Summary
Drugs administered to mothers have the potential to cross the placenta and reach the fetus. Under particular circumstances, the comparison of the drug concentration in the maternal and fetal plasma may give an idea of the exposure of the fetus to the maternally administered drugs. In this review drugs are classified according to their type of transfer across the placenta.
Several drugs rapidly cross the placenta and pharmacologically significant concentrations equilibrate in maternal and fetal plasma. Their transfer is termed ‘complete’. Other drugs cross the placenta incompletely, and their concentrations are lower in the fetal than in maternal plasma. The majority of drugs fit into 1 of these 2 groups. A limited number of drugs reach greater concentrations in fetal than maternal plasma. It is said that these drugs have an ‘exceeding’ transfer. The impression prevails that suxamethonium chloride (succinylcholine chloride) and doxorubicin do not cross the placenta. However, a careful analysis of the literature suggests that this impression is wrong and that all drugs cross the placenta, although the extent transfer varies considerably.
The following parameters were considered as possible factors determining the extent of placental transfer: (i) the molecular weight of the drug; (ii) the pKa (pH at which the drug is 50% ionised); and (iii) the extent of drug binding to the plasma protein. Drugs with molecular weights greater than 500D have an incomplete transfer across the human placenta. Strongly dissociated acid drug molecules should have an incomplete transfer, but this does not seem to be an absolute rule. For example, ampicillin and methicillin transfer completely and they are strongly dissociated at physiological pH. The extent of drug binding to plasma protein does not influence the type of drug transfer across the human placenta.
Similar content being viewed by others
References
Anonymous. The Pharmaceutical Codex. 11th ed. London: The Pharmaceutical Press, 1979
Anonymous, The Merk Index. 10th ed. Rahway, NJ: Merk & Co. Inc, 1983
Goodman-Gilman A, Rall TW, Nies AS, et al. The pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1992
Mammen M. Clinical pharmacokinetics drug data handbook. 2nd ed. Auckland: Adis International Ltd., 1990
Melmon KL, Morelli HF, Hoffman BB, et al. Clinical pharmacology basic principles in therapeutics. 3rd ed. New York: McGraw-Hill Inc., 1992
Moffat AC, Jackson IV, Moss MO, et al. Clarke’s isolation and identification of drugs. 2nd ed. London: The Pharmaceutical Press, 1986
Reynolds EF. Martindale: the extra pharmacopoeia. 29th ed. London: The London Pharmaceutical Press, 1992
MacAulay MA, Abou-Sabe N, Charles D. Placental transfer of ampicillin. Am J Obstet Gynecol 1966; 96: 943–50
MacAulay MA, Molloy WB, Charles D. Placental transfer of methicillin. Am J Obstet Gynecol 1973; 115: 58–65
Waddell WJ, Marlowe C. Transfer of drugs across the placenta. Pharmacol Ther 1981; 14: 375–90
Apgar V, Papper EM. Transmission of drugs across the placenta. Anesth Analg 1952; 30: 309–20
Hagerman DD, Villee CA. Transport functions of the placenta. Physiol Rev 1960; 40: 313–30
Moya F, Thorndike V. Passage of drugs across the placenta. Am J Obstet Gynecol 1962; 84: 1778–98
Asling J, Way EL. Placental transfer of drugs. In: La Du BN, Mandel HG, Way EL, editors. Fundamentals of drug metabolism and drug disposition. Baltimore: The Williams and Wilkins Co, 1972: 88–105
Mellin GW. Drugs in the first trimester of pregnancy and the foetal life of homosapiens. Am J Obstet Gynecol 1964; 90: 1169–80
Karnofsky DA. Drugs as teratogens in animals and man. Ann Rev Pharm 1965; 5: 447–72
Done AK. Perinatal pharmacology. Ann Rev Pharmacol 1966; 6: 189–208
Ginsburg J. Placental drug transfer. Ann Rev Pharmacol 1971; 11: 387–408
Finster M, Mark LC. Placental transfer of drugs and their distribution in foetal tissues. In: Brodie BB, Gillette JR, Ackermann HS, editors. Handbuch der experimentellen pharmakologie. Berlin: Springer-Verlag, 1971; 28: 276–85
Krauer B, Krauer F, Hytten FE. Drug disposition and pharmacokinetics in the maternal-placental-foetal unit. Pharmacol Ther 1980; 10: 301–28
Mirkin BL. Perinatal pharmacology placental transfer, foetal localization and neonatal disposition of drugs. Anesthesiology 1975; 43: 156–70
Mirkin BL, Singh S. Placental transfer of pharmacologically active molecules. In: Mirkin BL, editor. Perinatal pharmacology and therapeutics, New York: Academic Press, 1976: 1–69
Beppu K. Transmission of the anesthetic agents through the placenta in painless delivery and their effects on newborn infants. Keio J Med 1968; 17: 81–107
Caton D. Obstetric anesthesia and concepts of placental transport a historical review of the nineteenth century. Anesthesiology 1977; 46: 132–7
Huter J, Meyer-Menk W, Huter S. Placental passage of anesthetics. J Perinat Med 1978; 6: 223–30
Marx GF. Placental transfer and drugs used in anesthesia. Anesthesiology 1961; 22: 294–313
Moya F, Smith BE. Uptake, distribution and placental transport of drugs and anesthetics. Clin Pharmacol Ther 1963; 4: 628–53
Moya F, Thorndike V. The effects of drugs used in labor on the foetus and newborn. Anesthesiology 1965; 26: 465–76
Nau H. Clinical pharmacokinetics in pregnancy and perinatology I: placental transfer and foetal side effects of local anaesthetic agents. Dev Pharmacol Ther 1985; 8: 149–81
Torri G. Passaggio transplacentare dei farmaci anestetici. Minerva Anestesiol 1978; 44: 871–6
Yurth DA. Placental transfer of local anesthetics. Clin Perinatol 1982; 9: 13–28
Nau H, Kuhnz W, Egger HJ, et al. Anticonvulsants during pregnancy and lactation. Clin Pharmacokinet 1982; 7: 508–43
Charles D. Placental transmission of antibiotics. J Obstet Gynaecol 1954; 61: 750–7
Witter FR. Clinical pharmacokinetics in the treatment of rheumatoid arthritis in pregnancy. Clin Pharmacokinet 1993; 25: 444–9
Adamsons K, Joelsson I. The effects of pharmacological agents upon the foetus and newborn. Am J Obstet Gynecol 1966; 96: 437–60
Hill RM, Stern L. Drugs in pregnancy: effects on the foetus and newborn. Drugs 1979; 17: 182–97
Mirkin BL. Effects of drugs on the foetus and neonate. J Appl Med 1970; 47: 91–5
Pomerance JJ, Yaffe SJ. Maternal medication and its effect on the foetus. Curr Probl Pediatr 1973; 4: 2–60
Rao JM, Arulappu R. Drug use in pregnancy: how to avoid problems. Drugs 1981; 22: 409–14
Shnider SM. Fetal and neonatal effects of drugs in obstetrics. Anesth Analg 1966; 45: 372–8
Day NL, Cottreau CN, Richardson GA. The epidemiology of alcohol, marijuana, and cocaine use among women of childbearing age and pregnant women. Clin Obstet Gynecol 1993; 36: 232–45
Szeto HH. Kinetics of drug transfer to the foetus. Clin Obstet Gynecol 1993; 36: 246–54
Glantz JC, Woods JR. Cocaine, heroin, phencyclidine: obstetric perspectives. Clin Obstet Gynecol 1993; 36: 279–301
Richardson GA, Day NL, Mcgauhey PJ. The impact of prenatal marijuana and cocaine use on the infant and child. Clin Obstet Gynecol 1993; 36: 302–18
Barcroft J. Research on perinatal life. Springfield, Illinois: Charles C Thomas, 1946
Aherne W, Dunnill MS. Morphometry of the human placenta. Br Med Bull 1966; 22: 5–8
Aherne W, Dunnill MS. Quantitative aspects of placental structure. J Pathol Bacteriol 1966; 91: 123–39
Ferreres L, Paz M, Martin G, et al. New studies on placental transfer of fosfomycin. Chemotherapy (Basel) 1977; 23 Suppl.: 175–9
Hay DM. Nitrous oxide transfer across the placenta and condition of the newborn at delivery. Br J Obstet Gynaecol 1978; 85: 299–302
Little WA. The significance of placental/fetal weight ratios. Am J Obstet Gynaecol 1960; 79: 134–7
Assali Jr NS, Douglass RA, Baird WM, et al. Measurement of uterine blood flow and uterine metabolism: IV. Results in normal pregnancy. Am J Obstet Gynecol 1953; 66: 248–53
Metcalfe J, Rommey SL, Ramsey LH, et al. Estimation of uterine blood flow in normal pregnancy at term. J Clin Invest 1955; 34: 1632–8
Rowland M, Tozer TN. Clinical pharmacokinetics concepts and applications. Philadelphia: Lea & Febiger, 1980: 35
Dawes GS, A theoretical analysis of fetal drug equilibration. In: Boreus LO, editor. Fetal pharmacology. New York: Raven Press, 1973: 381–99
Goldstein A, Aronow L, Kalman SM. Principles of drug action. The basis of pharmacology. New York: John Wiley & Sons, 1974: 205–10
Moore WMO, Hellegers AE, Battaglia FC. In vitro permeability of different layers of human placenta to carbohydrates and urea. Am J Obstet Gynecol 1966; 96: 951–5
Faber JJ, Hart FM. Transfer of charged and uncharged particles in the placenta of the rabbit. Am J Physiol 1967; 213: 890–4
Pacifici GM, Viani A. Methods of determining plasma and tissue binding of drugs. Clin Pharmacokinet 1992; 23: 449–68
Metcalfe J. Placental gas transfer. Anesthesiology 1965; 26: 460–4
Metcalfe J, Moll W, Bartels H. Gas exchange across the placenta. Fed Proc 1964; 23: 774–80
Folkart GR, Dancis J, Monye WL. Transfer of carbohydrates across guinea pig placenta. Am J Obstet Gynecol 1960; 80: 221–3
Seeds AE. Placental transfer. In: Barnes AC, editor. Intrauterine development. Philadelphia: Lea & Febiger, 1968: 103–28
Page EW, Glendening MB, Margolis AJ, et al. Transfer of D-and L-histidine across the human placenta. Am J Obstet Gynecol 1957; 73: 589–97
Abouleish Jr E, Wingard LB, de la Vega S, et al. Pancuronium in caesarean section and its placental transfer. Br J Anaesth 1980; 52: 531–6
Nau H, Welsch F, Ulbrich B, et al. Thiamphenicol during the first trimester of human pregnancy placental transfer in vivo, placental uptake in vitro and inhibition of mitochondrial function. Toxicol Appl Pharmacol 1981; 60: 131–41
Clark SL. The ingestion of proteins and colloid materials by columnar absorptive cells of the small intestine in suckling rats and mice. J Bioph Biochem Cyt 1959; 3: 41–50
Boyd JD, Hamilton WL. The human placenta. Cambridge: W Heffer & Sons Ltd, 1970
Muir AR. On the phagocytosis of iron-dextran by the human plasmoditrophoblast. J Obstet Gynecol 1966; 73: 966–72
Dempsey EW, Luse SA. Regional specializations in the syncytial trophoblast of early human placenta. J Anat 1971; 108: 545–61
Amoroso EC. The functional role of the placenta. In: Flexner LB, editor. Transaction of the first conference on gestation. New York: Josiach Jr Macy Foundation, 1955
Wislocki GB. The functional role of the placenta. In: Flexner LB, editor. Transaction of the first conference on gestation. New York: Josiach Jr Macy Foundation, 1955
Widdas WF. Transport mechanism in the fetus. Br Med Bull 1961; 17: 107–11
Brown CEL, Christmas JT, Bawdon RE. Placental transfer of cefazolin and piperacillin in pregnancies remote from term complicated by Rh-isoimmunization. Am J Obstet Gynecol 1990; 163: 938–43
Moise Jr KJ, Ou C-N, Kirshon B, et al. Placental transfer of indomethacin in the human pregnancy. Am J Obstet Gynecol 1990; 162: 549–54
Pons JC, Taburet AM, Singlas E, et al. Placental passage of azathiothymidine (AZT) during the second trimester of pregnancy study by direct fetal blood sampling under ultrasound. Eur J Obstet Gynecol Reprod Biol 1991; 40: 229–31
Monfort JA, Diamond I, MacGregor A, et al. Maternal and foetal blood levels after administration of oxytetracycline. NY J Med 1963; 26: 263–6
Martinez G, Snyder RD. Transplacental passage of primidone. Neurology 1973; 23: 381–3
Gillet JY, Garraffo R, Abrar D, et al. Fetoplacental passage of zidovudine. Lancet 1989; 2: 269–70
Cartwright DP, Dann WL, Hutchinson A. Placental transfer of alfentanil at caesarean section. Eur J Anaesthesiol 1989; 16: 103–10
Fox GS, Houle GL. Transmission of lidocaine hydrochloride across the placenta during caesarian section. Can Anaesthesiol Soc J 1969; 16: 135–43
Melchior JC, Svensmark O, Trolle D. Placental transfer of phenobarbitone in epileptic women, and elimination in newborns. Lancet 1967; 2: 860–1
Fujimoto S, Tanaka T, Akahane M. Levels of ritodrine hydrochloride in fetal blood and amniotic fluid following long term continuous administration in late pregnancy. Eur J Obstet Gynecol Reprod Biol 1990; 38: 15–8
Hirsch HA, Herbst S, Lang R, et al. A transfer of a new cephalosporin antibiotic to the foetus and the amniotic fluid during a continuous infusion (steady state) and a single repeated intravenous injections to the mother. Arch Gynak 1974; 216: 1–14
Bakke OM, Haram K, Lygre T, et al. Comparison of the placental transfer of thiopental and diazepam in cesarean section. Eur J Clin Pharmacol 1981; 21: 221–7
Moreland TA, Brice JEH, Mohamdee O, et al. The influence of dose-delivery time interval on neonatal plasma pethidine levels. Acta Obstet Gynecol Scand 1983; 62: 549–53
Bergogne-Berenzin E, Lambert-Zechovsky N, Rouvillois JL. Etude du passage transplacentaire des beta-lactamines. J Gynecol Obstet Biol Reprod (Paris) 1979; 8: 359–64
Kraybill NE, Chaney NE, McCarthy LR. Transplacental ampicillin inhibitory concentrations in neonatal serum. Am J Obstet Gynecol 1980; 138: 793–6
Blecher TE, Edga WM, Melville HAH, et al. Transplacental passage of ampicillin. BMJ 1966; 1: 137–9
Stewart KS, Shafi M, Andrews J, et al. Distribution of parenteral ampicillin and cephalosporins in late pregnancy. J Obstet Gynaecol 1973; 80: 902–8
Jordheim O, Hagen AG. Study of ampicillin levels in maternal serum, umbilical cord serum and amniotic fluid following administration of pivampicillin. Acta Obstet Gynecol Scand 1980; 59: 315–7
Williams JD, Felton DJC. The passage of ampicillin into the liquor amnii and the foetal circulation. J Obstet Gynaecol 1966; 73: 654–7
Fisha AM, Smith MR. The prophylactic use of ampicillin and its trans-placental passage after amniotomy. J Obstet Gynaecol 1967; 74: 855–61
Kafetzis DA, Brater DC, Fanourgakis JE. Materno-foetal transfer of azlocillin. J Antimicrob Chemother 1983; 12: 157–62
MacAulay MA, Berg SR, Charles D. Placental transfer of dicloxacillin at term. Am J Obstet Gynecol 1968; 102: 1162–8
Depp R, Kind AC, Kirby WMM, et al. Transplacental passage of methicillin and dicloxacillin into the foetus and amniotic fluid. Am J Obstet Gynecol 1970; 107: 1054–7
Miyakawa I, Taniyama K, Inoue H, et al. Placental transfer of disodium sulbenicillin. Antimicrob Agents Chemother 1982; 21: 838–9
Bergogne-Berenzin E, Bryskier A, Berthelot G, et al. Placental transfer of cefmenoxime in late pregnancy. Chemotherapy (Basel) 1985; 31: 1–5
Pierre J, Bergogne-Berezin E, Ravina J, et al. Etude du passage transplacentaire du cefotaxime. Nou Press Med 1981; 10: 587–9
Dubois M, Delapierre D, Chanteux L, et al. A study of the transplacental transfer and the mammary excretion of cefoxitin in humans. J Clin Pharmacol 1981; 21: 477–83
Bergogne-Berenzin E, Pierre J, Rouvillois JL, et al. Placental transfer of cefuroxime. Curr Chemother Infect Dis, Proceedings of the 11th ICC and 19th ICAAC, Boston, 1980: 1168–9
Craft I, Mullinger BM, Kennedy MRK. Placental transfer of cefuroxime. Br J Obstet Gynaecol 1981; 88: 141–5
Gagliardi L, Xerri L. Cefuroxim passaggio transplacentare e concentrazioni nell’utero e annessi. Ann Ostetri Gineco Medi Perina 1980; 101: 235–43
De Leeuw JW, Roumen FJME, Bouckaert PXJM, et al. Achievement of therapeutic concentrations of cefuroxime in early preterm gestation with premature rupture of the membranes. Obstet Gynecol 1993; 81: 225–60
Holt DE, Fisk NM, Spencer JAD, et al. Transplacental transfer of cefuroxime in uncomplicated pregnancies and those complicated by hydrops or changes in amniotic fluid volume. Arch Dis Child 1993; 68: 54–7
Barr W, Graham RM. Placental transmission of cephaloridine. J Obstet Gynaecol 1967; 74: 739–45
Arthur LJH, Burland WL. Transfer of cephaloridine from mother to foetus. Arch Dis Child 1969; 44: 82–3
Prakash A, Chalmers JA, Onojobi OI, et al. Transfer of limecycline and cephaloridine from mother to foetus: a comparative study. J Obstet Gynaecol 1970; 77: 247–52
Sheng KT, Huang N, Promadhattavedi V. Serum concentrations of cephalothin in infants and children and placental transmission of the antibiotic. Antimicrob Agents Chemother 1964; 4: 200–6
Corson SL, Bolognese RJ. The behavior of cephalothin in amniotic fluid. J Reprod Med 1970; 4: 59–62
Paterson L, Henderson A, Lunan CB, et al. Transfer of cephalothin sodium to the foetus. J Obstet Gynaecol 1970; 77: 565–6
Bernard B, Abate M, Thielen PF, et al. Maternal-foetal pharmacological activity of amikacin. J Infect Dis 1977; 135: 925–32
Santi F, Figini E. Studio del passaggio transplacentare di amminosidina. Ann Ostet Ginecol Med Perin 1975; 116: 387–94
Yoshioka H, Monma T, Matsuda S. Placental transfer of gentamicin. Pediatr Pharmacol 1972; 80: 121–3
Kauffman RE, Morris JA, Azarnoff DL. Placental transfer and foetal urinary excretion of gentamicin during constant rate maternal infusion. Pediatr Res 1975; 9: 104–7
Good RG, Johnson GH. The placental transfer of kanamycin during late pregnancy. Obstet Gynecol 1971; 38: 60–2
Woltz JHE, Wiley MM. Transmission of streptomycin from maternal blood to the foetal circulation and the amniotic fluid. Proc Soc Exp Biol Med 1945; 60: 106–7
Pompa PAP. The transfer of clomocycline (Megaclor) across the human placenta. Clin Trials J 1969; 6: 211–6
Leblanc AL, Perry JE. Transfer of tetracycline across the human placenta. Tex Reports Biol Med 1967; 25: 541–5
Decio R, Alamanni V. Sul passaggio transplacentare del cloroamfenicolo somministrato alla madre per via orale. Riv Ostet Ginecol 1955; 96(10): 748–54
MacAulay MA, Charles D. Placental transmission of colistimethate. Clin Pharmacol Ther 1967; 8: 578–86
Rubin A, Dvornik D. Placental transfer of griseofulvin. Am J Obstet Gynecol 1965; 92: 882–5
Mainardi L, Sacchetti G. Osservazioni sul passaggio transplacentare delle rifamicine. Ann Ostet Ginecol 1966; 88: 27–32
Khan AK, Truelove SC. Placental and mammary transfer of sulphasalazine. BMJ 1979; 2: 1553–4
Bourget P, Fernandez H, Delouis C, et al. Transplacental passage of vancomycin during the second trimester of pregnancy. Obstet Gynecol 1991; 78: 908–11
Frenkel LM, Brown ZA, Bryson YJ, et al. Pharmacokinetics of acyclovir in the term human pregnancy and neonate. Am J Obstet Gynecol 1991; 164: 569–76
Chavanet P, Qiquet B, Waldner A, et al. Perinatal pharmacokinetics of zidovudine. N Engl J Med 1989; 321: 1548–9
Lyman WD, Tanaka KE, Kress Y, et al. Zidovudine concentrations in human fetal tissues implications for perinatal AIDS. Lancet 1990; 1: 1280–1
Lopez-Anaya A, Unadkat JD, Schumann LA, et al. Pharmacokinetics of zidovudine (Azidothymidine): I transplacental transfer. J Acquir Immune Defic Syndr 1990; 3: 959–64
Roboz J, Gleicher N, Wu K, et al. Does doxorubicin cross the placenta? Lancet 1979; 2: 1382–3
Karp GI, von Oeyen P, Valone F, et al. Doxorubicin in pregnancy: possible transplacental passage. Cancer Treat Rep 1983; 67: 773–7
D’Incalci M, Broggini M, Buscaglia M, et al. Transplacental passage of doxorubicin. Lancet 1983; 1: 75
D’Incalci M, Sessa C, Colombo N, et al. Transplacental passage of cyclophosphamide. Cancer Treat Rep 1982; 66: 1681–2
Siker ES, Wolfson B, Dubnansky J, et al. Placental transfer of methoxyflurane. Br J Anaesth 1968; 40: 588–92
Gepts E, Heytens L, Camu F. Pharmacokinetics and placental transfer of alfentanil in parturient women. Anesth Analg 1986; 65: 1155–60
Little B, Chang T, Chucot L, et al. Study of ketamine as an obstetric anesthetic agent. Am J Obstet Gynecol 1972; 113: 247–69
Ellingson A, Haram K, Sagen N, et al. Transplacental passage of ketamine after intravenous administration. Acta Anaesthesiol Scand 1977; 21: 41–4
Fealy J. Placental transmission of pentobarbital sodium. Obstet Gynecol 1958; 11: 342–9
Dailland P, Cockshott ID, Lirzin JD, et al. Intravenous propofol during cesarean section placental transfer, concentrations in breast milk, and neonatology effect: a preliminary study. Anesthesiology 1989; 71: 827–34
Gin T, Yau G, Chan K, et al. Disposition of propofol infusions for caesarean section. Can J Anaesth 1991; 38: 31–6
Root B, Eichner E, Sunshine I. Blood secobarbital levels and their clinical correlation in mothers and newborn infants. Am J Obstet Gynecol 1961; 81: 948–56
Kosaka Y, Takahashi T, Mark LC. Intravenous thiobarbiturate anesthesia for cesarean section. Anesthesiology 1969; 31: 489–506
Crawford JS. Some aspects of obstetric anaesthesia. Br J Anaesth 1956; 28: 146–58
McKechnie FB, Converse JG. Placental transmission of thiopental. Am J Obstet Gynecol 1955; 70: 639–44
Finster M, Morishima HO, Lester CM, et al. Tissue thiopental concentrations in the fetus and newborn. Anesthesiology 1972; 36: 155–8
McGuinness A, Merkow AJ, Kennedy RL, et al. Epidural anesthesia with bupivacaine for cesarean section: neonatal blood levels and neurobehavioral responses. Anesthesiology 1978; 49: 270–3
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
Beazley JM, Taylor G, Reynolds F. Placental transfer of bupivacaine after paracervical block. Obstet Gynecol 1972; 39: 2–6
Hyman MD, Shnider SM. Maternal and neonatal blood concentrations of bupivacaine associated with obstetrical conduction anesthesia. Anesthesiology 1971; 34: 81–6
Thomas J, Long G, Moore G, et al. Plasma protein binding and placental transfer of bupivacaine. Clin Pharmacol Ther 1976; 19: 426–34
Morgan DJ, Cousins MJ, McQuillan D, et al. Disposition and placental transfer of etidocaine in pregnancy. Eur J Clin Pharmacol 1977; 12: 359–65
Shnider SM, Way EL. Plasma levels of lidocaine (xylocaine) in mother and newborn following obstetrical conduction. Anesthesiology 1968; 29: 951–8
Epstein BS, Banerjee SG, Coakley CS. Passage of lidocaine and prilocaine across the placenta. Anesth Analg 1968; 47: 223–7
Shnider SM, Way EL. The kinetics of transfer of lidocaine (xylocaine) across the human placenta. Anesthesiology 1968; 29: 944–50
Brown WU, Bell GC, Lurie AO, et al. Newborn blood levels of lidocaine and mepivacaine in the first postnatal day following maternal epidural anesthesia. Anesthesiology 1975; 42: 698–707
Finster M, Morishima HO, Boyes RN, et al. Placental transfer of lidocaine and its uptake by the fetal tissues. Anesthesiology 1972; 36: 159–63
Houle GL, Fox GS, Torkington MG. Transmission of carbonated lidocaine across the placenta during caesarean section. Can Anaesthesiol Soc J 1971; 18: 505–11
Petrie RH, Paul WL, Miller FC, et al. Placental transfer of lidocaine following paracervical block. Am J Obstet Gynecol 1974; 120: 791–801
Thomas J, Climie CR, Long LE. The influence of adrenaline on the maternal plasma levels and placental transfer of lignocaine following lumbar epidural administration. Br J Anaesth 1969; 41: 1029–34
Lurie AO, Weiss JB. Blood concentration of mepivacaine and lidocaine in mother and baby after epidural anesthesia. Am J Obstet Gynecol 1970; 106: 850–6
Morishima HO, Daniel SS, Finster M, et al. Transmission of mepivacaine hydrochloride (carbocaine) across the human placenta. Anesthesiology 1966; 27: 147–54
Asling JH, Shnider SM, Margolis AJ, et al. Paracervical block anesthesia in obstetrics. Am J Obstet Gynecol 1970; 107: 626–34
Gordon HR. Foetal bradycardia after paracervical block. N Engl J Med 1968; 279: 910–4
Teramo K, Rajamaki A. Foetal and maternal plasma levels of mepivacaine and foetal acid-base balance and heart rate after paracervical block during labour. Br J Anaesth 1971; 43: 300–11
Gerdin E, Rane A, Lindberg B. Transplacental transfer of morphine in man. J Perinat Med 1990; 18: 305–12
Duncan SLB, Ginsburg J, Morris NF. Comparison of pentazocine and pethidine in normal labor. Am J Obstet Gynecol 1969; 105: 197–202
Naga RMA, Narayanan JTR. Placental transfer of paracetamol. J Indian Med Assoc 1989; 87: 182–3
Kuhnert BR, Kuhnert PM, Tu AL, et al. Meperidine and normeperidine levels following meperidine administration during labor. Am J Obstet Gynecol 1979; 133: 909–14
Crawford JS, Rudofsky S. The placental transmission of pethidine. Br J Anaesth 1965; 37: 929–33
Morselli PL, Rovei V. Placental transfer of pethidine and norpethidine and their pharmacokinetics in the newborn. Eur J Clin Pharmacol 1980; 18: 25–30
Moore J, McNabb TG, Glynn JP. The placental transfer of pentazocine and pethidine. Br J Anaesth 1973; 45 Suppl.: 798–805
Poppers PJ, Finster M. The use of prilocaine hydrochloride (citanest) for epidural analgesia in obstetrics. Anesthesiology 1968; 29: 1134–8
Usubiaga J, La Iuppa M, Moya F, et al. Passage of procaine hydrochloride and para-aminobenzoic acid across the human placenta. Am J Obstet Gynecol 1968; 100: 918–23
Turner G, Collins E. Foetal effects of regular salicylate ingestion in pregnancy. Lancet 1975; 2: 338–9
Elis J, Sechserova M, Stribnry J, et al. The distribution of sodium salicylate in the human foetus. Int J Clin Pharmacol 1978; 16: 365–7
Garrettson LK, Procknal JA, Levy G. Foetal acquisition and neonatal elimination of a large amount of salicylate. Clin Pharmacol Ther 1975; 17: 98–103
Levy G, Garrettson LK. Kinetics of salicylate elimination by newborn infants of mothers who ingested aspirin before delivery. Pediatrics 1974; 53: 201–10
Pynnonen S, Kanto J, Sillanpaa M, et al. Carbamazepine: placental transport, tissue concentrations in foetus and newborn, and level in milk. Acta Pharmacol Toxicol 1977; 41: 244–53
Rane A, Bertilsson L, Palmer L. Disposition of placentally transferred carbamazepine (tegretol) in the newborn. Eur J Clin Pharmacol 1975; 8: 283–4
Nau H, Rating D, Hauser I, et al. Placental transfer and pharmacokinetics of primidone and its metabolites phenobarbital, PEMA, hydroxyphenobarbital in neonates and infants of epileptic mothers. Eur J Clin Pharmacol 1980; 18: 31–42
Ishizaki T, Yokochi K, Chiba K, et al. Placental transfer of anticonvulsants (phenobarbital, phenytoin and valproic acid) and the elimination from neonates. Pediatr Pharmacol 1981; 1: 291–303
Mirkin BL. Placental transfer and neonatal elimination of diphenylhydantoin. Am J Obstet Gynecol 1971; 109: 930–3
Mirkin BL. Diphenylhydantoin placental transport, foetal localization and neonatal metabolism: possible teratogenic effects. J Pediatr 1971; 78: 329–37
Dickinson GR, Harland RC, Lynn RK, et al. Transmission of valproic acid (depakene) across the placenta: half-life of the drug in mother and baby. J Pediatr 1979; 94: 832–5
Nau H, Rating D, Koch S, et al. Valproic acid and its metabolites placental transfer, neonatal pharmacokinetics and transfer via mother’s milk: clinical status in neonates of epileptic mothers. J Pharmacol Exp Ther 1981; 219: 768–77
Kaneko S, Otani K, Fukushima Y, et al. Transplacental passage, half-life of sodium valproate in infants born to epileptic mothers. Br J Clin Pharmacol 1983; 15: 503–6
de Silva JAF, D’Arconte L, Kaplan J. The determination of blood levels and the placental transfer of diazepam in humans. Curr Ther Res 1964; 6: 115–20
Cavanagh D, Condo CS. Diazepam: a pilot study of drug concentrations in maternal blood, amniotic fluid and cord blood. Curr Ther Res 1964; 6: 122–6
Cree JE, Meyer J, Hailey DM. Diazepam in labour: its metabolism, effect on clinical condition and thermogenesis of newborn. BMJ 1973; 4: 251–5
Gamble JAS, Moore J, Lamki H, et al. A study of plasma diazepam levels in mother and infant. Br J Obstet Gynaecol 1977; 84: 588–91
Kanto J, Erkkola R, Sellman R. Accumulation of diazepam, N-demethyldiazepam in the foetal blood during the labour. Ann Clin Res 1973; 5: 375–9
Mandelli M, Morselli PL, Nordio S, et al. Placental transfer of diazepam: its disposition in the newborn. Clin Pharmacol Ther 1975; 17: 564–72
Scher J, Haley DM, Beard RW. The effects of diazepam on the foetus. J Obstet Gynaecol 1972; 79: 635–8
Shannon RW, Fraser GP, Aitken RG, et al. Diazepam in pre-eclamptic toxaemia with special reference to its effect on the newborn infant. Br J Clin Pract 1972; 26: 271–5
Haram K, Sagen N, Brandt RD. Transplacental passage of diazepam following intravenous injection immediately prior to operative vaginal delivery. Int J Gynaecol Obstet 1976; 14: 545–9
Haram K, Bakke OM, Johannessen KH, et al. Transplacental passage of diazepam during labor: influence of uterine contractions. Clin Pharmacol Ther 1978; 24: 590–9
Haram K, Bakke OM, Sandvei R, et al. Foetal drug exposure following intravenous injection of diazepam immediately before breech delivery. Ann Chir Gynaecol 1979; 68: 104–8
Bakke OM, Haram K. Time-course of transplacental passage of diazepam influence of injection-delivery interval on neonatal drug concentrations. Clin Pharmacokinet 1982; 7: 353–62
Haram K, Bakke OM. Diazepam as an induction agent for cesarean section: a clinical, pharmacokinetic study of foetal drug exposure. Br J Obstet Gynaecol 1980; 87: 506–12
Idanpaan-Heikkila JE, Jouppila PI, Puolakka JO, et al. Placental transfer and foetal metabolism of diazepam in early human pregnancy. Am J Obstet Gynecol 1971; 109: 1011–6
Erkkola R, Kanto J, Sellman R. Diazepam in early human pregnancy. Acta Obstet Gynecol Scand 1974; 5: 135–8
Lean TH, Ratnam SS, Sivasamboo R. The use of chlordiazepoxide in patients with severe pregnancy toxaemia. J Obstet Gynaecol 1968; 75: 853–5
Kangas L, Kanto J, Erkkola R. Transfer of nitrazepam across the human placenta. Eur J Clin Pharmacol 1977; 12: 355–7
McBridge RJ, Dundee JW, Moore J, et al. A study of the plasma concentrations of lorazepam in mother and neonate. Br J Anaesth 1979; 51: 971–8
Kangas L, Erkkola R, Kanto J, et al. Transfer of free, conjugated oxazepam across the human placenta. Eur J Clin Pharmacol 1980; 17: 301–4
Tomson G, Lunell NO, Sundwall A, et al. Placental passage of oxazepam: its metabolism in mother and newborns. Clin Pharmacol Ther 1979; 25: 74–81
Kanto J, Sjovall S, Erkkola R, et al. Placental transfer and maternal midazolam kinetics. Clin Pharmacol Ther 1983; 33: 786–91
Rey E, Giraux P, d’Athis P, et al. Pharmacokinetics of the placental transfer and distribution of clorazepate and its metabolite nordiazepam in the feto-placental unit and neonate. Eur J Clin Pharmacol 1979; 15: 181–5
Pacifici GM, Cuoci L, Guarnieri M, et al. Placental transfer of pinazepam and its metabolite N-desmethyldiazepam in women at term. Eur J Clin Pharmacol 1984; 27: 307–10
Sjoqvist F, Bergfors PG, Borga O, et al. Plasma disappearance of nortriptyline in a newborn infant following placental transfer from an intoxicated mother: evidence for drug metabolism. Br J Clin Pharmacol 1972; 80: 496–500
Crawford JS, Rudofsky S. The mode of administration of promazine as a factor in determining the extent of placental transmission. Br J Anaesth 1965; 37: 310–3
Boutroy MJ, Bianchetti G, Dubruc C, et al. Placental transfer, pharmacokinetics of acebutolol in pregnant women and their newborn. 1st European Congress of Biopharmaceutics, Pharmacokinetics: 1981 April 1–3, France: Clermont Ferrand, 1981: 315–20
Bianchetti G, Boutroy MG, Dubruc C, et al. Placental transfer and pharmacokinetics of acebutolol and N-acetyl acebutolol in the newborn. Br J Pharmacol 1981; 72: 135–6
Melander A, Niklasson B, Ingemarsson I. Transplacental passage of atenolol in man. Eur J Clin Pharmacol 1978; 14: 93–4
Morselli PL, Boutroy MJ, Bianchetti G, et al. Placental transfer and perinatal pharmacokinetics of betaxolol. Eur J Clin Pharmacol 1990; 38: 477–83
Boutroy MJ, Morselli PL, Bianchetti G, et al. Betaxolol a pilot study of its pharmacological and therapeutic properties in pregnancy. Eur J Clin Pharmacol 1990; 38: 1–5
Kofahl B, Henke D, Hettenbach A, et al. Studies on placental transfer of celiprolol. Eur J Clin Pharmacol 1993; 44: 381–2
Boutroy MJ, Gisonna CR, Legagneur M. Clonidine placental transfer and neonatal adaption. Early Hum Dev 1988; 17: 275–86
Lunell NO, Bondenson U, Grunewald C, et al. Transplacental passage of isradipine in the treatment of pregnancy-induced hypertension. Am J Hypertens 1993; 6: 1105–15
Jones H, Cummings AJ. A study of the transfer of alpha-methyldopa to the human foetus and newborn infant. Br J Clin Pharmacol 1978; 6: 432–4
Jones H, Cummings AJ, Setchell KDR, et al. Study of the disposition of alpha-methyldopa in newborn infants following its administration to the mother for the treatment of hypertension during pregnancy. Br J Clin Pharmacol 1979; 8: 433–40
Cappiello M, Giuliani L, Rane A, et al. Dopamine sulphotransferase is better developed than p-nitrophenol sulphotransferase in the human fetus. Dev Pharmacol Ther 1993; 16: 83–8
Bourget P, Fernandez H, Ribou F, et al. Weak transplacental passage of prazosin (Alpress) during the third trimester of pregnancy. Gynecol Obstet Biol Reprod 1993; 22: 871–4
Erkkola R, Lammintausta R, Liukko P, et al. Transfer of propranolol and sotalol across the human placenta. Acta Obstet Gynecol Scand 1982; 61: 31–4
Smith MT, Livingstone I, Eadie MJ, et al. Metabolism of propranolol in the human maternal-placental-foetal unit. Eur J Clin Pharmacol 1983; 24: 727–32
Mulley BA, Parr GD, Pau WK, et al. Placental transfer of chlorthalidone and its elimination in maternal milk. Eur J Clin Pharmacol 1978; 13: 129–31
Nau H, Steldinger R, Ivan E. Placental transfer of etozolin and ozolinone during the first half of gestation in man. Eur J Clin Pharmacol 1982; 23: 253–60
Beermann B, Groschinsky-Grind M, Fahraeus L, et al. Placental transfer of furosemide. Clin Pharmacol Ther 1978; 24: 560–2
Beermann B, Fahraeus L, Groschinsky-Grind M, et al. Placental transfer of hydrochlorothiazide. Gynecol Obstet Invest 1980; 11: 45–8
Thomas J, Climie CR, Mather LE. The placental transfer of alcuronium. Br J Anaesth 1969; 41: 297–302
Flynn PJ, Frank M, Hughes R. Use of atracurium in caesarean section. Br J Anaesth 1984; 56: 599–605
Morison DH. Placental transfer of dantrolene. Anesthesiology 1983; 59: 265
Kivalo I, Saarikoski S. Placental transfer of 14C-dimethyltubocurarine during cesarean section. Br J Anaesth 1976; 48: 239–42
Kivalo I, Saarikoski S. Placental transmission and foetal uptake of 14C-dimethyltubocurarine. Br J Anaesth 1972; 44: 557–61
Bertrand JC, Duvaldestin P, Henzel D, et al. Quantitative assessment of placental transfer of fazadinium in obstetric anaesthesia. Acta Anaesthesiol Scand 1980; 24: 135–7
Rainaldi MP, Busi T, Melloni C, et al. Pharmacokinetics, placental transmission of fazadinium in elective cesarean sections. Acta Anaesthesiol Scand 1984; 28: 222–5
Duvaldestin P, Demetriou M, Henzel D, et al. The placental transfer of pancuronium and its pharmacokinetics during cesarian section. Acta Anaesthesiol Scand 1978; 22: 327–33
Dailey PA, Fisher DM, Shnider SM, et al. Pharmacokinetics, placental transfer and neonatal effects of vecuronium and pancuronium administered during caesarean section. Anesthesiology 1984; 60: 569–74
Moya F, Kvisselgaard N. The placental transmission of succinylcholine. J Am Soc Anesthesiol 1961; 22: 1–6
Drabkova J, Crul JF, Van der Kleun E. Placental transfer of l4C-labelled succinylcholine in near-term Macaca mulatta Monkeys. Br J Anaesth 1973; 45: 1087–96
Cherala SR, Eddie DN, Sechezer PH. Placental transfer of succinylcholine causing transient respiratory depression in the newborn. Anaesth Intensive Care 1989; 17: 202–4
Older PO, Harris JM. Placental transfer of tubocurarine. Br J Anaesth 1968; 40: 459–63
Demetriou M, Depoix J-P, Diakite M, et al. Placental transfer of ORG NC45 in women undergoing caesarean section. Br J Anaesth 1982; 54: 643–5
Chan V, Tse TF, Wong V. Transfer of digoxin across the placenta and into breast milk. Br J Obstet Gynaecol 1978; 85: 605–9
Padeletti L, Porciani MC, Scimone G. Placental transfer of digoxin (beta-methyl-digoxin) in man. Int J Clin Pharmacol Biopharm 1979; 17: 82–3
Younis JS, Granat M. Insufficient transplacental digoxin transfer in severe hydrops foetalis. Am J Obstet Gynecol 1987; 157: 1268–9
Saarikoski S. Placental transfer and foetal uptake of a 3H-digoxin in humans. Br J Obstet Gynaecol 1976; 83: 879–84
Allonen H, Kanto J, Iisalo E. The foeto-maternal distribution of digoxin in early human pregnancy. Acta Pharmacol Toxicol 1976; 39: 477–80
Okita GT, Plotz EJ, Davis ME. Placental transfer of radioactive digitoxin in pregnant women and its foetal distribution. Circ Res 1956; 4: 376–80
Howe JP, McGowan WAW, Moore J, et al. The placental transfer of cimetidine. Anaesthesia 1981; 36: 371–5
Qvist N, Storm K, Holmskov A. Cimetidine as pre-anesthetic agent for cesarean section: perinatal effects on the infant and the placental transfer of cimetidine and its elimination in the infants. J Perinat Med 1985; 13: 179–83
Bylsma-Howell M, Riggs KW, McMorland GH, et al. Placental transport of metoclopramide assessment of maternal effects. Can Anaesthes Soc J 1983; 30: 487–92
Fujimoto S, Akahane M, Tanaka T, et al. Pharmacokinetics and maternal-fetal influence of ritodrine hydrochloride during the continuous treatment of threatened premature labor. Nippon Sanfujinka Gakkai Zasshi 1989; 41: 321–7
van Lierde M, Thomas K. Ritodrine concentrations in maternal and foetal serum and amniotic fluid. J Perinat Med 1982; 10: 119–24
Nandakumaran M, Gardey C, Rey E, et al. Transfer of ritodrine and norepinephrine in human placenta: in vivo study. Dev Pharmacol Ther 1982; 4: 71–80
Bergman B, Bokstrom H, Borga O, et al. Transfer of terbutaline across the human placenta in late pregnancy. Eur J Respir Dis 1984; 134: 81–6
Ingermasson I, Westgren M, Lindberg C, et al. Single injection of terbutaline in term labor: placental transfer and effects on maternal and foetal carbohydrate metabolism. Am J Obstet Gynecol 1981; 139: 697–701
Ron M, Hochner-Celnikier D, Menezel J, et al. Maternal-foetal transfer of aminophylline. Acta Obstet Gynecol Scand 1984; 63: 217–8
Arwood LL, Dasta JF, Friedman C. Placental transfer of theophylline: two case reports. Pediatrics 1979; 63: 844–6
Plomp TA, Vulsma T, de Vijder JJM. Use of amiodarone during pregnancy. Eur J Obstet Gynecol Reprod Biol 1992; 43: 201–7
Onnen I, Barrier G, d’Athis P, et al. Placental transfer of atropine at the end of pregnancy. Eur J Clin Pharmacol 1979; 15: 443–6
Kanto J, Virtanen R, Iisalo E, et al. Placental transfer and pharmacokinetics of atropine after a single maternal intravenous and intramuscular administration. Acta Anaesthesiol Scand 1981; 25: 85–8
Kivalo I, Saarikoski S. Quantitative measurements of placental transfer and distribution of radioactive atropine in human fetus. Ann Chir Gynaecol Fenniaie 1970; 59: 80–4
Petersen MC, Nation LR, Ashley JJ, et al. The placental transfer of betamethasone. Eur J Clin Pharmacol 1980; 18: 245–7
Blackard C, Tennes K. Human placental transfer of cannabinoids. N Engl J Med 1984; 311: 797
Saidi P, Hoag MS, Aggeler PM. Transplacental transfer of bishydroxycoumarin in the human. JAMA 1965; 191: 761–3
Landon MJ, Eyre DH, Hytten FE. Transfer of folate to the foetus. Br J Obstet Gynaecol 1975; 82: 12–9
Sandler M, Ruthven CR, Contractor SF, et al. Transition of noradrenaline across the human placenta. Nature 1963; 197: 598
Myant NB. Passage of thyroxine, tri-iodo-thyronine from mother to foetus in pregnant women. Clin Sci 1958; 17: 75–9
Briggs GG, Freeman RK, Yaffe SY, editors. Drugs in pregnancy and lactation. 3rd ed. Baltimore: Williams & Wilkins, 1994
O’Hanley PD, Tarn JY, Holodniy M. Infectious disorders. In: Melmon KL, Morelli KF, Hoffman BB, et al., editors. Clinical pharmacology basic principles in therapeutics. New York: McGraw-Hill Inc, 1992
Rothman KJ, Fyler DC, Goldblatt A, et al. Exogenous hormones, other drug exposures of children with congenital heart failure. Am J Epidemiol 1979; 109: 433–9
Jones HC. Intrauterine ototoxicity: a case report and review of the literature. J Natl Med Assoc 1973; 65: 201–3
Nishimura H, Tanimura T. Clinical aspects of the teratogenicity of drugs. Amsterdam: Excerta Medica, 1976: 131
Heinonen O, Slone D, Shapiro S. Birth defects and drugs in pregnancy. Littleton, MA.: Publishing Sciences, 1977
Teviotdale BM. Vecuronium-thiopentone induction for emergency caesarean section under general anaesthesia. Anaesth Intensive Care 1993; 21: 288–91
Hillman LS, Hillman RE, Dodson WE. Diagnosis, treatment and follow-up of neonatal mepivacaine intoxication secondary to paracervical and pudendal blocks during labor. J Pediatr 1979; 95: 472–7
Ralston DH, Shnider SM. The fetal and neonatal effects of regional anesthesia in obstetrics. Anesthesiology 1978; 48: 34–64
Blankebaker WL, DiFazio CA, Berry FA. Lidocaine and its metabolism in the newborn. Anesthesiology 1975; 42: 325–30
DiFazio CA. Metabolism of local anaesthetics in the fetus, newborn and adult. Br J Anaesthesiol 1979; 51 (Suppl.): 29S–33S
Dam M, Philbert A. Antiepileptic drug therapy in pregnancy. In: Krauer B, Krauer F, Hytten FE, et al., editors. Drugs and pregnancy. London: Academic Press, 1984: 115–29
Dam M, Dam AM. Epilepsy in pregnancy. Lancaster: MTP Press, 1980
Janz D. The teratogenic risk of antiepileptic drugs. Epilepsia 1975; 16: 159–69
Janz D. Antiepileptic drugs and pregnancy: altered utilization pattern and teratogenicity. Epilepsia 1982; 23 Suppl. 1: S53–63
Morselli PL, Pippenger CE, Richens A, et al. Antiepileptic therapy: advances in drug monitoring. New York: Raven Press, 1980
Morselli PL, Pippenger CE, Penry JK, et al. Drug therapy in pediatrics. New York: Raven Press, 1983
Rubin PC. Drugs in special patient groups: pregnancy and nursing. In: Melmon KL, Morelli HF, Hoffman BB, et al., editors. Clinical pharmacology and basic principles in therapeutics. 3rd ed. New York: McGraw-Hill Inc, 1992: 805–25
Redman CWG, Beilin LJ, Bonner J, et al. Fetal outcome in trial of antihypertensive treatment in pregnancy. Lancet 1976; 2: 754–6
Redman CWG, Beilin LJ, Bonner J. Treatment of hypertension in pregnancy with methyldopa blood pressure control: side effects. Br J Obstet Gynaecol 1977; 84: 419–26
Rubin PC. Beta-blockers in pregnancy. N Engl J Med 1981; 305: 1323–6
Butters L, Kennedy S, Rubin P. Atenolol in essential hypertension during pregnancy. BMJ 1990; 301: 587–9
Rubin PC, Butters L, Low RA, et al. Atenolol in the treatment of essential hypertension during pregnancy. Br J Clin Pharmacol 1982; 14: 279–81
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Pacifici, G.M., Nottoli, R. Placental Transfer of Drugs Administered to the Mother. Clin. Pharmacokinet. 28, 235–269 (1995). https://doi.org/10.2165/00003088-199528030-00005
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-199528030-00005