ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Nov. 2004, p. 4332–4336
0066-4804/04/$08.00?0 DOI: 10.1128/AAC.48.11.4332–4336.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.
Vol. 48, No. 11
Maternal-Fetal Transfer and Amniotic Fluid Accumulation of
Nucleoside Analogue Reverse Transcriptase Inhibitors in
Human Immunodeficiency Virus-Infected
He ´le `ne Chappuy,1,2Jean-Marc Tre ´luyer,1* Vincent Jullien,1Je ´ro ˆme Dimet,1
Elisabeth Rey,1Maria Fouche ´,3Ghislaine Firtion,3Ge ´rard Pons,1
and Laurent Mandelbrot4
Pharmacologie Clinique, Universite ´ Rene ´-Descartes, Ho ˆpital Cochin Saint-Vincent-de-Paul,1
De ´partement d’Urgences Pe ´diatriques, Universite ´ Rene ´ Descartes, Ho ˆpital Necker
Enfants Malades,2and Gyne ´cologie-Obste ´trique Ho ˆpital Cochin,3Paris, and
Gyne ´cologie-Obste ´trique Ho ˆpital Louis Mourier, Colombes,4France
Received 13 February 2004/Returned for modification 22 April 2004/Accepted 8 July 2004
This study was performed to investigate placental transfer of nucleoside analogue reverse transcriptase
inhibitors (NRTIs) and their concentrations in amniotic fluid when given to human immunodeficiency virus
(HIV)-infected pregnant women. A total of 100 HIV type 1-infected mothers receiving antiretroviral therapy,
including one or more NRTIs, for clinical indications at the time of delivery were enrolled. Maternal blood
samples and amniotic fluid were obtained during delivery or cesarean section, and paired cord blood samples
were obtained by venipuncture immediately after delivery. Drug concentrations were measured by using
high-performance liquid chromatography. A significant relationship between concentrations in maternal and
cord plasma samples was found for zidovudine, lamivudine, stavudine, and didanosine. The ratio between the
concentrations in cord and maternal plasma samples (R) was high for zidovudine (R ? 1.22), its glucuronide
metabolite (3?-azido-3?-deoxythymidine-?-D-glucuronide) (R ? 1.01), stavudine (R ? 1.32), lamivudine (R ?
0.93), and abacavir (R ? 1.03) and was low for didanosine (R ? 0.38). The ratio between the concentrations
in amniotic fluid and cord plasma samples was high for zidovudine (R ? 2.24), its glucuronide metabolite (R
? 2.83), stavudine (R ? 4.87), and lamivudine (R ? 3.99) and was lower for didanosine (R ? 1.14). These
findings indicate that most NRTIs cross the placenta by simple diffusion and are concentrated in the amniotic
fluid, probably through fetal urinary excretion. The efficacy or toxicity of NRTIs may vary according to
Treatment recommendations for pregnant women infected
with human immunodeficiency virus (HIV) type 1 have been
based on the belief that therapies of known benefit to women
should not be withheld during pregnancy unless they have
known adverse effects on the mother, fetus, or infant and
unless these adverse effects outweigh the benefit to the woman
(13). There is also evidence from observational studies that
combination antiretroviral therapies are more effective than
zidovudine monotherapy in reducing the risk of mother-to-
child HIV transmission (4, 24). For these reasons, the majority
of HIV-infected women in the industrialized countries are
treated during pregnancy with a combination of antiretroviral
regimens, usually consisting of two nucleoside analog reverse
transcriptase inhibitors (NRTIs) and a protease inhibitor (20).
However, the data about the safety of antiretroviral drugs
are limited, with the exceptions of zidovudine and, to a lesser
extent, lamivudine. A study conducted in France reported that
several infants with perinatal exposure to either zidovudine-
lamivudine or zidovudine alone developed persistent mito-
chondrial dysfunction (2). The causal relation between NRTI
exposure and mitochondrial disease remains controversial
(14). Follow-up is still insufficient to address the effect that
exposure to zidovudine or other antiretroviral agents in utero
might have on long-term risk for neoplasia or organ system
toxicities in children (5, 8).
The placental transfer and pharmacodynamics in the fetal
compartment are important to consider when prescribing
drugs during pregnancy. Zidovudine has been widely used and
studied in pregnancy, and high cord-to-maternal plasma drug
concentration ratios have been consistently reported (15, 26).
Similar results have been reported with lamivudine (12, 14).
There have been few clinical studies concerning didanosine or
stavudine (25) and no report concerning abacavir.
The present study was performed to compare the placental
transfers and amniotic fluid concentrations of the commer-
cially available nucleoside analogue reverse transcriptase in-
hibitors used in a clinical setting.
MATERIALS AND METHODS
The study enrolled 100 HIV-infected pregnant women who were receiving
NRTIs at the time of delivery and who were enrolled with informed consent in
the French Perinatal Cohort, as approved by the institutional review board. The
women were delivered at Cochin Saint Vincent de Paul Hospital between 1 April
* Corresponding author. Mailing address: Pharmacology, Ho ˆpital
Cochin-Saint Vincent de Paul, 82, avenue Denfert Rochereau, 75674
Paris Cedex 14, France. Phone: 33 1 40488209. Fax: 33 1 40488223.
1999 and 28 February 2002. Women were eligible for participation in this study
if they had received an antenatal antiretroviral drug regimen including an NRTI
at the time of delivery and had maternal blood, cord blood, and amniotic fluid
samples available. Women could receive any licensed antiretroviral agents for
prophylaxis of HIV transmission and treatment of their HIV infection. Every
woman received zidovudine intravenously during labor for prevention of mother-
to-child transmission of HIV. The dose used was 2 mg/kg of body weight intra-
venously over a 1-h period, followed by a continuous infusion of 1 mg/kg/h
intravenously until delivery. The clinical guidelines recommended continuing
other antiretroviral drugs orally at the usual hours, with the exception of stavu-
dine, because of its incompatibility with zidovudine.
Cord blood samples were collected at delivery by venipuncture into heparin-
ized tubes after the cord was carefully wiped to avoid potential contamination
with amniotic fluid or maternal blood. Maternal blood was drawn at the same
time. Amniotic fluid samples were obtained at the time of membrane rupture in
the case of planned cesarean deliveries and whenever possible in other deliveries,
with precautions taken to avoid contamination with maternal blood. Amniotic
fluid samples that contained visible contamination with blood were discarded.
Plasma was isolated by centrifugation.
All of the drugs were measured in a 100-?l plasma sample by high-perfor-
mance liquid chromatography. An internal standard was used with each analyt-
ical procedure. Zidovudine and its glucuronide metabolite zidovudine G were
measured simultaneously, extracted by using a solid-phase extraction procedure
on Bond Elut C18(conditioning step, methanol and phosphate-buffered saline
buffer; washing step, phosphate-buffered saline buffer; elution step, methanol),
and separated isocratically on a Satisfaction C8Plus column (250 by 3 mm) with
a mobile phase consisting of buffer (25 mM potassium phosphate, pH 2.9) and
methanol (80:20, vol/vol) at a flow rate of 0.5 ml/min. UV absorbance at 267 nm
was used for detection. The lower limit of quantification (LOQ) was 0.05 mg/
liter. The mean interassay precisions at the lowest concentration of the quality
controls were 10 and 13.9%, and inaccuracies at the LOQ (percent deviation
from the expected value) were 4.2 and 7.5%, for zidovudine and its metabolite,
respectively. Overall recovery from plasma was 89% for zidovudine and 82% for
zidovudine G. Lamivudine, stavudine, and didanosine were measured simulta-
neously, extracted by solid-phase extraction on Bond Elut C18, and separated on
a Satisfaction C8 Plus column (250 by 3 mm) with a gradient (flow rate, 0.5
ml/min) of solvent A (water with 0.01% trifluoroacetic acid) and solvent B
(acetonitrile) as follows: 98% solvent A and 2% solvent B for 10 min and 90%
solvent A and 10% solvent B for 20 min. UV absorbance at 270 nm was used for
detection of lamivudine and stavudine, and UV absorbance at 254 nm was used
for didanosine. The LOQs were 0.05 mg/liter for lamivudine and stavudine and
0.025 mg/liter for didanosine. Mean interassay precisions at the low quality
controls were 10% (lamivudine), 12.7% (stavudine), and 15% (didanosine), and
inaccuracies at the LOQ were 4.5% (lamivudine), 0.67% (stavudine), and 0%
(didanosine). Overall recoveries were 65% (lamivudine), 81% (stavudine), and
76% (didanosine). Abacavir was extracted with terbutylmethylether and sepa-
rated isocratically on a Satisfaction C8Plus column (250 by 3 mm) with a mobile
phase consisting of buffer (10 mM potassium phosphate, pH 7.2) and acetonitrile
(82:18, vol/vol) at a flow rate of 0.5 ml/min. UV absorbance at 280 nm was used.
The LOQ was 0.025 mg/liter. Mean interassay precision at the low quality
controls was 14%, and accuracy at the LOQ was 1%. Overall recovery was 60%.
Each blood and amniotic fluid sample was accompanied by the exact sampling
time and the hours of the last antiretroviral dose intakes before delivery. The
maternal-fetal transfer was evaluated by the ratio of the concentration in fetal
plasma to that in maternal plasma.
Descriptive statistics (median and range) were reported for all five NRTIs
measured in maternal, cord, and amniotic samples. Linear regression analysis
was used to correlate cord and maternal plasma samples. Quantitative values
were compared by using the t test.
The mothers’ mean age at delivery was 33 years (range, 23 to
43); 54% were African, 43% were European, and 3% were
Asian; and 80% were infected through sexual exposure. The
median (range) maternal plasma HIV RNA level at delivery
was ?50 copies/ml (?50 to 36,572 copies/ml), and the propor-
tion of women with a detectable viral load at delivery was 34%
(28 of 83). The median (range) CD4 lymphocyte count was 473
? 106/liter (98 ? 106to 1,580? 106/liter). The mode of delivery
was cesarean section in 78% of the cases. None of the infants
was HIV infected.
The NRTIs received by the 100 women included intravenous
zidovudine (n ? 100), oral zidovudine (n ? 60), lamivudine (n
? 67), stavudine (n ? 32), didanosine (n ? 24), and abacavir
(n ? 4). The majority of these women (83 of 100) received
antiretroviral regimens with two NRTIs, with the most fre-
quently prescribed combination (n ? 20) being zidovudine
with lamivudine and nelfinavir. Twelve patients were taking a
regimen with only one NRTI; these regimens included zidovu-
dine alone (n ? 6), one NRTI and nevirapine (n ? 5), and one
NRTI and two protease inhibitors (n ? 1).
Maternal antiretroviral therapy was initiated before the be-
ginning of pregnancy in 27% of cases, during the first trimester
in 14% of cases, during second trimester in 25% of cases, and
during third trimester in 34% of cases. The median time on
treatment with the current NRTI was 3 months (range, 0.23 to
81.7 months) for zidovudine, 4.78 months (range, 0.23 to 81.7
months) for lamivudine, 5.63 months (range, 0.53 to 45.8
months) for stavudine, 4.23 months (range, 0.53 to 37.3
months) for didanosine, and 21.2 months (range, 7.1 to 35
months) for abacavir. The median time elapsed between the
last NRTI oral dose and delivery was 5.0 h (range, 0.4 to
22.0 h) for zidovudine, 5.0 h (range, 0.4 to 22 h) for lamivudine,
13.0 h (range, 1.2 to 20 h) for stavudine, 9.0 h (range, 2.1 to
33 h) for didanosine, and 3.5 h (range, 0.4 to 9.0 h) for aba-
Median drug concentrations in maternal and cord plasma
samples are displayed in Table 1. Cord blood drug concentra-
tions were below the assay limit of detection in 14 of 32 sam-
ples (44%) for stavudine and in 15 of 24 samples (62%) for
didanosine but were detectable in all samples for zidovudine,
zidovudine G, lamivudine, and abacavir.
For paired samples with concentrations in maternal samples
TABLE 1. Drug concentrations in maternal and cord plasma samples
Maternal plasmaCord plasmaCord plasma/maternal plasma
Median (range) drug
Median (range) drug
drug concn ratio
aAZT, zidovudine; 3TC, lamivudine; D4T, stavudine; DDI, didanosine.
VOL. 48, 2004 PLACENTAL TRANSFER OF NRTIs4333
above the assay limit of quantification, cord-to-maternal
plasma drug concentration ratios was determined in order to
assess placental transfer. Among the 160 measurable maternal-
cord blood sample pairs, transplacental passage was assessed
for zidovudine (n ? 75), zidovudine G (n ? 90), lamivudine (n
? 59), stavudine (n ? 12), didanosine (n ? 10), and abacavir
(n ? 4). The median cord-to-maternal plasma drug concentra-
tion ratio was close to one for zidovudine (R ? 1.22; range,
0.18 to 17.2), zidovudine G (R ? 1.01; range, 0.36 to 12.1),
stavudine (R ? 1.32; range, 0.36 to 2.81), lamivudine (R ?
0.93; range, 0.21 to 4.03), and abacavir (R ? 1.03; range, 0.92
to 1.42) and was small for didanosine (R ? 0.38; range, 0.00 to
2.00). There was a significant correlation between maternal
and cord plasma drug concentrations for zidovudine (r2? 0.10;
P ? 0.01), zidovudine G (r2? 0.38; P ? 0.01), lamivudine (r2
? 0.65; P ? 0.01), stavudine (r2? 0.7; P ? 0.01), and di-
danosine (r2? 0.88; P ? 0.01) (Fig. 1). For abacavir, no
significant correlation between maternal and cord plasma drug
concentrations was seen. Furthermore, for lamivudine, a sig-
nificant relationship between cord/maternal drug concentra-
tion ratios and postdosing intervals was seen (Fig. 2). For the
FIG. 1. Relationship between concentrations of zidovudine (AZT), stavudine (D4T), lamivudine (3TC), and didanosine (DDI) in cord and
maternal plasma samples.
FIG. 2. Relationship between cord/maternal lamivudine (3TC)
concentration ratios in plasma and postdosing intervals.
4334 CHAPPUY ET AL.ANTIMICROB. AGENTS CHEMOTHER.
other drugs, the cord/maternal ratios were not affected by
postdosing time intervals.
There were 46 amniotic fluid samples available for zidovu-
dine, 45 for zidovudine G, 27 for lamivudine, 15 for stavudine,
8 for didanosine, and 1 for abacavir. Among these amniotic
fluid samples, the proportions with drug concentrations below
the detection limit were 1 of 27 for lamivudine, 1 of 15 for
stavudine, and 4 of 8 for didanosine, but drug was detectable in
all samples for zidovudine (46 of 46), zidovudine G (45 of 45),
and abacavir (1 of 1).
Median drug concentrations and ratios in amniotic fluid are
displayed in Table 2. Median concentrations in amniotic fluid
were higher than those in maternal and cord plasma samples
for lamivudine (0.45 and 0.41 mg/liter, respectively), zidovu-
dine (0.59 and 0.7 mg/liter, respectively), zidovudine G (1.60
and 1.62 mg/liter, respectively), and stavudine (0.0 and 0.04
mg/liter, respectively). Concentrations of zidovudine and its
metabolite in amniotic fluid were higher in mothers receiving
oral zidovudine prior to delivery than in mothers received only
intrapartum intravenous zidovudine; the median zidovudine
and zidovudine G concentrations were, respectively, 1.68 mg/
liter (range, 0.89 to 4.33 mg/liter) versus 1.31 mg/liter (range,
0.15 to 2.67 mg/liter) (P ? 0.01) and 8.8 mg/liter (range, 3.8 to
26.0 mg/liter) versus 2.9 mg/liter (range, 0.1 to 4.4 mg/liter) (P
? 0.01). Median (range) amniotic fluid/cord plasma drug con-
centration ratios, in samples with cord plasma drug concentra-
tions above the assay limit of detection, were as follows:
zidovudine, 2.25 (0.08 to 8.38); zidovudine G, 2.83 (0.06 to
19.6); stavudine, 4.87 (0.98 to 11.9); lamivudine, 3.99 (1.62 to
17.1); and didanosine, 1.14 (1.02 to 3.16). There was only one
such ratio for abacavir, 0.89. A significant relationship between
amniotic fluid and cord plasma drug concentrations was seen
for zidovudine G (r2? 0.10; P ? 0.01), lamivudine (r2? 0.10;
P ? 0.01), and stavudine (r2? 0.22; P ? 0.01). The ratio of the
amniotic fluid drug concentration to the maternal plasma drug
concentration was significantly related to the time elapsed
since the last maternal dose for lamivudine but not for stavu-
dine, didanosine, and abacavir.
These data on the NRTIs zidovudine, lamivudine, stavudine,
and didanosine show that they cross the placenta in HIV-
infected pregnant women, in agreement with previous studies
(12, 14, 15, 25, 26). Our study includes the first preliminary
clinical data available on abacavir, which suggest that its pla-
cental transfer is also high.
For zidovudine, lamivudine, and stavudine, the ratio of the
drug concentration in the fetal plasma to that in the maternal
plasma was about 1, which suggests that these drugs freely
crossed the placenta through a passive diffusion mechanism.
The physicochemical characteristics of these drugs, i.e., low
molecular weight and low protein binding, are compatible with
high placental transfer. These findings are consistent with
those obtained from animal studies (19), an ex vivo placental
perfusion model (1), and human clinical trials (15, 21). For
lamivudine, a significant relationship between cord/maternal
drug concentration ratios and postdosing intervals was seen,
which suggests that accumulation of the compound occurs in
the fetal compartment. For didanosine, the ratio of the con-
centration in the fetal plasma to that in the maternal plasma
was the lowest. Low concentrations of didanosine in the ma-
ternal circulation at delivery, largely due to once-a-day dosing,
are likely to contribute to the low fetal drug concentrations,
which is in accord with experimental findings obtained from
animal studies (17), the ex vivo placental perfusion model (6,
9), and one clinical trial (25).
The only antiretroviral drugs for which concentrations in
amniotic fluid have previously been studied in humans are
zidovudine (second trimester) (18) and lamivudine (12). In our
study, median concentrations in amniotic fluid were higher
than those in maternal and cord plasma samples for lamivu-
dine, stavudine, and zidovudine and its glucuronide metabo-
lite. These high concentrations in amniotic fluid could proba-
bly be explained by the fetal urinary excretion of these drugs in
the amniotic fluid and slow elimination from the amniotic
cavity by the paraplacental route and diffusion across the pla-
cental surface. This is consistent with previous animal (23) and
clinical (12) studies. Unlike others drugs, zidovudine, which is
metabolized to a glucuronide form in the maternal compart-
ment, is rapidly converted in the animal fetus to glucuronide
zidovudine (16). Thus, concentrations of intact zidovudine in
the fetus are lower, and fetal urinary excretion concerns the
glucuronide form of zidovudine.
The comparison of cord-to-maternal drug concentration ra-
tios has several limitations. The results are obtained at delivery
and thus cannot be extrapolated to earlier gestational ages.
Moreover, cord-to-maternal ratios offer data on only a single
point in time. The measured maternal drug concentrations
depend on the time between the last maternal dose and deliv-
ery, which is usually long. As shown from ex vivo placental
perfusion studies, placental transfer is dependent on the drug
concentration and is higher at peak concentrations (1, 3). Al-
TABLE 2. Drug concentrations in amniotic fluid and relationship to concentrations in plasma
Amniotic fluidAmniotic fluid/cord plasma Amniotic fluid/maternal plasma
Median (range) drug
drug concn ratio
drug concn ratio
aAZT, zidovudine; 3TC, lamivudine; D4T, stavudine; DDI, didanosine.
VOL. 48, 2004 PLACENTAL TRANSFER OF NRTIs4335
though we did not find a relationship between the time from
last dose to delivery and cord blood drug concentrations (ex-
cept for lamivudine), few of the maternal levels were peak
concentrations. Further studies are required to estimate pla-
cental transfer of NRTIs at peak concentrations.
The high concentrations of NRTIs found in the fetal circu-
lation may have beneficial or deleterious consequences. In
utero exposure carries a risk of toxicity to the fetus. It should
be kept in mind that most of the antiretroviral agents have
been introduced relatively recently, and long-term follow up is
not available. On the other hand, the efficacy of NRTIs in
decreasing the rate of mother-to-child transmission may be at
least in part attributable to their ability to provide postexpo-
sure prophylaxis in the fetal compartment (22). This would be
of importance during late pregnancy and delivery, when most
of the exposure occurs (10). However, obtaining low viral rep-
lication in the mother, as evidenced by plasma HIV RNA
levels below the detection limit, appears to be effective, and
may be sufficient, to achieve a low rate of transmission (below
The high concentrations of antiretroviral drugs that we ob-
served in the amniotic fluid may have important clinical impli-
cations. The presence of antiretroviral drugs in the digestive
tract may be protective against concomitant exposure to infec-
tious HIV by the oral route. Virus has been detected in oro-
pharyngeal or gastric aspirates from approximately one-third
of neonates born to HIV type 1-infected mothers receiving
zidovudine (11). Furthermore, antiretrovirals in the amniotic
fluid at delivery may amount to an oral loading dose, which
would continue to be absorbed in the hours following birth. On
the other hand, further investigations will be needed to study
whether the high amniotic fluid antiretroviral concentrations
have an impact on the long-term safety of children.
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