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Effects of Drugs and Chemicals on the Fetus and Newborn (First of Two Parts)

1984; Elsevier BV; Volume: 59; Issue: 10 Linguagem: Inglês

10.1016/s0025-6196(12)62060-6

1942-5546

Lyndon M. Hill, Fredric Kleinberg,

Birth, Development, and Health

Drug teratogenicity has been demonstrated experimentally for more than 30 years. After the discovery of the thalidomide-induced embryopathies, the fetal dangers of maternal drug ingestion were overemphasized. Accumulation of additional information during the past 15 years has led to a more balanced viewpoint concerning drug teratogenicity. A complex set of circumstances must prevail for a specific teratogenic effect to result. Not only the drug or environmental pollutant in question but also its dose, timing, and frequency of administration as well as the genetic and individual susceptibility of the embryo are important factors. Herein we review the currently available information on drug and environmental effects on the fetus and neonate. Drug teratogenicity has been demonstrated experimentally for more than 30 years. After the discovery of the thalidomide-induced embryopathies, the fetal dangers of maternal drug ingestion were overemphasized. Accumulation of additional information during the past 15 years has led to a more balanced viewpoint concerning drug teratogenicity. A complex set of circumstances must prevail for a specific teratogenic effect to result. Not only the drug or environmental pollutant in question but also its dose, timing, and frequency of administration as well as the genetic and individual susceptibility of the embryo are important factors. Herein we review the currently available information on drug and environmental effects on the fetus and neonate. Since biblical times, scattered reports have been published about the effects of maternal ingestion of drugs on the fetus.1Clarren SK Smith DW The fetal alcohol syndrome.N Engl J Med. 1978; 298: 1063-1067Crossref PubMed Scopus (1006) Google Scholar Only within the past few decades, however, have both the physician's interest in and his knowledge of this aspect of obstetrics substantially increased. Unfortunately, the understanding of fetal and placental physiology has not kept pace with the pharmaceutical industry's escalating production of drugs to which the mother, and hence her unborn child, may be exposed. At present, about 80% of all compounds on the drug market are not officially approved for use during pregnancy.2Yaffe SJ A clinical look at the problem of drugs in pregnancy and their effect on the fetus.Can Med Assoc J. 1975; 112: 728-733PubMed Google Scholar In 1961, McBride3McBride WC Thalidomide and congenital abnormalities (letter to the editor).Lancet. 1961; 2: 1358Abstract Scopus (800) Google Scholar established a relationship between limb-reduction malformations (phocomelia) and maternal ingestion of thalidomide during the first trimester of pregnancy. Since that report, the public's consciousness of drug use during pregnancy has been raised to the extent that the safety not only of medications but also of innumerable products available within the home is being questioned. Although past reports of maternal drug ingestion are no longer applicable to the therapeutic nihilism of the 1980s, they illustrate the large number of medications that were prescribed for the multitude of minor complaints that arise during pregnancy. The National Institutes of Health Collaborative Perinatal Study, for example, found that more than 90% of pregnant women take at least one prescribed medication during pregnancy.4Heinonen OP Slone D Shapiro S Birth Defects and Drugs in Pregnancy. Publishing Sciences Croup, Littleton, Massachusetts1977Google Scholar In several reports published between 1967 and 1982, the mean number of drugs used by pregnant women was 3 to 5.4. More than 60% of women received more than one drug. About 16% received an antiemetic, and more than 25% of women used an antibiotic at some time during pregnancy4Heinonen OP Slone D Shapiro S Birth Defects and Drugs in Pregnancy. Publishing Sciences Croup, Littleton, Massachusetts1977Google Scholar, 5Brocklebank JC Ray WA Federspiel CF Schaffner W Drug prescribing during pregnancy: a controlled study of Tennessee Medicaid recipients.Am) Obstet Gynecol. 1978; 132: 235-244PubMed Scopus (62) Google Scholar, 6Forfar JO Nelson MM Epidemiology of drugs taken by pregnant women: drugs that may affect the fetus adversely.Clin Pharmacol Ther. 1973; 14: 632-642Crossref PubMed Scopus (114) Google Scholar, 7Kullander S Källén B A prospective study of drugs and pregnancy. Parts 1–4.Acta Obstet Gynecol Scand. 1976; 55: 25-33Crossref PubMed Scopus (37) Google Scholar, 8Nora JJ Nora AH Sommerville RJ Hill RM McNamara DG Maternal exposure to potential teratogens.JAMA. 1967; 202: 1065-1069Crossref PubMed Scopus (42) Google Scholar, 9Rayburn W Wible-Kant J Bledsoe P Changing trends in drug use during pregnancy.J Reprod Med. 1982; 27: 569-575PubMed Google Scholar (Table 1).Table 1Drugs Commonly Used During PregnancyPercentage useDrugForfar*Cited in “News of Hospital Interest.”10Nelson and Forfar11Nelson MM Forfar JO Associations between drugs administered during pregnancy and congenital abnormalities of the fetus.Br Med J. 1971; 1: 523-527Crossref PubMed Scopus (274) Google ScholarAlcohol88… Occasional use43 Regular use31 Heavy use14Iron8282 First trimester26.4…Tobacco57…Analgesics4814.8Vitamins4039.8Antacids3411Antiemetics…16.3Antibiotics…15.6Cough medicine…8.3* Cited in “News of Hospital Interest.”10News of Hospital Interest Drugs in the ‘fetal echosphere.’.Hosp Pract. 1973; 8: 21-28Google Scholar Open table in a new tab In this article, our purpose is not to produce another compendium of drugs with known teratogenic effects, suspected teratogenicity, or presumed safety.12Adamsons Jr, K Joelsson I The effects of pharmacologic agents upon the fetus and newborn.Am J Obstet Gynecol. 1966; 96: 437-460PubMed Scopus (25) Google Scholar, 13Shepard TH: Teratogenicity from drugs—an increasing problem. DM, June 1974, pp 1–32Google Scholar, 14Sutherland JM Light IJ The effect of drugs upon the developing fetus.Pediatr Clin North Am. 1965; 12: 781-806PubMed Google Scholar, 15Tuchmann-Duplessis H Influence of certain drugs on the prenatal development.Int J Gynaecol Obstet. 1970; 8: 777-797Google Scholar We will instead describe the possible pathways of fetal teratogenicity and then review in some detail the evidence for and against the effects on the fetus of commonly used medications during pregnancy. Neither conception nor development can occur in a vacuum. Hence, the environment of not only the fetus in utero but also the sperm within the testes, the egg within the ovary, and the mother within her home or place of employment must be considered. Recently, the effects of the ingestion of drugs by males on the formation of sperm, the maturation and motility of sperm, and the development of the fetus and infant have been investigated. Within many animal species, litter size, birth weight, and neonatal survival decreased after the ingestion of lead, morphine, methadone, ethanol, caffeine, or thalidomide by the male before mating.16Soyka LF Joffe JM Male mediated drug effects on offspring.Prog Clin Biol Res. 1980; 36: 49-66PubMed Google Scholar Several clinical studies confirmed or implicated paternal exposure to drugs (caffeine, cigarettes, and anesthetic gases) when both reproductive loss and the incidence of low-birth-weight infants were increased.16Soyka LF Joffe JM Male mediated drug effects on offspring.Prog Clin Biol Res. 1980; 36: 49-66PubMed Google Scholar, 17Weathersbee PS Olsen LK Lodge JR Caffeine and pregnancy: a retrospective survey.Postgrad Med. 1977; 62: 64-69PubMed Google Scholar, 18Yerushalmy J The relationship of parents' cigarette smoking to outcome of pregnancy—implications as to the problem of inferring causation from observed associations.Am J Epidemiol. 1971; 93: 443-456Crossref PubMed Scopus (218) Google Scholar In litters of Chinese hamsters, Weathersbee and associates19Weathersbee PS Ax RL Lodge JR Caffeine-mediated changes of sex ratio in Chinese hamsters, Cricetulus griseus.J Reprod Fertil. 1975; 43: 141-143Crossref PubMed Scopus (14) Google Scholar found a significant skewing of the sex ratio toward females (61.4%) (control animals, 49.2%) after caffeine (0.02 g/100 ml) was added to the drinking water of the males. The authors hypothesized that a selective inhibition of Y-chromosome-bearing spermatozoa by caffeine might be responsible for the sex differences found in their study. Thus, the astute clinician must now consider the drugged sperm as a potentially possible preconception source of teratogenicity.20Editorial The drugged sperm.Br Med J. 1964; 1: 1063-1064PubMed Google Scholar Soyka and Joffe16Soyka LF Joffe JM Male mediated drug effects on offspring.Prog Clin Biol Res. 1980; 36: 49-66PubMed Google Scholar summarized the possible mechanisms involved in the effect of paternal ingestion of drugs on fetal outcome: (1) an indirect effect on the normal metabolic and endocrinologic function of the male, (2) damage to the spermatozoa themselves, and (3) the potential of the drug within the ejaculate to affect either the intrauterine environment or the newly fertilized ova. The primordial germ cells appear by the third week after conception. They originate within the yolk sac and then migrate to the developing gonad. In the gonad, the germ cells divide to form oogonia, which in turn differentiate into the larger primary oocytes. By birth, the primary oocyte has completed the prophase of the first meiotic division. It remains in this resting stage until the female attains sexual maturity. A still undefined process dictates when ovulation of a specific oocyte will occur. While awaiting ovulation, the oocyte may be exposed to innumerable compounds and chemotherapeutic agents. To assess the possibility of maternal oocyte damage from cytotoxic agents, Van Thiel and associates21Van Thiel DH Ross GT Lipsett MB Pregnancies after chemotherapy of trophoblastic neoplasms.Science. 1970; 169: 1326-1327Crossref PubMed Scopus (100) Google Scholar analyzed 88 pregnancies in 50 women who had been treated for gestational trophoblastic disease. In this admittedly limited study, no increase in fetal wastage or congenital abnormalities was found. Hence, the authors postulated that cells in the resting phase may be relatively immune to these agents. Once fertilization has occurred, the blastocyst may be affected by alterations of its tubal environment. During this phase of development, drugs reach the embryo by means of the interstitial fluid and thus are present in much lower concentrations. Although no major congenital malformations have been attributed to administration of drugs during this period, the potential for destruction of the embryo exists. Intrauterine growth retardation has been observed in the offspring of pregnant rabbits that, during preimplantation, had been given an “environmental cocktail” of ethanol, nicotine, caffeine, sodium salicylate, and dichlorodiphenyltrichloroethane (DDT). Thus, exposure at this stage of pregnancy can produce embryonic damage that is reparable.22Fabro S McLachlan JA Dames NM Chemical exposure of embryos during the preimplantation stages of pregnancy: mortality rate and intrauterine development.Am) Obstet Gynecol. 1984; 148: 929-938PubMed Google Scholar Each organ system has a critical period after conception during which its development may be disrupted. By the end of the embryonic period (56th day of gestation), the location and general shape of the various organ systems have been established. Consequently, the teratogenic effects of various medications are greatly reduced.15Tuchmann-Duplessis H Influence of certain drugs on the prenatal development.Int J Gynaecol Obstet. 1970; 8: 777-797Google Scholar Histogenesis, however, is far from complete. The fetal period extends from the eighth week after conception until the end of intrauterine life. Although the central nervous system continues to proliferate throughout this stage of development, specific areas of the brain have their own critical periods for differentiation. This process necessitates the attainment of adult size by the nerve cell, maturation of the enzymatic processes of the cell, and development of the capacity to respond to both external and internal stimuli. Myelinization begins as early as the fifth month in utero, follows the order in which tracts were formed, and is not completed until adolescence. This process results in a severalfold increase in the rate of conduction. Thus, in effect, administration of drugs to the mother throughout pregnancy can potentially alter development of the nervous system and, hence, postnatal function.23Monie IW Development and physiology of the fetus.in: Sciarra JJ Gerbie AB Gynecology and Obstetrics. Vol 2. Harper & Row, Publishers, Hagerstown, Maryland1980: 1-28Google Scholar, 24Windle WF Physiology of the Fetus: Relation to Brain Damage in the Perinatal Period. Charles C Thomas, Publisher, Springfield, Illinois1971: 63-76Google Scholar Labor and delivery should be considered a specific subdivision of the fetal period. Transport of drugs is affected by uterine contractility and the secondary alterations in blood flow that this produces. Medications that were equilibrated between the mother and the fetus and were metabolized by the former must suddenly, after delivery, be handled by the neonate. The enzymatic processes necessary for the metabolism of drugs by the liver are not fully developed in the neonate. In addition, the kidney of the newborn has limited excretory capabilities. Both the gestational age and the duration of extrauterine life contribute to maturation of renal function. At term, the creatinine clearance is 23 ml/min. By day 14, the creatinine clearance has increased to 50 ml/min; at 2 months, it is 69 ml/min; and by 1 year of age, an adult level of renal function has been obtained25Grupe WE The kidney.in: Klaus MH Fanaroff AA Care of the High-Risk Neonate. Second edition. WB Saunders Company, Philadelphia1979: 324-340Google Scholar (Table 2).Table 2Effects of Drugs on the Developing HumanStage of reproductive developmentEffectSpermatozoa Increased reproductive lossLow birth weightOocyteNo effect noted to datePlacenta Alteration in uteroplacental blood flowInterference with active transportEmbryo Primary period of potential teratogenesisCongenital anomaliesFetus Growth retardationAlteration of external genitaliaCentral nervous system effectsAltered skeletal growthNeonate Respiratory depressionNeurobehavioral abnormalitiesHypothermiaHypotoniaNarcotic withdrawalLearning disabilities Open table in a new tab Some investigators have shown that administration of phenobarbital to gravid female rats results in reproductive dysfunction in both male and female offspring. Experimental evidence seems to indicate that phenobarbital acts at or above the level of the hypothalamus. The administration of phenytoin during the period of neuroendocrine differentiation similarly adversely affects the fertility of offspring.26Sonawane BR Yaffe SJ Delayed effects of drug exposure during pregnancy: reproductive function.Biol Res Pregnancy Perinatal. 1983; 4: 48-55PubMed Google Scholar The effect of drugs on the developing human need not be restricted to embryotoxicity, mutagenicity, or teratogenicity. By altering the time and the rate of cellular development, a medication may produce long-term effects that are not demonstrable to the observer. Because the brain continues to develop not only through the embryonic and fetal periods but also well into infancy, the intricate interrelationship between two adjacent neurons could potentially be affected. It is extremely difficult, however, to relate subtle infant neurologic abnormalities to maternal ingestion of drugs during pregnancy. With some impairments, either genetic or environmental (for example, drug use) factors could be of primary importance. Once delivery ensues, the neonate is subjected to a host of maternal, socioeconomic, and environmental factors that have the potential to modify any intrauterine effects that might have occurred. By using the laboratory animal, one can suitably control many environmental factors; however, extrapolations from the mammal or even the primate model to humans must be made with extreme caution. Rodier27Rodier PM Correlations between prenatally-induced alterations in CNS cell populations and postnatal function.Teratology. 1977; 16: 235-246Crossref PubMed Scopus (70) Google Scholar showed that the time of ingestion of a drug is critical in assessing the resultant effect on the neonate. Drug-induced lesions of the central nervous system on embryonic day 15 in the mouse resulted in hyperactivity, delays in visual development, and changes in emotional behavior. When the same medication was given either on embryonic day 19 or on postnatal day 3, the effect was noted primarily on motor tasks such as righting. Spyker and associates28Spyker JM Sparber SB Goldberg AM Subtle consequences of methylmercury exposure: behavioral deviations in offspring from treated mothers.Science. 1972; 177: 621-623Crossref PubMed Scopus (175) Google Scholar investigated the long-term developmental and behavioral effects of maternal ingestion of methyl mercury in mice. They found that although no overt signs of exposure to mercury were noted in utero, subtle deviations in behavior were apparent at various stages of postnatal life. When placed in water, for example, the mice that had been exposed to mercury in utero swam differently from the control mice. At 2½ months, gait disturbances were apparent, and at 2 years, results of various neuromuscular tests were still abnormal. As the animals exposed to mercury in utero reached old age, the incidence of muscular atrophy and general debilitation was also higher. Longitudinal studies of the Minamata Bay (Japan) victims who were exposed to methyl mercury may yet detect similar subtle behavioral abnormalities.29Takeuchi T Biological reactions and pathological changes in human beings and animals caused by organic mercury contamination.in: Hartung R Dinman BD Environmental Mercury Contamination. Ann Arbor Science Publishers, Ann Arbor, Michigan1972: 247-289Google Scholar Although reports on amphetamine teratogenicity are conflicting, normal intrauterine and extrauterine growth has been found after fetal exposure to amphetamines.30Billing L Eriksson M Larsson G Zetterstrom R Amphetamine addiction and pregnancy. III. One year follow-up of the children: psychosocial and pediatric aspects.Acta Paediatr Scand. 1980; 69: 675-680Crossref PubMed Scopus (38) Google Scholar A neurobehavioral effect of the drug has been demonstrated in laboratory animals.31Nora JJ McNamara DG Fraser FC Dexamphetamine sulphate and human malformations (letter to the editor).Lancet. 1967; 1: 570-571Abstract Google Scholar, 32Nora JJ Vargo TA Nora AH Love KE McNamara DG Dexamphetamine: a possible environmental trigger in cardiovascular malformations (letter to the editor).Lancet. 1970; 1: 1290-1291Abstract PubMed Scopus (58) Google Scholar Hitzemann and associates33Hitzemann BA Hitzemann RJ Brase DA Loh HH Influence of prenatal d-amphetamine administration on development and behavior of rats.Life Sci. 1976; 18: 605-612Crossref PubMed Scopus (26) Google Scholar administered 1 or 3 mg/kg of d-amphetamine sulfate (a pharmacologic dose) to rats subcutaneously twice daily from the fifth day of gestation until term. For the 3-month duration of the study, the amphetamine-exposed offspring showed a considerable reduction in the ability to habituate and a concomitant increase in activity for 10 to 20 minutes when placed in new surroundings. In addition, these animals had a decreased concentration of catecholamines within the brainstem. These differences between the study group and the control group might serve as a model for the minimal brain dysfunction syndrome seen in children, inasmuch as Snyder and Meyerhoff34Snyder SH Meyerhoff JL How amphetamine acts in minimal brain dysfunction.Ann NY Acad Sci. 1973; 205: 310-320Crossref PubMed Scopus (34) Google Scholar found a correlation between this learning and behavioral disorder and a deficiency of norepinephrine in the brain. Methadone has been found to be teratogenic in some laboratory animals but not in others.35Geber WF Schramm LC Comparative teratogenicity of morphine, heroin and methadone in the hamster (abstract).Pharmacologist. 1969; 11: 248Google Scholar, 36Markham JK Emmerson JL Owen NV Teratogenicity studies of methadone HCI in rats and rabbits.Nature. 1971; 233: 342-343Crossref PubMed Scopus (18) Google Scholar To date, no reports of teratogenicity in the human have been published.37Blinick G Jerez E Wallach RC Methadone maintenance, pregnancy, and progeny.JAMA. 1973; 225: 477-479Crossref PubMed Scopus (105) Google Scholar Besides the acute signs of narcotic withdrawal immediately after delivery, hyperactivity and sleep disturbances are believed to persist in the neonate for 2 years after delivery.38Ting R Keller A Berman P Finnegan LP Follow-up studies of infants born to methadone-dependent mothers (abstract).Pediatr Res. 1974; 8: 346Crossref Google Scholar Hutchings and co-workers39Hutchings DE Towey JP Gorinson HS Hunt HF Methadone during pregnancy: assessment of behavioral effects in the rat offspring.J Pharmacol Exp Ther. 1979; 208: 106-112PubMed Google Scholar administered methadone to pregnant rats from day 8 of gestation until term. During adulthood, the offspring showed no differences in learning ability from that of a control group of animals. The methadone-exposed rats, however, had a significantly higher rate of response to each of the given tasks. They also displayed difficulties in performing tasks that required paced responses to a stimulus. Hence, this study suggests that opiates, or their derivatives, may produce a long-term effect characterized by increased behavioral arousal. Szeto40Szeto HH Effects of narcotic drugs on fetal behavioral activity: acute methadone exposure.Am J Obstet Gynecol. 1983; 146: 211-216PubMed Scopus (33) Google Scholar arrived at a similar conclusion when studying the effect of acute methadone exposure on fetal behavioral activity. His results indicated that methadone suppressed fetal quiet and rapid eye movement sleep and thereby produced a hyperactive state. Studies from several laboratories41McGinty JF Ford DH Effects of prenatal methadone on rat brain catecholamines.Dev Neurosci. 1980; 3: 224-234Crossref PubMed Scopus (36) Google Scholar have confirmed that levels of biogenic amine neurotransmitters are altered in the offspring of perinatally addicted rats. A delay in cellular maturation of the brain may produce deficits in synaptogenesis. These effects could be of importance in the behavioral alterations noted in the perinatal opiate syndrome.42Slotkin TA Effects of perinatal exposure to methadone on development of neurotransmission: biochemical bases for behavioral alterations.Monogr Neural Sci. 1983; 9: 153-158PubMed Google Scholar Similarly, diazepam, when administered to pregnant rats during the last week of gestation, induces behavioral and neurochemical alterations in the offspring which are evident long after the drug has disappeared from the brain.43Kellogg CK Chisholm J Simmons RD Ison JR Miller RK Neural and behavioral consequences of prenatal exposure to diazepam.Monogr Neural Sci. 1983; 9: 119-129PubMed Google Scholar Wilson and associates44Wilson GS Desmond MM Wait RB Follow-up of methadone-treated and untreated narcotic-dependent women and their infants: health, developmental, and social implications.J Pediatr. 1981; 98: 716-722Abstract Full Text PDF PubMed Scopus (143) Google Scholar studied 68 narcotic-dependent women (29 heroin-dependent and 39 methadone-treated women) who gave birth to 69 live-born infants; a drug-free control group was also studied. At a 1-year follow-up examination, mean developmental scores were within the normal range for both groups. Subtle signs of neurodevelopmental dysfunction (reduced attention span), however, were significantly more common in the children of the drug group than in those of the drug-free control subjects. These signs may be early indications of potential learning or behavioral deviance that may surface when the children enter school. On the basis of the aforementioned studies, if certain types of minimal brain dysfunction (such as restlessness, hyperactivity, and poor concentration) have a neurochemical basis, maternal ingestion of drugs must be carefully evaluated as a possible cause.45Weiss B Spyker JM Behavioral implications of prenatal and early postnatal exposure to chemical pollutants.Pediatrics. 1974; 53: 851-856PubMed Google Scholar First-trimester exposure to progestins or estrogens has been reported to affect personality development.46Reinisch JM Prenatal exposure of human foetuses to synthetic progestin and oestrogen affects personality.Nature. 1977; 266: 561-562Crossref PubMed Scopus (63) Google Scholar Progesterone-exposed subjects were found to be more independent and individualistic, whereas members of the estrogen-treated group were more group-oriented and less self-sufficient than their collective sibling control subjects. Additional longitudinal studies on the long-term effects of in utero exposure to hormones are needed. Obstetric premedication may also have an effect on the neonate. Stechler47Stechler G Newborn attention as affected by medication during labor.Science. 1964; 144: 315-317Crossref PubMed Scopus (57) Google Scholar showed that babies whose mothers received large doses of analgesia during labor were less attentive for the first 4 days after delivery than those babies whose mothers received smaller doses. Brackbill and co-workers48Brackbill Y Kane J Manniello RL Abramson D Obstetric premedication and infant outcome.Am J Obstet Gynecol. 1974; 118: 377-384PubMed Scopus (61) Google Scholar evaluated 25 babies whose mothers had received different doses of meperidine in labor. Rates of habituation to an auditory orienting reflex and to the Neonatal Behavioral Assessment Scale were studied. Infants of mothers who had not been premedicated with meperidine habituated twice as fast as infants whose mothers had been premedicated. In effect, the infants of the former group were able to assess the inutility of the auditory stimulus much more rapidly. Infants whose mothers had received no medication performed more capably on many of the items of the Neonatal Behavioral Assessment Scale. Consolability (a measure of inhibitory capacity) and cuddliness were both higher in babies of nonpremedicated mothers. This difference may be of importance for the appropriate development of maternal-infant bonding in the early postpartum period. Finally, the infants of premedicated mothers had fewer changes in state—for the most part, they remained asleep or drowsy. Additional effects of maternal administration of meperidine on the neonate include respiratory depression and feeding difficulties for as long as 48 hours after delivery.49Wiener PC Hogg MIJ Rosen M Effects of naloxone on pethidine-induced neonatal depression.Br Med J. 1977; 2: 228-231Crossref PubMed Scopus (27) Google Scholar By the fourth to fifth week after conception, the placental circulation has been established. This functions as a transporter of oxygen and nutrients to the rapidly growing embryo. Transport of drugs across the placenta occurs primarily by simple diffusion and hence depends on the molecular weight, lipid solubility, the percentage and tenacity of protein binding, and the concentration gradient of the particular drug under evaluation. As the placenta matures, the distance between the maternal and fetal circulations is reduced, the capillaries of the villi enlarge severalfold, and the amount of connective tissue diminishes.50Clewell WH Stys SJ Battaglia FC Fetal pathophysiology.in: Quilligan EJ Kretchmer N Fetal and Maternal Medicine. John Wiley & Sons, New York1980: 181-219Google Scholar Hence, diffusion is further facilitated. Although the placenta is virtually impermeable to compounds with a molecular weight of more than 1,000 (for example, heparin), most medications have a molecular weight of less than 500. Therefore, size is rarely a factor in the transfer of drugs between the maternal and fetal circulations. The concept of the placenta as a “barrier” between two independent organisms is, at best, simplistic. This belief is derived from the observations that substances of a molecular weight of more than 1,000 do not cross the placenta and that substances of low lipid solubility (for example, succinylcholine) diffuse across the placenta only if the concentration gradient is extremely high.51Moya F Kvisselgaard N The placental transmission of succinylcholine.Anesthesiology. 1961; 22: 1-6Crossref PubMed Scopus (31) Google Scholar In rabbits, Kvisselgaard and Moya52Kvisselgaard N Moya F Investigation of placental thresholds to succinylcholine.Anesthesiology. 1961; 22: 7-10Crossref PubMed Scopus (24) Google Scholar demonstrated that 1,000 times the maternal paralyzing dose was necessary to permit the passage of succinylcholine to the fetus. For some substances, the barrier concept functions in reverse: vitamin C may rapidly cross the placenta from the mother to the fetus but cannot return across the placenta to the mother.53Barnes AC Intra-uterine Development. Lea & Febiger, Philadelphia1968: 362-377Google Scholar Most drugs are fat-soluble. This characteristic greatly facilitates bidirectional transport across the placental barrier. The diffusion of specific drugs (for example, penicillin, barbiturates, and ethanol) may occur within minutes after administration to the mother. Equilibration of a drug between the mother and the fetus ranges from 2 minutes to 2 hours with various medications.