| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
ORIGINAL RESEARCH |
From the 1 Department of Obstetrics and Gynaecology, the Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong; and 2 Department of Pharmacology, the Chinese University of Hong Kong, Hong Kong.
 |
ABSTRACT |
|---|
TOP
 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
METHODS: Twenty-six pregnant women were given 2 oral doses of zidovudine (200 mg) before first trimester surgical termination of pregnancy. Maternal blood, fetal tissue, and coelomic and amniotic fluid were collected for drug analysis.
RESULTS: Zidovudine was detected in all samples of maternal serum and fetal tissue but present in only 7 samples of amniotic and coelomic fluid. Zidovudine concentration in fetal tissue was similar to that of maternal serum. The median fetal/maternal ratio was 0.92 and was not associated with gestational age (r = 0.03, P = .89).
CONCLUSION: Zidovudine crossed the first trimester human placenta readily and achieved the level of maternal serum rapidly. Patients who choose to take zidovudine in first trimester of pregnancy should be counseled about the potential fetal effects.
LEVEL OF EVIDENCE: II-2
|
MATERIALS AND METHODS |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Patients who agreed to take part in the study were given two oral doses of zidovudine 200 mg (Retrovir, GlaxoSmithKline, Uxbridge, Middlesex, UK) before their surgery. The first dose was given at 2200 hours on the night before surgery, with the second dose being given 90 minutes before the scheduled operation time. All operations were performed between 0830 and 1330 hours. Surgical termination of pregnancy was performed under general anesthesia, according to the standard clinical protocol. Propofol and fentanyl were used for induction of anesthesia and analgesia respectively, and anesthesia was maintained by inhalation of 70% nitrous oxide and 1% isofluorane mixed with oxygen. After induction of anesthesia, fetal viability and gestation were confirmed by ultrasonography. Four types of biologic samples were collected at defined time points as previously described.5 Maternal venous blood was drawn immediately before induction of anesthesia. Coelomic and amniotic fluid were aspirated under transvaginal ultrasonography guidance before suction curettage. Aspiration of coelomic fluid was always performed before the aspiration of amniotic fluid sample, using different new needles to prevent cross contamination. All identifiable fetal parts removed as a result of the suction curettage were washed with normal saline to remove maternal blood. Maternal serum was separated from maternal blood by centrifugation at 1,250 g for 10 minutes. The fetal tissues were weighed, homogenized in physiological saline and centrifuged to obtain a clear supernatant for chemical analysis. All samples were kept at –70°C until analysis.
Zidovudine concentrations in all specimens were measured by high performance liquid chromatography (HPLC) with ultraviolet detection. Briefly, zidovudine in serum, coelomic fluid, and amniotic fluid (100 µL) were first extracted with 20 µL 2M perchloric acid followed by centrifugation and collection of the clear supernatant for injection (50 µL) for HPLC analysis. The fetal tissues were extracted with 500 µL of 0.2% acetonitrile in water. The supernatant was evaporated under a gentle stream of nitrogen, reconstituted in 500 µL of 0.2% acetonitrile, and extracted through a Sep-Pak (Waters Corporation, Milford, MA) C-18 solid-phase extraction cartridge. The eluate was washed with 2 mL acetonitrile, then 2 mL of 0.2% acetonitrile in water and the residue reconstituted in 10% acetonitrile in 40 mM sodium acetate (pH 7.0).
The separation was by an Alltech (Alltech Applied Science Ltd, Hong Kong) Hypersil BDS C18 HPLC column (150 x 4 mm) with a mobile phase containing 10% acetonitrile in 40 mM sodium acetate (pH 7.0) at a flow rate of 1 mL/min. Peaks were detected using an ultraviolet detector set at 270 nm. Linear relationship was observed over the concentration range of 20–500 ng/mL zidovudine concentrations. 3'-Azido-2', 3'-dideoxyuridine (AZDU) was used as the internal standard to determine the extraction and sampling efficiency of the protocol. The minimal detection limit of the assay was 20.0 ng/mL. The intra-assay and interassay coefficients of variation at 0.5 µg/mL zidovudine were 3.48% and 3.15%, respectively. Zidovudine metabolites in the samples were not analyzed.
The overall extent of placental transfer was determined by calculating the ratio of the concentration of the zidovudine in the fetal parts relative to that in maternal serum. Drug concentrations in serum, amniotic fluid, and coelomic samples were expressed in drug per unit volume (in milliliters), while the drug concentrations in fetal tissue were expressed as drug per unit weight (in grams). The numerical value of fetal drug concentration should be higher when expressed in nanograms per milliliter than when expressed in nanograms per gram because the density of fetal tissue should be more than 1 g/mL. Thus, the calculated fetal-maternal drug ratio might underestimate the true fetal serum drug level.
Data were presented as median (interquartile range, IQR). Between-group difference was analyzed using Wilcoxon signed ranks test. Spearman's rank test was used to study potential correlation between gestational age and zidovudine concentrations in various specimens and the fetal/maternal ratio. P values less than 0.05 were considered statistically significant.
The study was approved by the Institutional Clinical Research Ethics Committee and written consent was obtained from all patients participating in the study.
|
RESULTS |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
Zidovudine was detected in all maternal serum and fetal tissue samples. The median maternal serum and fetal tissue drug concentration were 237.2 ng/mL (IQR 155.1–325.5 ng/mL) and 211.9 ng/g (IQR 147.3–306.9 ng/g) respectively. These concentrations were not significantly different (P = .248). Zidovudine was positively detected in 7 of 26 coelomic fluid samples, with a median concentration of 57.6 ng/mL (IQR 45.5–77.5 ng/mL). Zidovudine was positively detected in 7 of 26 amniotic fluid samples, with a median concentration 39.2 ng/mL (IQR 33.1–46.3 ng/mL). Over all, zidovudine was detected in both coelomic and amniotic fluid samples in 5 patients.
The median ratio of zidovudine in fetal tissue to maternal serum was 0.92 (IQR 0.40–1.36). No association could be demonstrated between these ratios and the gestational age (r = 0.03, P = .89) (Fig. 1).
|
|
DISCUSSION |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Placental transfer of zidovudine has been well studied at term and is known to pass through term placenta readily by simple diffusion.4 However, its transferral rate in the first trimester was unknown. Data obtained from studies on term placenta cannot be extrapolated to the first trimester pregnancy, because they are at different stages of trophoblastic invasion and placental development. It is known that term placenta is different from first trimester placenta histologically, developmentally and functionally.10 Previously we proposed a model to investigate the drug placental transferral rate in first trimester pregnancy.11 We used this model to investigate the placental transfer of zidovudine in human first trimester pregnancy, aimed to investigate the effect of zidovudine in the embryonic stages of human fetal development.
We employed a two dose regimen in this study. This regimen enabled adequate time for equilibrium between maternal and fetal compartments, which provides a close estimation of zidovudine concentration in different fetal compartments after maternal exposure. Our study showed that zidovudine was readily passed through the human placenta in the first trimester and that its concentration in fetal tissue was similar to that in the maternal serum. Zidovudine was present in only one quarter of the samples of amniotic and coelomic fluid, at a significantly lower concentration than that found in the fetal tissue and maternal serum. The relatively lower level of drug concentration in amniotic fluid in comparison to that in fetal tissue and maternal serum can be explained by the fact that amniotic fluid is either exudates from fetal skin or fetal urine. However, the low level of zidovudine in coelomic fluid suggests that there is a preferential transfer to the fetus when zidovudine crosses the chorionic leave, which is the major barrier between maternal and fetal circulation in the first trimester. This phenomenon was also observed in our previous studies with diclofenac and naproxen,5,12 the drug levels in fetal tissue were higher than the other two compartments. The exact mechanism of this preferential transfer to fetal tissue is unknown, but one of the possible mechanisms was the active uptake by the secondary yolk sac from coelomic fluid.13 In fact, preferential transfer of zidovudine to fetal tissue at first trimester carries both potential benefits and risks. The primary concern of course is whether zidovudine may have teratogenic effects at the organogenesis stage. On the other hand, the presence of zidovudine at high concentration in fetal tissue may enhance its protective role against vertical HIV transmission.
The effect of zidovudine on early pregnancy has been studied using animal models. It was shown that exposing animals to zidovudine in the peri-conception period resulted in a higher rate of embryonic resorptions and thus lower litter size.14 However, no adverse effect was observed with zidovudine administrated at mid to late murine pregnancy.8 On the other hand, sporadic reports on the use of zidovudine at first trimester of human pregnancy did not appear to result in fetal abnormality.14,15 Thus, it may well be that zidovudine caused early pregnancy failure, but not fetal malformation at organogenesis phase.
The exact mechanism of how zidovudine prevents vertical transmission of HIV to the fetus is still unknown. The proposed mechanisms are reduction of maternal viraemia, placental viraemia or prevention of HIV infection in the fetus through placental transfer of AZT.4 A previous clinical trial has shown that a shortened antenatal zidovudine regimen resulted in a higher in utero transmission rate when compared with a longer regimen.16 Since the presence of zidovudine in the fetal circulation may play a major role in the reduction of vertical transmission, as well as maintaining therapeutic benefit to the infected pregnant women, earlier implementation of zidovudine in first trimester may be one of the modalities to further decrease the vertical transmission rate. However, further study is required to assess whether starting zidovudine therapy in the first trimester of pregnancy improved its efficacy in the prevention of vertical transmission. Before the results of further clinical studies are available, HIV infected mothers who choose to take zidovudine during their first trimester should be counseled about both the potential benefits of its use as well as the potential risk of its embryotoxic effects in this gestational period.
|
Footnotes |
|---|
Corresponding author: Dr. Shing Shun N. Siu, Department of Obstetrics and Gynaecology, Prince of Wales Hospital, Shatin, Hong Kong; email: nelsonsiu{at}cuhk.edu.hk.
doi:10.1097/01.AOG.0000178160.38042.04
|
REFERENCES |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
2. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O'Sullivan MJ, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994;331:1173–80.
3. Perinatal HIV-1 Guidelines Working Group. Public Health Service Task Force recommendations for the 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. Available at: http://www.aidsinfo.nih.gov/guidelines/default_db2.asp?id=66. Retrieved July 14, 2005.
4. Boal JH, Plessinger MA, van den Reydt C, Miller RK. Pharmacokinetic and toxicity studies of AZT (zidovudine) following perfusion of human term placenta for 14 hours. Toxicol Appl Pharmacol 1997;143:13–21.[Medline]
5. Siu SS, Yeung JH, Lau TK. A study on placental transfer of diclofenac in first trimester of human pregnancy. Human Reprod 2000;15:2423–5.
6. Newell ML. Prevention of mother-to-child transmission of HIV: challenges for the current decade. Bull World Health Organ 2001;79:1138–44.[Medline]
7. Jungmann EM, Mercey D, DeRuiter A, Edwards S, Donoghue S, Booth T, et al. Is first trimester exposure to the combination of antiretroviral therapy and folate antagonists a risk factor for congenital abnormalities? Sex Transm Infect 2001;77:441–3.
8. Sieh E, Coluzzi ML, Cusella De Angelis MG, Mezzogiorno A, Floridia M, Canipari R, et al. The effects of AZT and DDI on pre- and postimplantation mammalian embryos: an in vivo and in vitro study. AIDS Res Hum Retroviruses 1992;8:639–49.[Medline]
9. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 6th ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2002:1507–23.
10. Castellucci M, Kosanke G, Verdenelli F, Huppertz B, Kaufmann P. Villous sprouting: fundamental mechanisms of human placental development. Hum Reprod Update 2000;6:485–94.
11. Siu SS, Yeung JH, Chan MT, Chan LY, Lau TK. An in-vivo model for investigation of drug transfer in early human pregnancy. Ceska Gynekol 2002;67(suppl):43.
12. Siu SS, Yeung JH, Lau TK. An in-vivo study on placental transfer of naproxen in early human pregnancy. Human Reprod 2002;17:1056–9.
13. Gulbis B, Jauniaux E, Cotton F, Stordeur P. Protein and enzyme patterns in the fluid cavities of the first trimester gestational sac: relevance to the absorptive role of secondary yolk sac. Mol Hum Reprod 1998;4:857–62.
14. Toltzis P, Marx CM, Kleinman N, Levine EM, Schmidt EV. Zidovudine-associated embryonic toxicity in mice. J Infect Dis 1991;163:1212–8.[Medline]
15. Bloch M, Carr A, Vasak E, Cunningham P, Smith D. The use of human immunodeficiency virus postexposure prophylaxis after successful artificial insemination. Am J Obstet Gynecol 1999;181:760–1.[Medline]
16. Lallemant M, Jourdain G, Le Coeur S, Kim S, Koetsawang S, Comeau AM, et al. A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. Perinatal HIV Prevention Trial (Thailand) Investigators. N Engl J Med 2000;343:982–91.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
