CSPT 2011 - Prediction of Placental Drug Transfer Using the Human Placental Perfusion Model
Main Article Content
Keywords
Placental perfusion, computational model, pharmacokinetics, pregnancy
Abstract
The placental perfusion model and a newly developed complementary computational model are reviewed. Examples are provided, where the computational model can be applied to adjust drug pharmacokinetic data obtained from the perfusion model to more closely resemble the in vivo placental transfer of therapeutic agents. After modelling the data, placental perfusion experiments can be used to predict placental drug transfer and can be useful for clinical assessment of the risks and benefits of drug therapy in pregnancy.
References
1. Hutson JR, Koren G, Matthews SG. Placental Pglycoprotein and breast cancer resistance protein: influence of polymorphisms on fetal drug exposure and physiology. Placenta. 2010;31(5):351-7.
2. Ala-Kokko TI, Myllynen P, Vähäkangas K. Ex vivo perfusion of the human placental cotyledon: implications for anesthetic pharmacology. Int J Obstet Pharmacol. 2000;9(1):26-38.
3. Hutson JR, Garcia-Bournissen F, Davis A, Koren G. The human placental perfusion model: a systematic review and development of a model to predict in vivo transfer of therapeutic drugs. Clin Pharmacol Ther. 2011;90(1):67-76.
4. Barzago MM, Bortolotti A, Stellari FF, Diomede L, Algeri M, Efrati S, Salmona M, Bonati M. Placental transfer of valproic acid after liposome encapsulation during in vitro human placenta perfusion. J Pharmacol Exp Ther. 1996;277(1):79-86.
5. Fowler DW, Eadie MJ, Dickinson RG. Transplacental transfer and biotransformation studies of valproic acid and its glucuronide(s) in the perfused human placenta. J Pharmacol Exp Ther. 1989; 249(1):318-23.
6. Dickinson RG, Harland RC, Lynn RK, Smith WB, Gerber N. Transmission of valproic acid (Depakene) across the placenta: half-life of the drug in mother and baby. J Pediatr. 1979;94:832-5.
7. Nau H, Rating D, Koch S, Hauser I, Helge H. Valproic acid and its metabolites: placental transfer, neonatal pharmacokinetics, transfer via mother's milk and clinical status in neonates of epileptic mothers. J Pharmacol Exp Ther. 1981;219:768-77.
8. Takeda A, Okada H, Tanaka H, Izumi M, Ishikawa S, Noro T. Protein binding of four antiepileptic drugs in maternal and umbilical cord serum. Epilepsy Res. 1992;13:147-51.
9. Ishizaki T, Yokochi K, Chiba K, Tabuchi T, Wagatsuma T. Placental transfer of anticonvulsants (phenobarbital, phenytoin, valproic acid) and the elimination from neonates. Pediatr Pharmacol (New York); 1982;1:291-303.
10. Froescher W, Gugler R, Niesen M, Hoffmann F. Protein binding of valproic acid in maternal and umbilical cord serum. Epilepsia. 1984;25(2):244-9.
11. Myllynen P, Vähäkangas K. An examination of whether human placental perfusion allows accurate prediction of placental drug transport: studies with diazepam. J Pharmacol Toxicol Methods. 2002;48(3):131-8.
12. Moore RG, McBride WG. The disposition kinetics of diazepam in pregnant women at parturition. Eur J Clin Pharmacol. 1978;13:275- 84.
13. Ridd MJ, Brown KF, Nation RL, Collier CB. The disposition and placental transfer of diazepam in cesarean section. Clin Pharmacol Ther. 1989;45:506-12.
14. Cavanah D, Condo CS. Diazepam-- A pilot study of drug concentrations in maternal blood, amniotic fluid and cord blood. Curr Ther Res Clin Exp. 1964;6:122-6.
15. Cree JE, Meyer J, Hailey DM. Diazepam in labour: its metabolism and effect on the clinical condition and thermogenesis of the newborn. Br Med J. 1973;4:251-5.
16. Kanto J, Erkkola R, Sellman R. Accumulation of diazepam and N-demethyldiazepam in the fetal blood during the labour. Ann Clin Res. 1973;5:375-9.
17. Mandelli M, Morselli PL, Nordio S, Pardi G, Principi N, Sereni F, Tognoni G. Placental transfer to diazepam and its disposition in the newborn. Clin Pharmacol Ther. 1975;17:564-72.
18. Bakke OM, Haram K, Lygre T, Wallem G. Comparison of the placental transfer of thiopental and diazepam in caesarean section. Eur J Clin Pharmacol. 1981;21:221-7.
19. Erkkola R, Kangas L, Pekkarinen A. The transfer of diazepam across the placenta during labour. Acta Obstet Gynecol Scand. 1973;52:167-70.
20. Owen JR, Irani SF, Blair AW. Effect of diazepam administered to mothers during labour on temperature regulation of neonate. Arch Dis Child. 1972;47:107-10.
21. Haram K, Bakke OM. Diazepam as an induction agent for caesarean section: a clinical and pharmacokinetic study of fetal drug exposure. Br J Obstet Gynaecol. 1980;87:506-12.
22. Kanto J, Scheinin M. Placental and blood-CSF transfer of orally administered diazepam in the same person. Pharmacol Toxicol. 1987;61:72-4.
23. Haram K, Bakke OM, Johannessen KH, Lund T. Transplacental passage of diazepam during labor: influence of uterine contractions. Clin Pharmacol Ther. 1978;24:590-9.
24. Desilva JA, D'Arconte L, Kaplan J. The determination of blood levels and the placental transfer of diazepam in humans. Curr Ther Res Clin Exp. 1964;6:115-21.
25. Ridd MJ, Brown KF, Nation RL, Collier CB. The disposition and placental transfer of diazepam in cesarean section. Clin Pharmacol Ther. 1989;45(5):506-12.
26. Schneider H, Proegler M. Placental transfer of beta-adrenergic antagonists studied in an in vitro perfusion system of human placental tissue. Am J Obstet Gynecol. 1988;159(1):42-7.
27. Erkkola R, Lammintausta R, Liukko P, Anttila M. Transfer of propranolol and sotalol across the human placenta. Their effect on maternal and fetal plasma renin activity. Acta Obstet Gynecol Scand. 1982;61(1):31-4.
28. Belpaire FM, Bogaert MG, Rosseneu M. Binding of beta-adrenoceptor blocking drugs to human serum albumin, to alpha 1-acid glycoprotein and to human serum. Eur J Clin Pharmacol. 1982; 22(3):253-6.
29. Zakowski MI, Ham AA, Grant GJ. Transfer and uptake of alfentanil in the human placenta during in vitro perfusion. Anesth Analg. 1994;79(6):1089-93.
30. Gepts E, Heytens L, Camu F. Pharmacokinetics and placental transfer of intravenous and epidural alfentanil in parturient women. Anesth Analg.1986;65:1155-60.
31. Meuldermans W, Woestenborghs R, Noorduin H, Camu F, van Steenberge A, Heykants J. Protein binding of the analgesics alfentanil and sufentanil in maternal and neonatal plasma. Eur J Clin Pharmacol. 1986;30:217-9.
32. Heytens L, Cammu H, Camu F. Extradural analgesia during labour using alfentanil. Br J Anaesth. 1987;59:331-7.
33. Cartwright DP, Dann WL, Hutchinson A. Placental transfer of alfentanil at caesarean section. Eur J Anaesthesiol. 1989;6:103-9.
34. Johnson RF, Herman N, Arney TL, Gonzalez H, Johnson HV, Downing JW. Bupivacaine transfer across the human term placenta. A study using the dual perfused human placental model. Anesthesiology. 1995;82(2):459-68.
35. Johnson RF, Cahana A, Olenick M, Herman N, Paschall RL, Minzter B, Ramasubramanian R, Gonzalez H, Downing JW. A comparison of the placental transfer of ropivacaine versus bupivacaine. Anesth Analg. 1999;89(3):703-8.
36. Ala-Kokko TI, Alahuhta S, Jouppila P, Korpi K, Westerling P, Vahakangas K. Feto-maternal distribution of ropivacaine and bupivacaine after epidural administration for cesarean section. Int J Obstet Anesth. 1997;6:147-52.
37. Datta S, Camann W, Bader A, VanderBurgh L. Clinical effects and maternal and fetal plasma concentrations of epidural ropivacaine versus bupivacaine for cesarean section. Anesthesiology. 1995;82:1346-52.
38. Irestedt L, Ekblom A, Olofsson C, Dahlstrom AC, Emanuelsson BM. Pharmacokinetics and clinical effect during continuous epidural infusion with ropivacaine 2.5 mg/ml or bupivacaine 2.5 mg/ml for labour pain relief. Acta Anaesthesiol Scand. 1998;42:890-6.
39. Decocq G, Brazier M, Hary L, Hubau C, Fortaine MR, Gondry J, Andréjak M. Serum bupivacaine concentrations and transplacental transfer following repeated epidural administrations in term parturients during labour. Fundam Clin Pharmacol. 1997;11:365- 70.
40. de Barros Duarte L, Moises EC, Carvalho Cavalli R, Lanchote VL, Duarte G, Pereira da Cunha S. Placental transfer of bupivacaine enantiomers in normal pregnant women receiving epidural anesthesia for cesarean section. Eur J Clin Pharmacol. 2007;63:523-6.
41. Papini O, Mathes AC, Cunha SP, Lanchote VL. Stereoselectivity in the placental transfer and kinetic disposition of racemic bupivacaine administered to parturients with or without a vasoconstrictor. Chirality. 2004;16:65-71.
42. Kuhnert BR, Zuspan KJ, Kuhnert PM, Syracuse CD, Brown DE. Bupivacaine disposition in mother, fetus, and neonate after spinal anesthesia for cesarean section. Anesth Analg. 1987;66:407-12.
43. Thomas J, Long G, Moore G, Morgan D. Plasma protein binding and placental transfer of bupivacaine. Clin Pharmacol Ther. 1976;19:426- 34.
44. Thomas J, Climie CR, Mather LE. The maternal plasma levels and placental transfer of bupivacaine following epidural analgesia. Br J Anaesth.1969;41:1035-40.
45. Scanlon JW, Ostheimer GW, Lurie AO, Brown wu JR, Weiss JB, Alper MH. Neurobehavioral responses and drug concentrations in newborns after maternal epidural anesthesia with bupivacaine. Anesthesiology. 1976;45:400-5.
46. Magno R, Berlin A, Karlsson K, Kjellmer I. Anesthesia for cesarean section IV: placental transfer and neonatal elimination of bupivacaine following epidural analgesia for elective cesarean section. Acta Anaesthesiol Scand. 1976;20:141-6.
47. McGuinness GA, Merkow AJ, Kennedy RL, Erenberg A. Epidural anesthesia with bupivacaine for Cesarean section: neonatal blood levels and neurobehavioral responses. Anesthesiology. 1978; 49:270-3.
48. Beazley JM, Taylor G, Reynolds F. Placental transfer of bupivacaine after paracervical block. Obstet. Gynecol. 1972;39:2-6.
49. Reynolds F, Taylor G. Maternal and neonatal blood concentrations of bupivacaine: a comparison with lignocaine during continuous extradural analgesia. Anaesthesia. 1970;25:14- 23.
50. Bader AM, Tsen LC, Camann WR, Nephew E, Datta S. Clinical effects and maternal and fetal plasma concentrations of 0.5% epidural levobupivacaine versus bupivacaine for cesarean delivery. Anesthesiology. 1999;90:1596-1601.
51. Datta S, Camann W, Bader A, VanderBurgh L. Clinical effects and maternal and fetal plasma concentrations of epidural ropivacaine versus bupivacaine for cesarean section. Anesthesiology. 1995;82:1346-52.
52. Loftus JR, Holbrook RH, Cohen SE. Fetal heart rate after epidural lidocaine and bupivacaine for elective cesarean section. Anesthesiology. 1991;75:406-12.
53. Sudhakaran S, Ghabrial H, Nation RL, Kong DC, Gude NM, Angus PW, Rayner CR. Differential bidirectional transfer of indinavir in the isolated perfused human placenta. Antimicrob Agents Chemother. 2005;49(3):1023-8.
54. Sudhakaran S, Rayner CR, Li J, Kong DC, Gude NM, Nation RL. Inhibition of placental Pglycoprotein: impact on indinavir transfer to the foetus. Br J Clin Pharmacol. 2008;65(5):667- 73.
55. Mirochnick M, Dorenbaum A, Holland D, Cunningham-Schrader B, Cunningham C, Gelber R, Mofenson L, Culnane M, Connor J, Sullivan JL. Concentrations of protease inhibitors in cord blood after in utero exposure. Pediatr Infect Dis J. 2002;21:835-8.
56. Chappuy H, Tréluyer JM, Rey E, Dimet J, Fouché M, Firtion G, Pns G, Mandelbrot L. Maternal-fetal transfer and amniotic fluid accumulation of protease inhibitors in pregnant women who are infected with human immunodeficiency virus. Am J Obstet Gynecol. 2004;191:558-62.
2. Ala-Kokko TI, Myllynen P, Vähäkangas K. Ex vivo perfusion of the human placental cotyledon: implications for anesthetic pharmacology. Int J Obstet Pharmacol. 2000;9(1):26-38.
3. Hutson JR, Garcia-Bournissen F, Davis A, Koren G. The human placental perfusion model: a systematic review and development of a model to predict in vivo transfer of therapeutic drugs. Clin Pharmacol Ther. 2011;90(1):67-76.
4. Barzago MM, Bortolotti A, Stellari FF, Diomede L, Algeri M, Efrati S, Salmona M, Bonati M. Placental transfer of valproic acid after liposome encapsulation during in vitro human placenta perfusion. J Pharmacol Exp Ther. 1996;277(1):79-86.
5. Fowler DW, Eadie MJ, Dickinson RG. Transplacental transfer and biotransformation studies of valproic acid and its glucuronide(s) in the perfused human placenta. J Pharmacol Exp Ther. 1989; 249(1):318-23.
6. Dickinson RG, Harland RC, Lynn RK, Smith WB, Gerber N. Transmission of valproic acid (Depakene) across the placenta: half-life of the drug in mother and baby. J Pediatr. 1979;94:832-5.
7. Nau H, Rating D, Koch S, Hauser I, Helge H. Valproic acid and its metabolites: placental transfer, neonatal pharmacokinetics, transfer via mother's milk and clinical status in neonates of epileptic mothers. J Pharmacol Exp Ther. 1981;219:768-77.
8. Takeda A, Okada H, Tanaka H, Izumi M, Ishikawa S, Noro T. Protein binding of four antiepileptic drugs in maternal and umbilical cord serum. Epilepsy Res. 1992;13:147-51.
9. Ishizaki T, Yokochi K, Chiba K, Tabuchi T, Wagatsuma T. Placental transfer of anticonvulsants (phenobarbital, phenytoin, valproic acid) and the elimination from neonates. Pediatr Pharmacol (New York); 1982;1:291-303.
10. Froescher W, Gugler R, Niesen M, Hoffmann F. Protein binding of valproic acid in maternal and umbilical cord serum. Epilepsia. 1984;25(2):244-9.
11. Myllynen P, Vähäkangas K. An examination of whether human placental perfusion allows accurate prediction of placental drug transport: studies with diazepam. J Pharmacol Toxicol Methods. 2002;48(3):131-8.
12. Moore RG, McBride WG. The disposition kinetics of diazepam in pregnant women at parturition. Eur J Clin Pharmacol. 1978;13:275- 84.
13. Ridd MJ, Brown KF, Nation RL, Collier CB. The disposition and placental transfer of diazepam in cesarean section. Clin Pharmacol Ther. 1989;45:506-12.
14. Cavanah D, Condo CS. Diazepam-- A pilot study of drug concentrations in maternal blood, amniotic fluid and cord blood. Curr Ther Res Clin Exp. 1964;6:122-6.
15. Cree JE, Meyer J, Hailey DM. Diazepam in labour: its metabolism and effect on the clinical condition and thermogenesis of the newborn. Br Med J. 1973;4:251-5.
16. Kanto J, Erkkola R, Sellman R. Accumulation of diazepam and N-demethyldiazepam in the fetal blood during the labour. Ann Clin Res. 1973;5:375-9.
17. Mandelli M, Morselli PL, Nordio S, Pardi G, Principi N, Sereni F, Tognoni G. Placental transfer to diazepam and its disposition in the newborn. Clin Pharmacol Ther. 1975;17:564-72.
18. Bakke OM, Haram K, Lygre T, Wallem G. Comparison of the placental transfer of thiopental and diazepam in caesarean section. Eur J Clin Pharmacol. 1981;21:221-7.
19. Erkkola R, Kangas L, Pekkarinen A. The transfer of diazepam across the placenta during labour. Acta Obstet Gynecol Scand. 1973;52:167-70.
20. Owen JR, Irani SF, Blair AW. Effect of diazepam administered to mothers during labour on temperature regulation of neonate. Arch Dis Child. 1972;47:107-10.
21. Haram K, Bakke OM. Diazepam as an induction agent for caesarean section: a clinical and pharmacokinetic study of fetal drug exposure. Br J Obstet Gynaecol. 1980;87:506-12.
22. Kanto J, Scheinin M. Placental and blood-CSF transfer of orally administered diazepam in the same person. Pharmacol Toxicol. 1987;61:72-4.
23. Haram K, Bakke OM, Johannessen KH, Lund T. Transplacental passage of diazepam during labor: influence of uterine contractions. Clin Pharmacol Ther. 1978;24:590-9.
24. Desilva JA, D'Arconte L, Kaplan J. The determination of blood levels and the placental transfer of diazepam in humans. Curr Ther Res Clin Exp. 1964;6:115-21.
25. Ridd MJ, Brown KF, Nation RL, Collier CB. The disposition and placental transfer of diazepam in cesarean section. Clin Pharmacol Ther. 1989;45(5):506-12.
26. Schneider H, Proegler M. Placental transfer of beta-adrenergic antagonists studied in an in vitro perfusion system of human placental tissue. Am J Obstet Gynecol. 1988;159(1):42-7.
27. Erkkola R, Lammintausta R, Liukko P, Anttila M. Transfer of propranolol and sotalol across the human placenta. Their effect on maternal and fetal plasma renin activity. Acta Obstet Gynecol Scand. 1982;61(1):31-4.
28. Belpaire FM, Bogaert MG, Rosseneu M. Binding of beta-adrenoceptor blocking drugs to human serum albumin, to alpha 1-acid glycoprotein and to human serum. Eur J Clin Pharmacol. 1982; 22(3):253-6.
29. Zakowski MI, Ham AA, Grant GJ. Transfer and uptake of alfentanil in the human placenta during in vitro perfusion. Anesth Analg. 1994;79(6):1089-93.
30. Gepts E, Heytens L, Camu F. Pharmacokinetics and placental transfer of intravenous and epidural alfentanil in parturient women. Anesth Analg.1986;65:1155-60.
31. Meuldermans W, Woestenborghs R, Noorduin H, Camu F, van Steenberge A, Heykants J. Protein binding of the analgesics alfentanil and sufentanil in maternal and neonatal plasma. Eur J Clin Pharmacol. 1986;30:217-9.
32. Heytens L, Cammu H, Camu F. Extradural analgesia during labour using alfentanil. Br J Anaesth. 1987;59:331-7.
33. Cartwright DP, Dann WL, Hutchinson A. Placental transfer of alfentanil at caesarean section. Eur J Anaesthesiol. 1989;6:103-9.
34. Johnson RF, Herman N, Arney TL, Gonzalez H, Johnson HV, Downing JW. Bupivacaine transfer across the human term placenta. A study using the dual perfused human placental model. Anesthesiology. 1995;82(2):459-68.
35. Johnson RF, Cahana A, Olenick M, Herman N, Paschall RL, Minzter B, Ramasubramanian R, Gonzalez H, Downing JW. A comparison of the placental transfer of ropivacaine versus bupivacaine. Anesth Analg. 1999;89(3):703-8.
36. Ala-Kokko TI, Alahuhta S, Jouppila P, Korpi K, Westerling P, Vahakangas K. Feto-maternal distribution of ropivacaine and bupivacaine after epidural administration for cesarean section. Int J Obstet Anesth. 1997;6:147-52.
37. Datta S, Camann W, Bader A, VanderBurgh L. Clinical effects and maternal and fetal plasma concentrations of epidural ropivacaine versus bupivacaine for cesarean section. Anesthesiology. 1995;82:1346-52.
38. Irestedt L, Ekblom A, Olofsson C, Dahlstrom AC, Emanuelsson BM. Pharmacokinetics and clinical effect during continuous epidural infusion with ropivacaine 2.5 mg/ml or bupivacaine 2.5 mg/ml for labour pain relief. Acta Anaesthesiol Scand. 1998;42:890-6.
39. Decocq G, Brazier M, Hary L, Hubau C, Fortaine MR, Gondry J, Andréjak M. Serum bupivacaine concentrations and transplacental transfer following repeated epidural administrations in term parturients during labour. Fundam Clin Pharmacol. 1997;11:365- 70.
40. de Barros Duarte L, Moises EC, Carvalho Cavalli R, Lanchote VL, Duarte G, Pereira da Cunha S. Placental transfer of bupivacaine enantiomers in normal pregnant women receiving epidural anesthesia for cesarean section. Eur J Clin Pharmacol. 2007;63:523-6.
41. Papini O, Mathes AC, Cunha SP, Lanchote VL. Stereoselectivity in the placental transfer and kinetic disposition of racemic bupivacaine administered to parturients with or without a vasoconstrictor. Chirality. 2004;16:65-71.
42. Kuhnert BR, Zuspan KJ, Kuhnert PM, Syracuse CD, Brown DE. Bupivacaine disposition in mother, fetus, and neonate after spinal anesthesia for cesarean section. Anesth Analg. 1987;66:407-12.
43. Thomas J, Long G, Moore G, Morgan D. Plasma protein binding and placental transfer of bupivacaine. Clin Pharmacol Ther. 1976;19:426- 34.
44. Thomas J, Climie CR, Mather LE. The maternal plasma levels and placental transfer of bupivacaine following epidural analgesia. Br J Anaesth.1969;41:1035-40.
45. Scanlon JW, Ostheimer GW, Lurie AO, Brown wu JR, Weiss JB, Alper MH. Neurobehavioral responses and drug concentrations in newborns after maternal epidural anesthesia with bupivacaine. Anesthesiology. 1976;45:400-5.
46. Magno R, Berlin A, Karlsson K, Kjellmer I. Anesthesia for cesarean section IV: placental transfer and neonatal elimination of bupivacaine following epidural analgesia for elective cesarean section. Acta Anaesthesiol Scand. 1976;20:141-6.
47. McGuinness GA, Merkow AJ, Kennedy RL, Erenberg A. Epidural anesthesia with bupivacaine for Cesarean section: neonatal blood levels and neurobehavioral responses. Anesthesiology. 1978; 49:270-3.
48. Beazley JM, Taylor G, Reynolds F. Placental transfer of bupivacaine after paracervical block. Obstet. Gynecol. 1972;39:2-6.
49. Reynolds F, Taylor G. Maternal and neonatal blood concentrations of bupivacaine: a comparison with lignocaine during continuous extradural analgesia. Anaesthesia. 1970;25:14- 23.
50. Bader AM, Tsen LC, Camann WR, Nephew E, Datta S. Clinical effects and maternal and fetal plasma concentrations of 0.5% epidural levobupivacaine versus bupivacaine for cesarean delivery. Anesthesiology. 1999;90:1596-1601.
51. Datta S, Camann W, Bader A, VanderBurgh L. Clinical effects and maternal and fetal plasma concentrations of epidural ropivacaine versus bupivacaine for cesarean section. Anesthesiology. 1995;82:1346-52.
52. Loftus JR, Holbrook RH, Cohen SE. Fetal heart rate after epidural lidocaine and bupivacaine for elective cesarean section. Anesthesiology. 1991;75:406-12.
53. Sudhakaran S, Ghabrial H, Nation RL, Kong DC, Gude NM, Angus PW, Rayner CR. Differential bidirectional transfer of indinavir in the isolated perfused human placenta. Antimicrob Agents Chemother. 2005;49(3):1023-8.
54. Sudhakaran S, Rayner CR, Li J, Kong DC, Gude NM, Nation RL. Inhibition of placental Pglycoprotein: impact on indinavir transfer to the foetus. Br J Clin Pharmacol. 2008;65(5):667- 73.
55. Mirochnick M, Dorenbaum A, Holland D, Cunningham-Schrader B, Cunningham C, Gelber R, Mofenson L, Culnane M, Connor J, Sullivan JL. Concentrations of protease inhibitors in cord blood after in utero exposure. Pediatr Infect Dis J. 2002;21:835-8.
56. Chappuy H, Tréluyer JM, Rey E, Dimet J, Fouché M, Firtion G, Pns G, Mandelbrot L. Maternal-fetal transfer and amniotic fluid accumulation of protease inhibitors in pregnant women who are infected with human immunodeficiency virus. Am J Obstet Gynecol. 2004;191:558-62.