an average increase in their CD4 cell counts of +41 cells/mm3 and a decline in viral load of 0.85 log10 (Table 1). Fifty-six percent (n = 221) had undetectable viral loads of less than 400 copies/mL at the time of delivery. Gestational diabetes was seen in 3 women (1.3%), a rate comparable to the rates in the general population (2.6%)12 and our earlier review of PIs in pregnancies (3.3%).6
Antiretroviral regimens were generally well tolerated with no significant adverse events reported. No discontinuations of HAART occurred; however, maternal toxicity remains a concern. A substudy analysis was performed on all 17 cases at 1 site where more extensive laboratory data were available All women were on nelfinavir and 12% were coinfected with hepatitis C. Twenty-four percent had at least 1 elevated transaminase level during pregnancy. None had sustained transaminitis. Four women had transiently elevated amylase without increases in lipase. None had clinical pancreatitis. No abnormalities in creatinine were observed.
The mean duration of pregnancy was 38.3 weeks. During pregnancy, 3 women developed gestational diabetes, 3 had cerclages placed (2 for incompetent cervixes and 1 for unknown reason), and 5 were treated for group B Streptococcus infection. Twelve women (5.2%) had premature rupture of membranes and 10 (4.3%) had preterm labor. Other obstetric adverse events included 8 (3.4%) with preeclampsia, 5 (2.1%) with chorioamnionitis, 4 (1.7%) with oligohydramnios, 2 (0.9%) with abruption, and 2 (1.9%) with placenta previa. These rates are comparable to rates in the general population and our previous review.6,12,13 After delivery 9 women had vaginal bleeding (amount not quantified), 2 had a wound infection, and 2 had endometritis. Cesarean section was common, with 56% having elective procedures and 10% having unscheduled cesareans. Seventy-six (34%) delivered vaginally.
Infant and Fetal Outcomes
The average birth weight was 2828 g. Fifty-three infants, including 4 sets of twins and 1 set of triplets, weighed less than 2500 g, for a rate for low birth weight of 22.8% (95% CI, 17.6-28.8). Excluding multiples, the mean birth weight for viable infants was 2884 g, with a low birth rate of 20.0%. The mean length was 48.1 cm. Very low birth weight (<1500 g) was seen in 5 infants. Multiple logistic regression analysis was performed to identify risks for low birth weight. Low birth weight less than 2500 g was associated with increasing maternal age, multiple gestation, and mother's mode of HIV acquisition. For each year of increased age, there was a 1.11 times risk of low birth weight. For women whose mode of HIV acquisition was intravenous drug use, there was a 9.39 times increased risk. Women with multiple gestation had a 29.1 times increased risk (Table 2).
Infant and fetal adverse events included 41 with anemia, 10 with cardiac abnormalities, 7 with pulmonary problems, and 5 with hyperbilirubinemia. Isolated cases of other adverse events or complications were reported and may be underreported; however, there did not seem to be a pattern to these.
Of the 6 pregnancies ending in fetal death, spontaneous abortion, or stillbirth, 2 women were living with symptomatic AIDS. Three other women were actively using cocaine, heroin, or alcohol. Three of 6 (50%) women receiving the combination of didanosine and stavudine during their pregnancies had fetal demise or stillbirth. None of these women had active substance use. Two were on didanosine and stavudine at the time of conception and 1 had these started at week 12 of gestation. The losses occurred at 23.86, 27.86, and 38.14 weeks' gestation.
The gestational age was <37 weeks' gestation in 50 of 233 pregnancies, giving an overall prematurity rate of 22.0% (95% CI, 17-28.2), including 3 sets of twins and 1 set of triplets. Extreme prematurity (<32 weeks' gestation) was seen in 6 of these.
Multiple logistic regression was performed to identify risk factors for prematurity. The following factors were examined: age, race, mode of maternal HIV acquisition, HIV class of mother, baseline and delivery viral loads, baseline and delivery CD4 counts, gestational age at the start of antiretroviral therapy and PIs, individual PIs, tobacco, alcohol and drug use during pregnancy, sexually transmitted diseases or bacterial vaginosis during pregnancy, hepatitis, history of preterm deliveries, prior multiple gestation pregnancies, and current multiple gestation.
The risk of prematurity was 9.2 times greater with multiple gestation than single gestation, after controlling for other significant factors. The risk was increased 3.9 times with intravenous drug use as the mode of HIV acquisition. Other factors were not associated. No association was noted for individual PIs or the week of gestation that PIs were initiated in this series.
Infant HIV Infection Status
In this series in which mothers received PI-based HAART regimens, perinatal transmission occurred in 0.9% of infants (95% CI, 0.1-3.1). The HIV status of 3 infants is not known due to loss to follow-up. Spontaneous abortion, fetal demise, or stillbirth occurred in 6 pregnancies. Of the 76 women delivering vaginally, none transmitted.
The following are descriptions of the 2 cases in which perinatal HIV transmission occurred. Transmission case 1 occurred in an 18-year-old African American woman with asymptomatic HIV infection. Baseline CD4 count was 307 cells/mm3; HIV RNA was 6339 copies/mL. Antiretroviral therapy included a PI initiated at gestational week 24. The patient was treated for gonorrhea, Chlamydia infection, and herpes simplex. Anemia was present. At delivery, CD4 count was 274 cells/mm3 and HIV RNA was 43 copies/mL. Complications included premature rupture of membranes, chorioamnionitis, and endometritis. Delivery was at week 32.86 by unscheduled cesarean delivery. The HIV-infected infant weighed 1900 g; cardiac abnormalities and hyperbilirubinemia were present. Timing of transmission was not known.
Transmission case 2 occurred in a 20-year-old asymptomatic Latina woman coinfected with hepatitis C virus. Baseline CD4 count was 420 cell/mm3; HIV RNA was 33,516 copies/mL. Antiretroviral therapy included a PI initiated at week 32 of gestation. CD4 count at delivery was 420 cells/mm3; HIV RNA was 5403 copies/mL. Delivery was at 37.14 weeks' gestation by elective cesarean section. The HIV-infected infant weighed 3182 g. Timing of transmission was thought to be intrapartum based on initial negative polymerase chain reaction and positive polymerase chain reaction at 1 month of age.
HAART is now the standard of care and in the guidelines of the United States Public Health Service14 for treating HIV-infected women in the United States during pregnancy to effectively treat the woman, maintain maximal future treatment options, and decrease perinatal transmission. Though there is no lower limit of viral load below which perinatal transmission does not occur, maternal HIV-1 RNA level is the best predictor of perinatal HIV transmission.1,2 In this series, with treatment with PI-based regimens, 56% of women had undetectable viral loads at the time of delivery with a mean decline in viral load of 0.85 log during the course of pregnancy. At delivery 66% of all women had viral loads <1000 copies/mL. This generally represents a nonclinical trial cohort in which adherence was not monitored.
Although an early small series7 suggested a possible link between PIs and prematurity, a larger series demonstrated no increase over HIV-infected women not on PIs in a previous series of 89 pregnancies6 in which the prematurity rate was 19.1%. In this current report of 233 pregnancies, the prematurity rate is 22.0%, with the only significant factors being known causes for prematurity. Causes of preterm birth are multifactorial, are not fully understood, and require more investigation in HIV-infected women.
The rates of adverse obstetric outcomes in mothers in the current series compare favorably to what was seen in our earlier report and to what has been reported in the general population.
Anemia, likely related to the zidovudine component of the maternal regimens, was reported in 17.5% of infants in this series. This falls within the range (13%-24%) for hemoglobin concentration <9.0 g/dL at birth seen in the infants born to women treated with placebo or zidovudine alone in the original AIDS Clinical Trial Group 076 protocol.3
The prematurity rate (22.0%) and the low birth weight rate (22.8%) are both somewhat higher than what was seen in our earlier series, in which the rates were 19.1% and 20.6%, respectively. In the Women and Infants Transmission Study of 525 pregnancies, the gestational age was <37 weeks in 18.7% and the rate of low birth weight (<2500 g) was 18.7%.15
There are several study limitations. The limited number of participating sites may allow bias and lessen the generalizability of these findings, though our demographics suggest that the population represented is typical of the overall population of HIV-infected pregnant women. Bias as the result of regional practice patterns cannot be excluded. Data obtained from retrospective chart reviews are likely not to be complete, especially in the area of adverse events. Data were not collected on women who were treated with non-PI-based regimens and therefore are not applicable to all women. Short-term infant data may also be incomplete due to inaccessibility to some study investigators of all infant data outside of the immediate peripartum period. This may have resulted in the underreporting of certain adverse events or concomitant diagnoses. No long-term data are available on maternal outcomes or infants' clinical outcomes following in utero exposure to PIs. CD4 cell and viral load data were not obtained in a systematic or standardized manner and therefore cannot be used to assess the impact of these variables on maternal or infant outcomes.
In this series of 233 HIV-infected women treated with PIs during pregnancy, the efficacy in preventing perinatal transmission of HIV with HAART was again seen. Prematurity and low birth weights were not significantly increased when compared with other studies involving HIV-infected women not treated with PIs. PIs also appeared generally safe in mothers and infants. The Antiretroviral Pregnancy Registry will be an important ongoing source of data regarding treatment of pregnant women until larger prospective trials are available.16
The authors thank Michelle Watson for her support and input to the project.
1. Mofenson LM, Lambert JS, Steihm ER, et al. Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. N Engl J Med
2. Garcia PM, Kalish LA, Pitt J, et al. Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission. Women and Infants Transmission Study Group. N Engl J Med
3. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med
4. Shapiro D, Tuomala R, Samelson R, et al. Mother to child HIV transmission rates according to antiretroviral therapy, mode of delivery and viral load (PACTG 367). Paper presented at: 9th Conference on Retroviruses and Opportunistic Infections; February 24-28, 2002. Seattle, WA. Abstract 114.
5. Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1 infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr
6. Morris AB, Cu-Uvin S, Harwell JI, et al. Multicenter review of protease inhibitors in 89 pregnancies. J Acquir Immune Defic Syndr
7. Lorenzi P, Spicher VM, Laubereau B, et al. Antiretroviral in pregnancy: maternal, fetal, and neonatal effects: Swiss HIV Cohort Study, the Swiss Collaborative HIV and Pregnancy and the Swiss Neonatal HIV Study. AIDS
8. Scott G, Shapiro D, Scott W, et al. Safety and tolerance of ritonavir in combination with lamivudine and zidovudine in HIV-1 infected pregnant women and their infants. Paper presented at: 6th Conference on Retroviruses and Opportunistic Infections; January 31-February 4, 1999; Chicago, IL. Abstract #688.
9. Tuomala RE, Shapiro DE, Mofensen LM, et al. Antiretroviral therapy during pregnancy and the risk of an adverse outcome. N Engl J Med
10. Cox DR. Analysis of Binary Data
. London: Methuen; 1970:76-99.
11. Lee ET. Statistical Methods for Survival Data Analysis
, 2nd ed. New York: John Wiley & Sons; 1992:72-73.
12. Ventura SJ, Martin JA, Taffel SM, et al. Advance report of final natality statistics, 1993. Mon Vital Stat Rep
13. Cunningham FG, MacDonald PC, Grant NF, et al, eds. Williams Obstetrics,
20th ed. Stamford, CT: Appleton and Lange; 1997.
14. Department of Health and Human Services. Public Health Service Task Force recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States. Rockville, MD: HIV/AIDS Treatment Information Service. Available at: http://AIDSinfo.nih.gov
. Accessed July 8, 2005.
15. Landesman SH, Kalaish LA, Burns DN, et al. Obstetrical factors and the transmission of human immunodeficiency virus type 1 from mother to child. The Women and Infants Transmission Study. N Engl J Med
16. Antiretroviral Pregnancy Registry. Wilmington, NC: Pharmaresearch Corp.; 2004. Available at: http://apregistry.com
. Accessed July 8, 2005.