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Protease Inhibitor Use in 233 Pregnancies
JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 40(1) 1
September 2005 pp 30-33
Morris, Anne B MD*; Dobles, Ana Rua RN, ACRN†; Cu-Uvin, Susan MD‡; Zorrilla,
Carmen MD§; Anderson, Jean MD‖; Harwell, Joseph I MD‡; Keller, Jean
PA-C‖; Garb, Jane MS#
>From the *Community Research Initiative of New England, Springfield, MA;
†Arnold Palmer Hospital for Children and Women Hug Me Program, Orlando, FL;
‡The Miriam Hospital, Brown University, Providence, RI; §University of Puerto
Rico, San Juan, Puerto Rico; ‖Johns Hopkins University, Baltimore, MD; and
#Baystate Medical Center, Springfield, MA.
Abstract
Background: In the United States, as most highly active antiretroviral therapy
(HAART) regimens used during pregnancy in HIV-infected women include a protease
inhibitor (PI), it is important to determine the effects of PIs specifically
rather than all HAART regimens. Prospective trials employing HAART during
pregnancy are ongoing.
Objective: To better understand the effects of PI use during pregnancy on
prematurity, maternal and infant adverse events, and infant outcomes.
Results: A total of 233 pregnancies in which PIs were used were reported,
including 5 sets of twins and 1 set of triplets. Perinatal transmission is
documented in 2 of 221 infants for a rate of 0.9% (95% CI, 0%-2.2%). Both
HIV-positive infants were delivered by cesarean section (one elective at 37 1/7
weeks and one unscheduled at 32 6/7 weeks). The prematurity rate (<37 weeks'
gestation) was 22.0% (95% CI, 16.9%-28.0%) including 3 twin and 1 triplet
pregnancies. In multiple regression analysis no association was noted for
individual PIs or the week of gestation that PIs were initiated. Adverse
maternal, obstetric, and infant events possibly related to PIs were uncommon.
Conclusions: In this series, PIs during pregnancy appeared generally safe for
mothers and infants. Perinatal transmission was low and the prematurity rate is
similar to prior data in HIV-positive women not on PIs.
INTRODUCTION
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.
METHODS
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.
RESULTS
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.
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.
Patient Characteristics
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.
Maternal Outcomes
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.
Obstetric Outcomes
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.
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.
Prematurity
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.
DISCUSSION
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.
CONCLUSIONS
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
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