The effects of pharmacologic agents upon the fetus and newborn

CURRENT DEVELOPMENTS An evaluation

The effects of pharmacologic agents upon the fetus and newborn KARLIS ADAMSONS, ]R., M.D., PH.D.* INGEMAR JOELSSON, M.D.** New York, New York

MoRPHoLoGIc abnormalities resulting from the influence of exogenous substances upon the embryo during development have been studied exhaustively and the myriad of reports give testimony to the diligence and resourcefulness of the teratologist. In contrast, little attention has been directed to the pharmacologic effects of these agents upon the fetus, and serendipity rather than systematic research has played the major role in furthering our knowledge. This has not been due to lack of concern or diffidence, but to unawareness of the problem. It seemed unlikely that administration of drugs in therapeutic amounts to the mother could exert an adverse effect on the fetus because the placenta was assumed to provide a protective barrier. In many respects, the chemotherapist envisaged the intrauterine patient

as a transient organ of the mother not deserving particular reflection. He found it n·assuring to recall the high tolerance of immature organisms to oxygen lack and was tempted to consider the inability to respond synonymous with being invulnerable. The validity of these contentions was first challenged by those concerned with the care of the offspring. A score of substances was encountered which, although of proved safety to the adult, created unusual sequelae in the newborn. In some instances, the adverse effect was inconsequential, disturbing the physician more than the patient, in others it was detrimental or even lethal. The degree of maturity after completed ontogenesis was gradually recognized as an important variable, and time was introduet·d as a new dimension in assessing the responses of living systems to pharmacologic agents. More than the usual difficulties confront the investigator. Little is known about the physiologic functions of the fetus and only a few of these have been studied under undisturbed conditions. Uncertainty escorts extrapolation of conclusions from species to species, and the search still continues for a meaningful denominator in order to compare dosages and elicited responses. Excep-

From the Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia Uni1•ersity. Supported by United States Public Health Service Grants GM09069 and HD 11801 and by a Senior Research Training Grant of the W arid Health Organization. *IV ell come Senior Research Fellow. **United States Public Health Service Trainee in Reproductive Biology.

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tiona! demands are imposed on one's mgenuity in the interpretation of results because of the dependence of fetal homeostasis on rnaternal performance. A further problem (~xists in quantitating transfer of substances from mother to fetus, particularly for those which are rapidly cleared from maternal circulation or enter the curious pathway of the amnioenteric shunt. While we are still in a stage of defining thP principal objectives of this new discipline, advice is hPing sought not only by those who have resorted to therapeutic nihilism for ft>ar of jeopardizing· the intrauterine patient by maternal medication, but also by those who have begun to administer drugs directly to the fetus for diagnostic and therapeutic purposes. lrmnediatt:' answers cannot be provided for most of their questions. and the extraordinary number of agents used during pregnancy renders e\·en the prospects for the future unpromising. During the last decade, investigators from other disciplines, notably physiology and biochemistry, have recognized that developing systems are worthy of attention, and it is the pragmatist's good fortune that a considerable body of information regarding normal function is already a\~ailable. With increased knowledge of the peculiarities of the fetus, it might become possible to make generalizations in predicting the effect of drugs on the intrauterine patient. It is beyond the scope of this communication to summarize even the major advances regarding development of body functions during prenatal life. Only a few aspects particularly relevant to drug action will be outlined briefly. The reader is referred to a number of original contributions, reviews, and proceedings of symposia available on most of the topics.'"·"'· 57·59, Gz, 63. H9, roo, Hz, "'s Discussion on the teratogenic effects of th(·rapeutie agents has been omitted on purpose since extensive coverage already exists in recent literature. 37 • ""· 9 ·1• 1 2 "· De. JH, c:ir. Thus, emphasis has been placed on the evaluation of drugs commonly used in obstetric practice. However, even \·vith this qualification, the coverage will be incomplete. Many 1 " '·

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substances or whole classes of agl'nts ,.,,;lei not he considert>d becausl' (ll paucitv ol illrormation. ( :hronologic St'lj lll'll('(' liaS IH't' ll chosen for presentation oi th<' \·ariuw; gTolljl" of drugs, beginning with agents t·mploy,·d ill l'arly g·estation. The n·adt'l' is t'IIt·ouragetl t" consult otlll'r summaries on tilt' ph an 1 1~1cologie dfl'ct of drugs on tlw fd us ami 1 w-., · horn that have appean·cl in n·ct·nt \ra!s.''

Peculiarities of the intrauterine patient

The mandatory passagt· uf dm~s throul!li the li\er befon· entering the ·') ->tt·mic , nr ulation is for the pharmacologist orw of til!' most significant features of ktal t·irculati .. rL ( :ontrarv to earlier beliefs. onh' a relati\·t·h small fraction of umbilical wnom blood is shunted directly into tlw \ella ca\·a \ ia tlw ductus \'enosus. [n somP species. likl' tlw rhesus monkey, this channel is oftt·n mitlltt<·. in tht> fetal horse it is absent. Although it i-. generally accepted that the retal liver has ,! low capacity to inacti\'att, most phannacologic agents, distinct differencP>; haVl' bt•f•n r·ncountered in the elicited response following adrninistration o.f dru~·s into the unthil!cal and femoral \'eins. Hepatic inactiYatiott might be of particular import for polypep~ tides and steroids. The n·cently clemonstratl'cl high rcacti\ it> of pulmomuy vessels to vasoconstrictor ~t!ld \'asoclilator substances as wdl as to hydrogi'II ion concentration and g-as composition of tlw perfusate is of greater inten,st to the pediatrician than the obstetrician. \·\'lwn p 1acental ('Xchange is sufficientlv enrbarTassed to cause fetal asphyxia, it is lllllikely that administration of a vasodilator to the motlwr for tlw relief of pulrnona ry vasoconstrict ior in the fettts would be tlw preferred treat· rnenL The response of the ductus arteriosu· to a variety of agents injected into tlw h·u circulation has been studi<•d l'xtemin~h I >at a, howen·r. are not available to jud.~, whether drugs administered l<> tht· mothc alter blood flow through the ductus. Simila comments also apply to the umbilical all\ placental arteries. A... further characr<·risti· of fetal circulation is the high proport j.,,

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of total cardiac output allocated to brain perfusion. This is relevant when comparison is made of drug concentration in various fetal body compartments before equilibrium conditions are established. The arrangement of n·ntricles working in parallel rather than in series should minimize disturbances resulting from unequal effect of drugs on their performance. RPgulation of body temperature during prenatal life is chiefly accomplished by the placenta which, functioning as a heat exchange between the two circulations, deprives the fetus of thermal autonomy. In a -;teady state, the human fetus is about 0.5° ( :. warmer than the mother; the transplacental gradient depends on the ratio of heat output by the fetus to the rate of placental perfusion, and the direction of flow through ,·illous capillaries and intervillous space. 5 It is improbable that, under normal conditions, the small thermal differences between mother and frtus have a bearing on the drug action ••r their metabolism. During induced maternal hypothermia, the effects of previously administered agents, however, might become sufficiently modified by the fall in fetal te!nperature to be of clinical significance. IntTeased sensitivity of the newborn animal to the depressant effect of barbiturates at low body temperatures is well known. In contrast to the rarity of fetal hypothermia, lowering of body temperature in the immediate neonatal period is the rule rather than the exception. Under normal deliwry room conditions, deep body temperature of the vigorous full-term infant falls by 2 or TJ C. The fall in temperature is greater in the depressed infant and even more pronounced in the immature and malnourished. Prenatally acquired hypnotics, analgesics, and certain tranquilizers might further reduce thermal stability of the newborn. Due to slower metabolism of drugs at lower temperatures, prolonged depression might result. Agents eliminated chiefly by renal excretion are affected less by changes in body temperature than those dependent on inactivation by the liver. Low body temperature has a protective effect against drugs which are

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relatively inert or even without pharmacologic action prior to their conversion into an active form. The activation process might involve oxidation, demcthylation, cyclization with formation of ethylene-imonium groups and many other metabolic performances. Examples include such drugs as colchicine, codeine, amphetamine, and certain adrenergic blocking agents. Morphologic characteristics of adult liN"! arc present already in the older fetus; however, the activity of most enzymes concerned with homeostasis is low by adult standards even at birth. The deficiency appears to bl· marked for oxidative enzymes but less so fot systems concerned with reduction and hydrolysis. Activity nf the hexose monophosphate shunt, which is the principal sourct· of the reduced form of nicotinamide adenint' dinucleotide phosphate (NADP), is high in the fetal liver, and glucose-6-phosphate dehydrogenase is more active than in the adult. Nevertheless, reduced NADP levels are low at birth even in species with morr matun· neonates, such as the guinea pig. The levei rises sharply following birth and adult values arc reached \Vithin 24 hours. Oxidative enzymes play a major role in the detoxification of drugs. They arc concerned not only with substrates that are rendered biologically inactive by oxidative deamination, hydroxylation, or dcalkylation but also with those that require such changes prior to being conjugated with uridine diphosphoglucuronic acid (UDGAJ. Conjugation with UDGA by glucuronyltransfcrase is the principal metabolic pathway of numerous endogeneous and exogeneous substances such as bilirubin, adrenal steroids, salicylates, bishydroxycournarins, and morphine and its congeners. The activity of these enzymes is low at birth, 3 "· '" and values of the adult are reached gradually. Differences in activity are encountered depending on substrate. Thus, the Gunn strain rat has minimal ability to conjugate bilirubin or ortho-aminophenol, but readily forms glucuronide with para-nitrophenol. It appears that, in the fetus and newborn, conjugating systems might reside in different intracellular

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structures than in the adult'""; if this applies, microsomal preparations would not reflect the enzymatic performance of the liver in VIVO.

The activity of oxidating and conjugating enzymes of the fetal liver is readily increased hy administration of substances such as barbiturates, chlorcyclizine. and chloroquine to the mother.''''· 1 '" As will be discussed later. premature activation of conjugating enzymes might not be advantageous because of the lack of excretory facilities for conjugates. The low ability of the fetus to form glucuronicles is an important feature when one considers the distribution of certain substances and their penetration into the central nervous syst!:'m. Acetylation by the fetus and the newborn is also deficient and explains the small fraction of acetylated sulfonamides appearing in the urine. Conjugation with glycine is similarly low. Sulfation, on the other hand, proceeds with exceptional facility. a feature of particular import to the metabolism of estrogens. A unique feature of the liver of the newborn is the tolerance to carbon tetrachloride. Since the toxic eflect of carbon tetrachloride appears to be mt>diated via stimulation of the sympathetic ncrYous system, it is likely that difference in responsiveness of this system to carbon tetrachloride accounts for the high tolerance of the newborn. It is known that transection of spinal cord or the administration of adrenergic blockmg agents exert a protecti\T effect against carbon tetrachloride toxicity in the adult."'' Particular susceptibility of the central navous system to external factors is likely to he present during the period of myelination. This is chiefly due to the high metabolic stability of constituents of myelin sheets. C 11 labeled cholesterol is known to persist in tlw white matter of the rabbit for one year when administered in the newborn period. It is probable that there is a similar stability for other substances of the brain, such as DNA. Thus, exposure to agents exerting an unto-

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ward effect upon fonnation of Illyelin could have long-lasting Sl'quelae. Extrapolation from animal data to man would place ttw \·ulnerable period of the human infant from the sen:nth intrauterine month to the first few months after birth. Tlw imrnatun· infant appears to he partintlarly SIISceptible to forei.gn substanrt•s. Dekctin· myelination associated with impaired intellectual dC'vdopment in the h urn an newborn is thought to be caused bv plwnylketcnws formPd in a rnetabolicallv aberrant pron·ss. Of most concern is thl' quest ion whdhl'r ntorc subtle interferencE's can produce pnrnanent changes in intellectual and emotional development. lntrauterinl' or m·cmatal hypoglycemia would be such an ent itv . Recentlv. attention has been focused on "'vera] tberapeu tic agents as being potential hehaviora I t cratogens. "''·"· "'' Access of drugs to brain tissue appears \(l ht· greater in the fetus and newborn than in tht' adult. This has been dnnonstrated fo1 \ arious dyes. amino acids, thioeyanatl'. plwnobarhital, and morphine and its congeners The effects of diffprent protein binding and difTt--.l'Prt('P" ~-------------

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ever, must he considered when conclusions are drawn regarding the perrneabilitv of the bloocl-hrairr harrier. The increased susceptibility of rul blood all.1 of newborn infants to a \a riety of oxidants is well known.'"· 1"· 1 '"· ""''The st'Cjltcla<· are hemolysis and methemoglobinemia. Patients with a vari!:'ty of inborn errors of red blood cell enzynlf's, such as glucose-6-phosphat(~ dehydrogenase cleficienn or gi mathione reductase deficiency. an· particula rlv \'tdnerable. Methemoglobinemia in tlw m·wborn has resulted from contact with aniline dyes, henzocairw, and following ingestion of nitrates and administration of
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stability of reduced glutathione which in turn is responsible for an impaired protection of -SH-containing enzymes. On the other hand, it is known that erythrocytes of the newborn contain at least equal concentration of reduced glutathione to that of the adult and have adequate levels of glutathione reductase. The same applies to NADPH 2 -gcnerating enzymes of the pentose pathway. Hemolysis of the erythrocyte with glucose-6phosphatc dehydrogenase deficiency has been reported following the use of numerous substances including antimalarials, antipyretics, sulfonamidcs, nitrofurans, menadione and its congeners, and chloramphenicol. The m\:'chanism of action of these agents is thought to he mediated through an inadequate reducing potential within the erythrocyte. Hormones

Steroids with androgenic properties or androgenic potential. Masculinization of the urogenital sinus of the female fetus resulting from administration of androgenic substances to the mother has been appreciated for more than two decades!~ A case has been reported in the literature in which m\:'thyltestosterone gi,·en to the mother for treatment of hyperemesis gravidarum produced such a degree of masculinization of the female fetus that the correct sex of the newborn infant \vas not apparent until the age of 6 months.'"' Initially it was believed that masculinization could result only from the usr of steroids with predominantly androgenic properties. With the introduction of synthetic progestins in the management of habitual or threatened abortion, evidence began to accumulate that a variety of these agents exerted biologic effects upon the fetus similar to those of methyltestosterone. More than a hundred cases are available in the literature of iatrogenic masculinization of thP female fetus associated with the use of oral progestins during early pregnancy."'" The more frequPntly used agents have been 17 -alpha-ethinyl-testosterone and 17 -alphaethinyl-19-nortestosterone. These compounds differ from the natural product progesterone

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by having the hydroxyl group on carbon 17 in beta rather than alpha position. Recalling that such configuration is present in the molecule of methyltestosterone, it is not surprising that the synthetic progestins posses' androgenic potential. In rare instanc<>s, masculinization has been observed following administration of natural progesteronr""' or synthetic estrogens. 2 ·1 It is likely that thesl' cases represent an abnormal susceptibility of the target organs or aberrations in st<>roicl metabolism. Besides influencing morphologic developm<>nt, substances with androgenic potential might lead to long-lasting functional disturbances. Recently, it has been shown that monkeys masculinized in utero by administration of progestins to the mother have permanent alterations in sexual behavior."'" It would be of interest to obtain follow-up data on humans masculinized by exposure to androgenic substances during prenatal life. The sex specificity of the hypothalamus or even hig·her centers has been known for a number of years, and it is not unexpected that a variety of substances administered during critical periods of developmPnt and difierPntiation of the central nervous system might exert a prolonged effectY"1 Insulin and oral hypoglycemic agents. No quantitative data are available regarding thr placental transfer of insulin in the human. Studies in the rhesus monkey have shown that administration of Jl"'-labeled insulin to the mother is followed within minutes by appearance of the isotope in fetal blood.'"" The permeability, however, must be limited, hence maximal concentration of the labeled polypeptide in the umbilical venous blood observed in these experiments was only a fraction of that present in the maternal circulation. The injected insulin was rapidly metabolized by the fetus as shown by the presence of various d\:'gradation products in the blood of the umbilical artery. Extrapolation of these data to the human would favor the view that administration of insulin to the mother, even in large doses, is unlikely to be harmful to the fetus, and that the

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detrimental effects associated with insulin shock of the mother are caused by a prolonged maternal hypoglycemia and its sequelae rather than by a direct effect of insulin upon the fetus. Tolbutamide, an oral hypoglycemic agent, crosses the human placenta and may he present in the blood of the newborn for several hours after birthY" Since the principal mechanism of action of tolbutamide is the release of insulin from beta cells, it is unlikely that ttw drug exerts an adverse effect upon the fetus. Administration of tolbutamide to the tllothcr prior tP delivery could, however, increase the propensity of certain newborn infants to hypoglycemia. It is known that the offspring of diabetic rnoth<:>rs often haw hyperplasia of the beta cells of pancreas. and possess an increased ability to release insulin in response to suitable stimuli. Large closes of oral hypoglycemic agents produce morphologic abnormalities in mice,cn" hut there is no evidence that these drugs are teratogenic 1!1 tlw h urn an."" Oxytocin. The difficulty in detecting oxytocin and related natural or synthetic polypeptides in body fluids appears to be responsible for the lack of information regarding their transfer from mother to fetus. It is probable that oxytocin reaches the fetal circulation following administration to the mother. This contention is supported by the observations of insulin transfer, and the fact that oxytocin and insulin share many structural and physicochemical properities. It is, however, unlikely that the concentration of neurohypophyseal octapeptides or their analogues could reach sufficiently high levels in the frtal circulation to exert a biologically detectable effect. Corticosteroids. Administration of cortisone to the mother very early in gestation has been associated with an increased inci-

dence of palatal lesions in the human infant.'"· 1 " ' Review of several hundred cases recorded in the literature"'· ''c indicates an incidence of this abnormality in the exposed population of nearly 1 per cent, which IS slightly higher than expected at random . .:A).

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similar abnormality has bel'n produced m the rodt·nt. 7 ·.. ''' In contrast, cortisone analogtws, such ,h prcdnisont·, triamcinolone, dexatncthasotH\ hctamethasone, and hyclrorortivme hau· not been implicated in producing abnnrmaliti<'s of the fda] palate in tlw human. In nm· case"" in which an infant with ddt palal<' was horn after administration of preclnis!nw to the !llother, the therap;, 11 as not he.gun until the eighteenth week of gestation. Sine(' tlw fusion of the palatt· prcwess in the ltllman fetus is completed :\! tht· 1 t'nth wt·t•k. there is nn jmtification for assuming tktt prednisone was responsiblP for tlw ct >rtgcnital anomaly. Cortisone analogw·s art' knm\·n to produce anomalies similar to 1 host· pmcluced hv cortisone in tlll' rnckni.'" Sucldt·n withdrawal ol adr!'nal conwnstl·roids might occur in tlw n1 fan t \\ h<>st· tnothn has recei\Td large ,unounb of steroids during g·estation. lt is 'ltrprising tn lind that only a ft·w cast's'' '''' kl\c' !wen reported in which the nt·wl_Hll'!J showed sigrh of adrenal cortical failure. On<' of liw mfants dit·d neonatallv: twnosi' ,,f tlw adn·JJ
Thyroxine and agents affecting thyroid function. Morphologic and biochemical sttJdit~s ha\"<· prm·iclt~cl eviclencl' that in man tlw thvm:d gland is functional hdotT birth.'"· "' It has also he1·n established tlwt tht· dc\Tlopnwnt of the thyroid is undn the inlhtenet' nf fetal rather than matnnal tltvThus Jl mid stimulatin[~; hormon(' TSH 11·mdcl he expected that ,.,ubstann·s a fl l'ct tnt' till' rl'kast· of TSH or the formation nf til\roxinc could t•xnt aclvt•rst' dfects upon thC' development of the ft·tal thvroid. Retarda· tion of thyroid clcvelopmen t in tht· fetal r;tt has hl·en observed following administration of large doses of thyroxirw to the rnothn.""' Since placental permeability of thyroxine and 1'-.

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likPlY that maternal hypt-rthyroiclism nr :tdministration of exog;enous thyroxine dming pregnancy could inflm·nce the dt·\clopuH'nt of tht· fetal thyroid in tlw lnulJan. Similarh. t•1cvation nf Inaterual 'TSI-I due to hypnth~-

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roidism is not expected to affect the fetal thyroid; observations in several species indicatP that this hom1one does not penetrate the placenta in biologically significant quantities.'"'· "n Abnormalities in the fetal thyroid can result from administration of propylthiouracil or its analogues to the mother during the second and third trimesters of pregnancy. Propylthiouracil readily crosses the placenta and interferes with thyroxine synthesis by the fetal thyroid. If maternal levels of thyroxine arc low, and thus unable to compensate for the reduced concentration of the hormone in the fetal circulation, increased amounts of TSH will be released from the fetal pituitary leading to goiter formation. Prenatal hypothyroidism can also have a systemic effect and he responsible for mental deficiency of the offspring."1 Administration of iodides to the mother during pregnancy has also resultt'cl in development of fetal goiter. 1'" .:VIarked enlargement of the thyroid can have serious sequelae for the newborn chiefly by the mechanical effect upon the airway. Obstruction of the trachea resulting in death by suffocation has been reported. In most instances. congenital goiter has not been implicated in producing metabolic disturbances of clinical significance. There are, however, occasional reports describing signs of hyperthyro!disrn in the newborn following administration of antithyroid drugs to the mother."" This complication is most likely to occur when large amounts of the hormone have been stored in the fetal thyroid during treatIIH'nt with iodides. The undesirable effects of this halogen upon the fetus is now gennally recognized, and the prolonged use of iodine-containing substances during pregnancy is being discouraged. Recently, radiopaque substances containing large amounts of iodine have been administered to erythroblastotic fetuses for visuali/.atwll of the gastrointestinal tract and the localization of the peritoneal cavity. Data, however, arc not available as to whether such an exposure to iodine has a bearing upon thP development of the fetal thyroid. Administration of radioactive iodine early

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m pregnancy has resulted in congenital hypothyroidism. The awareness that any radioactive substance constitutes a threat to the developing fetus has curtailed the usc of isotopes in pregnancy and has thereby virtuallv eliminated the occurrence of such fetal damage. Antimicrobials

Sulfonamides. Administration of sulfonamides to the mother during the second half of gestation results in a rapid appearance of these substances in fetal body fluids, and within one hour concentration in the fetal blood approaches that in the maternal circulation.1· B. u1. """· 210 Most likely this also holds true for the earlier part of pregnann although data in support of this contention. at least for the human, are presently lacking. It is unlikely that the normal fetus is affected adversely by sulfonamides. Even if sulfonamides reduce the binding of bilirubin by plasma proteins, thereby increasing the fraction of diffusible bilirubin,'GG, lG< the concentration in fetal plasma would be unlikely to approach dangerous levels because of the clearance of uncon juga ted bilirubin by the placenta. Exposure of a fetus with glucosc6-phosphate dehydrogenase deficiency could, on the other hand, lead to intravascular hemolysis and methemoglobinemia. Once the fetus is born and the placenta is no longer available for maintenance of homeostasis, the presence of sulfonamide-; might create undesirable effects by favoring the diffusion of bilirubin into the tissues. This is particularly relevant when "long-acting·· sulfonamides are given to the mother piTceding a premature birth. Administration of sulfonamides to the prPmature infant is known to be deleterious. ] t leads to an increase in the frequency of kernicterus and an increase in the over-all mortality rate.""" It has been inferred that this is caused by penetration of central nervous tissues by free, unconjugated bilirubin. This explanation rests on the assumption that intracellular deposits of bilirubin are detrimental to cell function. This adverse effect, however, has not been established, at least

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not for the concentrations of free bilirubin that can exist in an aqueous phase at the ionic strength and pH of body fluids. It i' generally agreed that sulfonamides do not enhance the severity of jaundice. Administration of sulfisoxazole to the Gunn strain rat with congenital jaundice increasE's the incidence of kernicterus which is accompanied by an actual lowerin~· of the serum bilirubin level.'""· 1 " 1 Penicillin. Penicillin readily crossf's the placenta and reaches therapeutic concentrations in fetal fluids following administration of conventional doses to the mother. 11 · 11 ''· 3 The drug has been used extensively """· "" during pregnancy. without causing ill effects in the fetus. This is in agreement with the experience in the adult in whom penicillin can be tolerated in almost unlimited amounts. Recently it has been suggested that there is a tolerance limit to penicillin in the newborn rat.'"' The toxic effect in this species has been ascribed to penicillic acid rather than to the accompanying potassium ion becaust' both the potassium and the sodium salts of the drug were found equally detrimental. The Yalidity of this inference can be challenged on the grounds that the newborn is adversely affected not only by large amounts of potassium ion but of sodium ion as well. Aqueous penicillin up to 1 million units per kilogram has been gin'n directly to the erythroblastotic fetus at the time of hvsterotomy or transabdominal laparocentesis for intraperitoneal administration of blood: no immediate Jilltoward reactions have been obser\'ed in these instances." In the newborn. penicillin levels in body fluids are expected to remain for longer periods of time compared to those observed in the adult because of the relati\'ely low clearancP capacitv of the kidney of the newborn for organic acids. It has been reported that the renal clearance of penicillin hy the prematme infant is only 17 per cent of that observed in older children when related to surface area. and :H per cent when related to body weight. J.> Streptomycin. Similarly to penicillin, streptomycin and dihydrostreptomycin penetrate the human placenta with facility. Following


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Streptomycin and dihydrostreptornyciu arc also present in therapeutic coJJCl'ntratiolb in the cen•brospinal fluid of tht· fvtus. It i-< <>I interest that the concentratiom in fetal ;tnd tnaternal cerebrospinal fluids nf dihydrostreptomycin are similar in spitt· of tilt' fact that considerable cliscn'p'tl \'j)tomycin represents a hazard to tlw kttb. The gradual replacement nf ,tn·ptnrnvcin bY otht•r agents in the trcatnH·nt of ruhN('\1Iosis during pregnancy, hm' ('\ t'l', ltt' brovvn discoloration of tlw primary ttTth ba, occurred in infants trcat(·d with tetr·a('vclirw in thl' neonatal period.'···· ""' Similar clentai abnormalities han' been rl'portecl to occur in infants whose mothers wen· treated with tetracyclines prior to dcli,·t>t'\'. "'"· ,, .... ""'· "''' J~'l'I

Since the deposition of tt'tracycline or tct.Lt-

cvclim· analogues occurs when tcl'l.lt an·

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undergoing mineralization, it is unlikely that untoward effects will result when the agents are administered during the first trimester of pregnancy. This is in agreement with clinical observations. Deposition of tetracycline fluorophor in the skeleton has been made responsible for growth retardation of premature human infants during tetracycline therapy 4 "; similar findings also have been reported for the fetal rat. 177 Whether the retardation of skeletal development is due to tetracycline deposition or merely associated with it remains conjectural. Novobiocin. A number of studies indicate that novobiocin may inhibit enzymatic processes concerned with the metabolism of bilirubin. Administration of the drug to newborn human infants enhances neonatal jaundice.219 Reduced activity of glucuronyltransferase has been observed in newborn rats following administration of a single dose of novobiocin. m The drug also inhibits hepatic conjugation of both bilirubin and orthoaminophenol in vitro. 103 • 117 In contrast, increased activity of glucuronyltransferase and UDPG dehydrogenase has been observed in newborn rats and guinea pigs following administration of novobiocin for 3 consecutive days. Although the exact mechanism underlying the effect of novobiocin is not known, it is most likely related to interference with . bilirubin conjugation rather than to hemolysis of red cells or hepatocellular damage.'"· "19 Since the fetus eliminates most of its bilirubin in the unconjugated form, novobiocin is not expected to lead to retention of this pigment during prenatal life. Chloramphenicol. Adverse effects of chloramphenicol upon the newborn infant, particularly the immature one, have been appreciated for several years. Extensive reports are available dealing with the clinical picture of the "gray syndrome" of the newborn infant, and with the analysis of underlying mechanisms responsible for the adverse effects of the antibiotic."'· 11 "· 11 "· 1 "u. 1 '<", 1 " 4 · e11, """ The toxicity of chloramphenicol increases rapidly with decreasing maturity at a constant dose per unit of body weight. The din-

Effects of pharmacologic agents

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ical symptoms usually develop within a few clays after initiation of therapy and consist of failure to feed, poor muscle tone, hypothermia, impaired ventilation, and a peculiar ash-gray cyanosis. These manifestations havP been encountered chiefly when the dosage of chloramphenicol exceeded 100 mg. per kilogram per clay, an amount considered ex· cessive by present standards. It appears that unduly high concentrations of the drug resulting from a low clearance rate have been responsible for the untoward effect. Detoxification of chloramphenicol is accomplished principally by conjugating it with glucuronic acid. Because the activity of glucuronyltransferase is low in the newborn infant, particularly in the immature one, chloramphenicol will remain in the active form in body fluids for prolonged periods. The elimination of the drug or its metabolites by the kidney is also low dul' to the functional limitations of this organ. It cannot be a priori inferred that reduction in dosage obviates the problem created bv slow excretion and metabolism becausP bactericidal efficacy does not nPcessarily havt· to be incorporated in the same chemical moiety as tissue toxicity. It has been proposed that a metabolite not formed in the adult organism is responsible for the toxicitv of chloramphenicol in the neonate. Such a metabolite has been identified: the compound, however, is of low toxicity,""· """ and thus unlikely to be of etiologic significanct·. Chloramphenicol inhibits protein synthesis. including that of enzymes. Since the survival in the extrauterine environment calls for extensive changes in enzyme activity, it is plausible that substances like chloramphenicol could interfere with the development of a variety of essential functions. In contrast to the high susceptibility of the newborn, the fetus docs not appear· to h<' affected adversely by chloramphenicol aclmm!stered to the mother during gestation. This is not because of a limited transfpr across the placenta, 41 but more likely becaust~ the amounts used; in the adult are, on a weight basis, small compared to those employed in the past in the newborn.

446

Adamsons and Joelsson

{ kt1rllt'l \ill

Recently. chloramphenicol has been administered directly to the fetus for prophylactic purposes after completion of intraperitoneal infusions of blood in patients with erythroblastosis fetalis. The high natural morbidity and mortality encountert>d in these cases make it impossible to n·nture an opinion regarding the safety of such treatment. If an analogy of other nonionized substances of similar molecular weight can bt· applied, placental clearanu· should prt'\Tnt undue rises in the concentration of chloramplwnicol in fetal tissues. Antiprotozoal agents

It is known that quininl' crosses the placenta""· '"' hut contrary to earlier beliefs. the drug does not seem to affect the fetus in an adncrsc fashion."' It is difficult tn envisage why quinine was considered toxic to the intrauterine patient. Tfw drug has been used extensively in the past for treatment of malaria, and thus therP should not havt" been a dearth of material upon which to base conclusions regarding its safety. Carefully conducted studit"s 100 • '"·· do not indicate that fetal losses an· increased by treatment of the mother with daily doses of quinin<·. It is possible that the obstetrician has been aware of the high incidence of passage of meconium in tht" treated cases and has interpreted this as a sign of intrauterine asphyxia. Mort> likely meconium passagr is due to a direct action of quinine on the fetal intestine rather than upon fetal circulation or intervillous space perfusion. Occasionally. claims have been made that quinine intrrferes with. the de\·eloprnrnt of the middle t·ar of the ft'tus and causrs congenital deafness. This notion cannot hP supported bv data aYailable in the literature. Furthermore. the incidence of deaf-mutes in areas where malaria is indigenous, and quinine consumption by the population is high, does not appear to be higher than elsewhere. This is not to deny that. in several species oi rodents, cochlear damag<" can he produced hy administration of lz,·ge doses of quinine to the mother.''"·""" Replacement of quinine bv more recently devdoywcl anti-

.I

j

f!jf,l_,

j )])'.:j, ,\,: ( r\ IJI'f

malarial drugs renders this topic chidh· ol historic interest. The only situation in which antimalarial drugs, such as f'rimaquin,·, /Jt Jltaquim. ami othns. could cause serious di-;turbamT'i in the fetus would be in tbt· ran· C
Volume 96 Kurnher 3

bradycardia, occasionally hypothermia, and nasal congestion." 4 More recent studies"" 4 • """ have provided evidence that administration of small doses of reserpine to pregnant guinea pigs during the second part of gestation leads to comparable depletion of catecholamine stores in both fetus and mother. Stillbirth and perinatal mortality increased in relation to the dose of reserpine over a range which did not affect maternal survival. The newborn showed marked impairment of thermal stability when compared to those from control litters. These studies focus attention on the role of catecholamines during fetal life and call for further investigation of substances or states known to alter the function of the autonomic nervous system."" The decreasing popularity of jJhnzotlzia~inn in the management of labor appears to he responsible for the paucity of data in the recent literature regarding the effect upon the fetus and newborn. The initial claims that phenothiazines potentiate the effect of anaJg·esic drugs without a concomitant in
Effects of pharmacologic agents 447

chlorpromazine to the mouse during gestation reduces the learning ability of the of spring and impairs the performance in sn·eral behavioral parametersY 1 Prenatal exposure to chlorpromazine was also associated with a decreased activity of alkaline phosphatase and leucine aminopeptidase in the serum at a postnatal age of 75 days. It is difficult to assess the relevance of these observations regarding the usc of tranquilizers in the human. There is little doubt that functional abnormalities resulting frolll exposure to foreig-n substances during pn·natal life will receive more attention in tlw future.

r-

Cardiac glycosides Although di[.;italis and its congeners arc extensively used in the management of a variety of cardiovascular disorders in pregnancy, information regarding their effect upon the fetus is virtually abst>n t. It ha o; hcen assumed generally that conventional doses of cardiac glycosides administered to the mother produce no ill effect in the fetus. This assumption has been based on the knowledge that the tolerance of the newborn infant to cardiac glycosides on a body weight basis is at least equal to that of the adult. 1 ""· 1 The justification of such an inference j, " uncertain. For example, it has been found that the concentration of raclioactivP digitoxin in the fetal heart can exceed that of the mother by a factor of l 0. u:s, 1 "'' Recently, cardiac glycosidcs have been administered directly to the fetus for treatment of presumed heart failure in cases of erythroblastosis fetalis. No conclusions regarding the efficacy of such treatment can be drawn from the few observations. Cardiac glycosides are readily absorbed from the gastrointestinal tract; thus there is the possibility of digitalizing the fetus by administration of the drug into the amniotic fluid. Since heart failure in utero resulting f rorn hemolytic anemia represents one of the few instances of fetal illness in the presence of normality in the mother, data regarding the effect of cardiac glycosides upon myocardial functions of the fetus vvould be desirable.

448 Adamsons and Joelsson

Anticoagulants

H c parin is known to cross tissue boundaries with difficulty'"'-'· 17 '' due partly to a relatively large molecular sizP and strong electronegative charge. Lack of complications in the fetus or newborn following maternal anticoagulation therapy with heparin has provided circumstantial evidence that this drug does not cross the placenta in biologically significant quantities. Only recently has an attempt been made to determine wheth<"r administration of heparin to the mother affects the blood coagulation of thP newborn.'''·"'" No prolongation in clotting or thrombin times was encountered in infants whose mothers had received heparin prior to delivery compared to those from a control group. Although the serit"S was small, the conclusion appears justified that administration of heparin to the mother has no untoward effects on the fetus. Heparin has been administered directly to the fetus at the time of intrauterine exchange transfusion." "" In view of the slow clearance of heparin by placenta, it is likely that prolonged anticoagulation results from such a treatment. In order to minimizP the effects of an extended disturbance in clotting mechanisms, citrate has been proposed as the anticoagulant of choice for this procedure.<· '" Because of the low pH of citratcd blood, objections have bePn raised against its use in exchange transfusions of newborn infants. This consideration, however, appears of minor significance when the procedure is performed during fetal life because of the possibility of elimination of the hydrogen ion by the placenta. The anticoagulant effect of citrate in the fetal circulation is probably transient owing· to the entry of calcium from the maternal compartment as well as to the clearance of citrate by the placenta and fetal tissues. The history of bishydroxycoumarin is of particular interrst ~ to the authors~ kno\vledge this is the only substance used in human therapeutics which was discovered by the recognition of an unusual syndrome in the offspring."'" Although bishydroxycoumarin and its analogues are nearly completely

( kt11lwr l. l~lt_,f_~ .\lll.

J.

Oh:-;t. & Cv1wr.

bound to plasma proteins, which should prevent their penetration into the fetal compartment, it is known that these compound' eros;. the placenta, eliciting a more pronounced anticoagulative effect in th<' fetns than in the mother. It is likely that minutt' quantities of free bishydroxycoumarin suffice to interfere with prothrombin syntlwsis hy the fetal li\·er. Nevertheless. bishvdruxycouma rin and related compounds h occurs in the fetus. If increasing doses of th( anticoagulant are used to maintain matnnal prothrombin time within desin·d limits thi, might create serious disturbanct•s in blood coagulation on the fetal side. It remains t< he elucidated whether prefnential protertinL of the fetus from the undesirl'd anticoagu· !ant l'ffect of bishydroxycoumarin giVt·n U the mother can he achie\·t•d b\· administra· tion of vitamin K or the svnthctic analogw·s of menadione either directh to th(· fetus 01 into the arnniotic cavit'~.,:. Compounds with activity that of vitamin K

resembling

Menadione and related svnthetic cnm pounds v;ith biologic properties sin1ilar h

Volume 96

Effects of pharmacologic agents

X umber~)

those of vitamin K are known to increase neonatal jaundice when large doses are administered to the infant after birth or to the mother shortly prior to delivery. 6 • 7 • 53 • 78 • 110 • 4 " " It is now appreciated that in some of the earlier studies in which menadione or its analogues were used prophylactically for prevention of hemorrhage, doses far in excess of the therapeutic requirements were employed. An increase in neonatal jaundice has not been observed following the use of the natural vitamin K.' 1 The mechanism by which menadione leads to hyperbilirubinemia in the newborn is not fully understood. At least two factors appear to play a role: hemolysis of fetal red cells and impaired clearance of bilirubin. It has been proposed that the red cell of the newborn. particularly that of the immature, is more likely to undergo hemolysis in the presence of oxidants such as menadione because of a lesser ability to maintain glutathione in a reduced state. This vulnerability is most often due to deficiency of other enzymes than glucose-6-phosphate dehydrogenase. Nevertheless, patients with glucose-6-phosphate dehydrogenase deficiency or with other inborn errors of red cell metabolism, such as glutathione reductase deficiency, arc particularly susceptible to oxidants because of the essential role of these enzymes in metabolic performance.''· 1 sG, 222 • 2 ''" Water-soluble salts of menadione, at least in vitro, can oxidize hemoglobin to methemoglobin."' It is possible that the reduced triphosphopyridine nucleotide is thereby drawn away from the glutathione pathway to serve in the methemoglobin reductase reaction. 74 In vitro menadione reduces the activity of glucuronyltransferase and the hepatic conjugation of bilirubin. 117 • """ Immature infants given large doses of the drug show diminished conjugation of the metabolites of acetaminophane with glucuronic acid. On the other hand, unchanged activity of glucuronyltransferase has been encountered in newborn rats treated with large doses of menadione sodium diphosphate. Since it is known that considerable differences m the actJnty of glucuronyltransferase can be ob-

449

tained depending on the substrate chosen, the implications of these observations remain uncertain. Large amounts of menadione ha\·e produced liver damage in the animal. It is unlikely that this occurs in the human following use of therapeutic doses. It has been shown that 30 mg. of menadiol given to immature infants does not increase the activity of glutamic-oxal-acetic acid transaminase in serum. 204 Cholinesterase inhibitors

Little information is available regarding the effects of cholinesterase inhibitors on the fetus because of the rarity of maternal conditions requiring their use during pregnancy. Most clinically used cholinesterase inhibitors, such as nt·ostigmine, edro jJ!wnium, and pyridostigminc, contain a quaternary ammonium and are expected therefore to cross the placenta only to a limited extent. This is in contrast to physostigmine which does not contain such a group and is therefore likely to penetrate biologic boundaries more readily. During prolonged treatment, particularly when large doses are used orallv, it is possible that even the synthetic cholinesterase inhibitors reach the fetus in biologically significant quantities. Sufficient information is lacking as to whether physostigmine is equally as safe as the synthetic analogues. Although of no apparent consequence during fetal life, cholinesterase inhibitors given to the mother during gestation might influence the condition of the newborn. Transient muscular weakness is obsen·ed in 10 to 20 per cent of newborn infants whose mothers have received these agents for treatment of myasthenia gravis. 152 This might represent a withdrawal phenomenon rathn than escape from a transplacentally acquired endogenous inhibitor. In this regard it would be of interest to determine the frequency of neonatal myasthenia among new·born infants whose mothers had discontinued medication some time prior to delivery. Ganglionic blocking agents

Although the physicochemical properties

450

Adamsons and Joelsson

of hexamethonium do not appear to favor its transfer across the placenta, the drug is rt'adily dt'tectt'd in the fetal compartment. Following intravenous administration in large dost's to tht' pregnant rabbit, ht'xamethonium in the fetal circulation reaches a concentration which amounts to nearly 50 per cent of that present in the matt'rnal blood. In oldt'r fetuses a substantial concentration of the drug is pn'St'nt in tlw amniotic fluid which may exceed that of fetal or maternal plasma."'" Hexamethonium has also been detected in cord blood and amniotic fluid in the human. 158 Due to differences in dosage. route of administration, and \'arying time intervals between discontinuation nf treatment and delivery, no statcmt'nt regardin,g the rate of transfer of hexamethonium can be made at present. Administration of hexamethonium during pregnancy has occasionally been associated with paralytic ileus of the newborn.'"" It is uncertain to what extent this is due to thr· action of the drug upon the gastrointestinal tract of the fetus because imrnatun~ infants. particularly those asphyxiated during the course of delivery, are known to develop paralytic ileus spontaneously. Declining popularity of ganglionic blocking agents in the management of hypertensive disorders associated with pregnancy renders this topic chiefly of interest to the experimental pharmacologist. Some of the more recently synthesized ganglionic blocking agents such as mecamylamine and jJ,·mpidine do not contain a quaternary ammonium and therefore would be expected to reach the fetus more readily than hexamethonium. Hypnotics

Oxybarbiturates and thiobarbiturates readily cross the placenta. 25 • 01 • 67 • "'· 8 "· 112 Following intravenous administration of the drug to the mother, thiopentone sodium is detectable in fetal blood within 45 srconds 1 G1 and maximal concentrations are reached within a few minutes. Thereafter, there is an exponential fall of comparable velocity in both the fetal and maternal compartments. The perineahility of barbiturates is not lirn-

\nr.

t lt toht'l J ltfhiJ J. Ohst. & ( ;'I.'TWI

itcd to the placenta at term smce an·umttlation of barbitone and phenobarbitone ">dium in fetal brain and li\·t·r has been dt•ntonstrated in human fetuses from therapt·tnic abortions early in gestation.''' :\t equilihriurn conditions. the concentration of harbitw lation. Tltt· conditions of tht' ft'tw;, howt'\ n. could lw jl'opardizl'd if maternal lt\-potension dt'\Tlops followi n.g intravenous ad min istJa tion of barbiturates. This would lead to asphvctic tkptTssion of thl' fetus ratlH'r titan to scd;!tion. It appears that in 111an\ stmlit"< ll'' distinction has IH'en attctuptl'd bl't\\ t't:'ll tltt''-'' two t'ntitit''· Barbiturates given shortlv hdore vaginal delinTv rat-ely depress the infant. Thi;; is due to till' small quantities of tlw drug n·~tclt­ ing tlw arterial side of tlw ft:tal circulation. \'Vht'n an equi\·alent dose is gi\ t'n at a similar tirnt· before deliw·ry by l'lt·ctin· cesan·an st•ction, depression of thl' newborn, as jud!_!t·d hv Apgar score, can occttr.'" No studir~s to date arc a\·ailable regarding thl' l'fi'ects of barbituratt:'s upon n·gulatiori of the hocly temperature of tlw nconatt'. Since it is known that administration nf svnthctic analgesics to the mntlwr lt,ad, to :1 ~n1a1I a1thou.u:h prnlon,ged ln\\Trin,g of dt't'P hody tt·mperature of the nt''' horn."' stwlt data would be of considerable intl'rt'st. In contrast to the abundanet' of data JH'Itaining tu the eflects of barhituratC's t!pon

Volume 96

Effects of pharmacologic agents

~umbt'r :~

attention has been paid to the influence of these agents upon the rate of development of enzymatic activity of the fetal liver. It is known that barbiturates and other drugs such as meprobamate, chlorpromazine, and primidone increase the rate of synthesis of liver enzymPs concerned not only with the metabolic degradation of these substances, but also of those involved in the formation of g·lucuronides. Since conjugated bilirubin does not cross the placenta in significant quantities, transplacental elimination of bilirubin would be impeded by premature activation of conjugating enzyme systems. It should be recalled that increased ability to conjugate bilirubin is not necessarily accompanied by an increase in biliary excretion. The dangers of excessive conjugation of bilirubin would be particularly great in instances of hemolytic disease of the fetus where the placenta is expected to clear large quantities of bilirubin. It is possible that some cases of unexplained hyperbilirubinemia of the newborn might have resulted from the combined effect of agents causing hemolysis of fetal red cells and the formation of bilirubin glucuronide. High levels of conjugated bilirubin of plasma have been obS('rwd in erythroblastotic infants following administration of red cells into the peritoneal cavity of the fetus.'"" Recently attempts have bef'n made to synthesize barbiturate analogues without hypnotic properties for the specific use of enhancing the rate of formation of a variety of liver enzymes in the nPwborn. This problem must be approached with caution in the prenatal patient. The low ability of the newborn to elimthe- nrolon!!ed exnlains inC>tr ,_) - -r---------· ---------------- h:irhitur;~tr.<; in encountered action of these substances however, doubtful, is animal experiments. It that the sensitivity of the newborn animal differs as much from that of the adult as has been implied. In most studies, thermal conditions have not been controlled and lowering of body temperature of the newborn animal might have contributed greatly to the prolongation of drug effect. A recent report" 13 suggests that administration of analgesic and hypnotic drugs to ~

451

the mother during labor might have longlasting effects upon the responsiveness of the newborn infant. The test procedUie, which was designed to measure the attentiveness of 2- to 4-day-old infants, revealt>d significant differences between infants whose mothers had received various depressant drugs and those born to mothers not rcceiving such medication during labor. The results are provocative and suggest that further inquiry in this area might be rewardmg. Ethyl alcohol has recently received attention because of its potential value in the management of premature labor. The extensive use of the drug in the past without evidence of undesirable effects upon the fetus appears to have established the safety of this agent. The previously held notion that ingestion of alcohol during pregnancy leads to damage of germ plasma and to degeneracy of the offspring is merely of historical interest. Ethyl alcohol readily crosses the placenta1 "· " · 1 ''" and is present in the fetus at the time of delivery. Little is known about the ability of the newborn to metabolize alcohol. There is circumstantial evidence that alcohol or its derivatives is more readily metabolized by the liver than other hypnotics. The tolerance of the ne\\born rabbit to ethylcarbamate is considerably greater than that of the adult on a body weight basis while the reverse is tnw for barbiturates. 331 Weak analgesics

Salicylates are known to cross the placenta of the human, rabbit, and guinea pig. m The absence of reports indicating untoward rffects of this drug upon the fetus in the presence of its widespread usc support the contention that administration of salicylates to the mother, even in large doses during pregnancy, is not hazardous to the fetus. The rare instances in which salicylates might create problems are those where erythrocyte metabolism is abnormal, for example in glucose-6-phosphate dehydrogenase deficiency. In the adult, salicylates are known to rP-

452

Adamsons and Joelsson

duce plasma prothrombin levels.''" The prolongation of prothrombin time is chiefly due to reduction in Factor VII. a phenomenon similar to that produced by bishydroxycoumarin and its congpners. Tfwse effects, howt>VCL have been observed only when large doses of salicy!ates have been given. No information to date is available as to whether this occurs in the fetus following administration of salicylate to the mother. The known susceptibility of the fetus and newborn to certain anticoagulants renders such inquiry of considerable interest. A few reports indicate that acetophenetidin can produce metht'moglobinemia in the newborn. This is not entirely unexpected since it is known from in vitro studies that the erythrocytes of young infants arc deficient in the enzyme system responsible for the reduction of methemoglobin. Although the possibility rt'mains that in certain patients with genetic deficiency of erythrocyte enzymes. the administration of a variety of substances with oxidant properties could be deleterious to the fetus. clinical experience suggests that administration of acetophenetidin in com·entional amounts during pregnancy is not hannfu!.

Strong analgesics There is a >vealth of direct and indirect evidence that morjJhin" and its congeners readily cross the placenta. This includes the development of addiction in utero,"'"· "'"'· "'' severe respiratory depression and the presence of myosis in the newborn infant, and 4ualitatiw identification of the agents in blood or excreta of the newborn.'· ,,,;, ""'" """ More recently, detailed information has been made available regarding the distribution of tritium-labeled clihydrornorphine between mother and fetus in the rat. "'l' This study revealed that maximal concentrations in both fetal and maternal plasma following administration of 2 mg. per kilogram subcutaneously to the mother were reached at 30 minutes. At this time the ratio between mother and fetus was + to 1 with approximately half of the substance present in maternal plasma in the conjugated form. Since this fraction is unlikely to participate in the

\1u.

1

Ocluber I, I!H)h oh~t. & c;\nt·(

t·xchangc between the two compartments tlw ratio of the free compound is mon· rl'levan t. An equilibrium between maternal and fptal plasma was reached at about 2 hours. Tlw conjugation in the fetal compartment proCl'Cdcd mon· slowly. and afttT 1 hor11· ll·s> than half of the total amount of dihydromorphine was in the conjugated form. Ol particular interest was thl' observation that concentration of the drug in fetal brain nm,iderablv t·xccedcd that in matemal hrair, in spite of consistently !own lt'n·ls in plasma. Littlf• is known about tht· t•ffects of lllotphine and its congeners upon thl· fl'tus. SitJCt' ktal homeostasis is not dqJt·ndt•tJl on till' actiYitY of the respiratory ct·ntt·r. it i.s >Ill .. likelv that trlt'se substanct's would <'Xt'n ;1 deleterious effect. DecTt'aSl' in respiratol'\ nlo\·enwnts of the fetal rabbit ha~ lwcn uhscrved following administration of morphine to the dot·. Large dost·s of the drug could intt-rfen· with fetal cardio\·ascular function: howenT, thne is no reason to lwlit'\l' tl!
Volutne 96 i\umher :~

As mentioned above, nalorphine, a synthetic congener of morphine, crosses the placenta. It is known to reverse some of the depressant effects of morphine and a variety of synthetic analgesics. The drug has been considered effective when given to the mother shortly before delivery of the fetus, or when given directly to the newborn. 17 • '1''· ""· 1 '" Nalorphine itself has analgesic and depressant properties and not infrequently its antagonistic effect is of short duration. Furthermore, it has been shown'"" that administration of nalorphine to morphine-treated dogs leads to an increased concentration of morphine in the brain. Meperidine and other synthetic analgesics also cross the placenta.""· "30 Meperidine is generally regarded as being less depressant upon the fetus, but conclusive evidence of the superiority of the substance is lacking.'r, '1 ~· ":J The evaluation of the depressant properties of any agent in the newborn is difficult because the drug effect varies with the degree of intrauterine asphyxia. It is of interest to note that poor correlation has been obtained between the concentration of meperidine in umbilical venous blood and the clinical condition of the newborn.

Oxygen and anesthetic gases Administration of gas mixtures containing high concentrations of OX)'[!,en to the mother is believed to increase oxygen saturation in the fetal blood. E\·idence in support of this contention is inconclusive""· 187 and several investigators have found similar concentrations of oxygen in cord blood among patients breathing 100 per cent oxygen and those breathing room air. A variety of factors explain the variable and unpredictable effect of oxygen breathing upon the fetus. Due to the low solubility of oxygen in plasma e\·en an increase in P 0 ~ in the inspired gas up to one atmosphere will add less than 10 per cent to the oxygen content of the blood. Thus, a minimal reduction in placental perfusion would nullify any benefit the fetus could have derived from a higher oxygen content in the intervillous space. It is well appreciated that disturbance in perfusion of

Effects of pharmacologic agents

453

the sites of gas exchange is the principal hazard in fetal homeostasis rather than a low partial pressure of oxygen in maternal arterial blood. In the rhesus monkey in which placental perfusion was impaired, administration of oxygen to the mother resulted in an insignificant change in P 0 " of the fetal arterial blood. 143 It is noteworthy that administration of oxygen-rich gas mixtures to the human during labor have been associatt·d with a fall in pH and a rise in carbon dioxide tension in capillary blood of the fetus.'"' Hypoventilation of the mother might ha\·c contributed to this phenomenon. Howewr, similar changes in the fetal acid-base state have been also observed in instances where administration of oxygen to the mother was not associated with a rise in maternal Pt'""' Maternal and fetal anemia and the presence of placental edema are among the few conditions in which oxygen breathing, at least theoretically, offers benefits to the fetus. E\·idently, more information is required before the therapeutic merits of oxygen breathing under conditions of fetal distress can he a~­ certained. As expected, all anesthetic gasn readily cross the placenta. The relative rates of transfer, however, vary from compound to compound and the ratios of concentration between the maternal and fetal compartments at equilibrium differ considerably. The halogenated hydrocarbons, such as halothanr, chloroform, and trichlorethylene, owing to their high lipid solubility appear to reach the fetus with greater facility than nitrous oxide."'· 110 • 11 1. "''" The same appears to he true also for cyclopropane which can be cktected in cord blood within 90 seconds following administration of the agent to the mother. 9 Difficulties have been encountered in assessing the specific effects of anesthetic gases upon the fetus because of concomitant changes in maternal ventilation, circulation, and uterine perfusion. Furthermore, it has not been possible to dissociate the contributions of anesthetic agents from those of analgesics, hypnotics, tranquilizers, or those caused by fetal asphyxia. Clinical experience in mothers undergoing operatiYe procedurc·s

454

Adamsons and Joelsson

during pregnancy has demonstrated that in the absence of maternal hypott>nsion or respiratory deprt>ssion, administration of ant'sthetic gases is not detrimental to the ft>tus. However, tlw use of these potent anesthetic agents for electin~ cesarean section is associated with lower Apgar scores and a delay in the onset of respiration of tht> newhorn. It is probable that tolerance of the fetus to halogenated hydrocarbons is greater than that of the mother. Administration of halothane in concentrations sufficient to produce maternal hypotension in the sheep had no effect on the blood pr<'ssure or heart rate of the fetus. 11 ' Newborn humans and young infants art> known to require higher concentrations of halog·enated hydrocarhons for surgical anesthesia. The extraordinary resistance of the fptal and newhorn Ji\·er to carbon tetrachloride and chloroform has been well appreciated.""· "" 7 Among thP anesthetic gases trichlorethylene occupies a unique position since, at least in tht> sheep and the goat, the concentration of the agent in the fetal blood frequently l'Xccecls that present in the maternal circulation.lll It is also known that tlw uptake of trichlorethyknt> by fetal blood in vitro exceeds that of maternal blood. This has been attributed to the rdatively large mass of the erythrocyte occupied by the cell wall, considered to be the principal site of trichlorethylene's storagP. The significance of this observation regarding the clinical use of trichlorethylene is uncertain. Local anesthetic agents

Local anesthetic agents not susceptible to the hydrolytic action of plasma esterase have been used for a number of years, but only recently attention has been focused on the systemic effect of these agents upon mother and fetus."''' Lidorainc, mcpiuarairu·, and jJH>jJitocain'' rapidly enter the systemic circulation of the- rnotht~r follo\ving their administration into the epidural space. l'vfaximal concentrations are reached within 30 minutes and maternal plasma levels remain elevated for more than two hours following a single injection of 300 to ~·00 mg. ~/[epivacaine has

\Ill

J.

\ ktuhl'r l, I ~lhh ()hod & {;YIII'f

been det('ctcd in the fetal ci rcula 1ion wt tlnn 1() minutes following administration of tltc drug to the mother. Thr· fl'lal li\ •·r does not st'l'lll to play a major rok in tfw r!t"a rivacaine since tlw conct·ntratiott II< umhilical arterial blood is
(:ompounds that affect thl' n•·uromusculat .Junction t•ither by stabilization or depolarization an· characterized bv tlw presencl' ot a quaternary ammonium ,~roup. Tht· higl1 degrt'l' of ionitation of this moietv togl'thn with low lipid soluhility of thi;; substann· t'xplains why the placenta j, 'irtualh· illlpctTiou;; to most neuromuscular blocking a,gents. rrhis has bctn apprrciatrd fo, ~l ntmt~lt'r of dl~cades in animal <'xperiltH'lll '·
Volume 9fi !\umbt·r 3

tative as demonstrated by the appearance of tubocurarine in the fetal circulation following injection of large doses into the uterine artery. 17 " Gallamine appears to reach the fetus more readily than tubocurarine or decamethonium iodide. 180 This fact, however, is of little or no clinical significance. In the pregnant rabbit a thousand times the minimal paralyzing dose for the mother was re-

quired to produce clinically detectable changes in the newborn. 131 If neuromuscular blocking agents are administered directly to the fetus of the experimental animal their effects are similar to those seen in the adult. The response, however. varies depending upon the state of dewlopment of the neuromuscular junction. This explains the different responses observed among the newborns of different specics such as the rat and the guinea pig. Paralysis of the neuromuscular junction of the fetus may lead to skeletal abnormalities. Thi:;; has been demonstrated in the chick embryo following administration of tubocurarine. succinylcholine, and decamethonium. It has been inferred that skeletal and joint abnormalities arc not caused by the specific effect of these agents but by the lack of body move1nen ts:'' The exceptionally high resistance of the placenta to neuromuscular blocking agents makes it unlikely that abnormalities of the fetus could result from the clinical use of these substances during early pregnancy. Hovvever, it leaves open the possibility that other agents affecting the neuromuscular junction, such as magnesium or dmgs altering the motility of the fetus by hypnotic or tranquilizing action, might have a bearing upon skclc-tal development. Proteins

A variety of proteins arc known to cross the placenta. This was first demonstrated more than six decades ago by the identification of diphtheria antitoxin in cord blood."3 In the human, proteins enter the fetal circulation via the chorioallantoic placenta in contrast to the rodent vvhere transmission

occurs chiefly through the yolk sac splanch-

Effects of pharmacologic agents

455

nopleure. Placental permeability is a highly selective process which is unrelated to the molecular weight of the protein molecule. Gamma globulin crosses the placenta with greater facility than albumin and intact molecules penetrate the fetal compartment more readily than their hydrolysates."" ABO saline isoagglutinins are not present in fetal circulation171 whereas albumin agglutinatir1g antibodies are. The method of transfer of protein molecules from the mother to the fetus is not known. A particular process of \·acuolizatiPn and engulfing the material, referred to a-; pinocytosis, is thought to be instrumental. The arguments in support of this contention, however, are not cogent. The functional si!.!;nificance of albumin transfer during the Ia lter part of gestation is uncertain since fetal liver is able to synthesize albumin at an early age."" In contrast, permeability to gamma globulin is of considerable importance at least to man in whom there is no postnatal transfer of passive immunity. s('\"eral blood group antibodies also cross the placenta and are responsible for hemolysis of fetal red cells. Particularly hazardous to the fetus are Rh agglutinins. A varictv of Sj)('cific antibodies are transfern·d to the fetus following active irnmuni;mtion of the motlwr during pregnancy. This would be expectt"cl to increase fetal resistance to certain viral diseases and to contribute to the defeme mechanism of the neonate. No attempt, as yet, has been made to transmit to the fetus antibodies to blood group antibodies. It is possible that such an approach will receiw attention in the future in the pn'n'ntion of erythroblastosis fetalis. Miscellaneous substances The effects of symjJathomimctic ammcs upon the cardiovascular system of the fetus have been extensively studied in a variety "f lower species, notably in the sheep and rabbit.';o ot, 7 " The sensitivity to catechobmines differs from species to species and is influenced by the state of maturity. When the change in blood pressure and he3rt rate is expressed as percentage change rathlT

456

Adamsons and Joelsson

than in absolute terms, the sensitivity of the older fetus to eatecholamines on a weight basis is similar to that of the adult. Occasionally, the relevance of the earlier observation has been questioned because of the use of anesthesia and partial exteriorization of the fetus. This criticism does not appear pertinent. In a more recent study 1 ~~ in which unanesthetized animals with chronically implantrd catheters wen~ used. similar sensitivity to norepinephrint> and epinephrine has bt:'<'ll encountered to that observed in the exteriorized preparations. Two reports are availablf' describing thf' effects of epinephrine upon the human ff'tus. In one instance intramuscular administration of 50 micrograms of l'pint>phrine resulted in a prolonged elevation of tht' fetal heart ratP. 38 In the other case in which 500 micrograms of norPpim·phrine was injt•cted into the buttock of an anencephalic fetus. a rise in fetal colonic temperature was noted. which was associated with an increase in the temperature gradient between the fetus and mother." 11 Administration of atropine to the fetus leads to a change in the fetal heart rate for a prolonged period.'"" There is an increase in the resting rate and a reduction in the fluctuations normally observed during uterine contractions. Without the knowledge of the biochemical state of the fetus. it cannot be inferred that partial elimination of vagal control of fetal circulation is beneficial. Because of their physicochemical properties br:n::othia::idcs are likely to cross the placenta. This. howc\·er, remains to be verified. On rare occasions, administration of henzothiazides to the mother during the

t ), robt"t \JII

J

t

I~NJt

Oh~.t. & fl\TJ~'I.

latter part of pregnancy has been assoriakc with tbromhocytopenia in llw rwwbom.'·· The disturbance has been ascribed to a din·ct effect of the diuretic upon tlw pmcluctioJ of megakaryocytes in the honf' nmrrnw '); the fetus. presumed to possc·;;s unusual ~It'· u·ptihility to tlw drug. Thromboc)·topeni;t ht'rvt·d ''nlv wit! doses many times that required tor dinn"sis \Vith the widespread JISt' ol lwnzothia:ti hazard 1h r. 1,,,, ,., f.,, tlwir suggf'stiow: and to J\fr,. Dnrotlw [)"I I•· ''' h<'r assi.st anr•· in preparing t ht' r•·l<'l <'Il<'<'·'·

1.. Stanley Jar]](:' and Dr. Jerold

REFERENCES

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Volume

~IIi

Effects of pharmacologic agents

:"i1l111hn· :~

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1966. 63. Desforges, Jane F.: New England J. M1·d. 273: 1310, 1965.

458

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6+. Desmond, M. M., Rogers, S. F .. Lindley, J. E., and Moyer. J. H.: Ohst. & (;ynec. 10: 140, 1957. 65. Dieckmann, 'v\'. J.. and Kramer. S.: Proc. Soc. Expcr. Bioi. & Med. 55: 2+~. 19H. Gti Dill, W. A., Thompcon, E. M .. Fishn. R. A .. and C:lazko, A. J.: :'{Jtun- 135: .7:)5. 1960. 67. Dille.]. M.: J. Pharmacal. 52: 1~9. 19:H. 6H. Dille, ]. M.: A~r. }. 0RST. & GY~EC. 32: :l2n. 19%. 69. Dillin~, W. J., and Gemmell. A. :\.: J. Obst. & Gynacc. Brit. Ernp. 36: :i5:.>, 19~9. 71l. Doi.S<. R. K .. and Coltrnan. 0. McK.: Lancet 2: 7:H1. 1956. 71. Done, A. K.: Clin. PharmacoL & Therap. 5: Ll~. 196+. 7'2. l)ornhorst. A. C., and }'"oung. I. :\f.: ]. Physiol. 118: 2H2, 1952. 7:\. E1phinstone, K: Lancet 1: 1:281. !95:\. 7+. Ernster, L.: A possible efl'ect of \'it,tmin K:: on ('rythrocyte metabolism, in Sass-Knrtsak, A .. editor: Kernicterus. Toronto, 1961, T...-nivt>rsity uf Tnronto Press, pp. 68-7~. 7"L Fainstat. T. C.: End"crinology 55: .102. J9:i+. 76. Fealy, J.. Obst. & c:ynec. 11: :H:.>. 19.73. 77. Fetchko, A. M .. Weber, J. E .. Canoll, J. H .. and Thomas, G. J.: AM. J. 0RST. & GYXEC. 62: 66~. 1951. 7H. Finkel. M. J.: Clin. Pharmacol. & Therap. 2: 795. 1961 79. Finland, M., and 1\iichols, R. L.: .\ntibiotica ct chcrnothnapin 4: ~09. 1957. Hll. Finster, M., Mark, L. C., Morishirna. H. 0., Moya, F .. Perc!, J., James, L S .. and Dayton, P. (;,: A~1. J. OnsT. & GY>:EC. 95: 621. 1966. 81. Finstt'l\ M .. Poppers. P. J, Siwlair, J C: .. Morishima, H. 0 .. and DanieL S. S.: AM. ]. OnsT. & GYNEC. 92: 922, 196.5. H~. Fisch. R. 0 .. Berglund, E. B .. Bridge. A. G, Finlt·y. P. R .. Quie, P. G .. and Rai!t·, R.: .J. A.M. A. 185: 760, 196:L H3. Fischl. R. von Wunschcim: Ztschr. Heilk.

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%

Goodfriend, M . .).. Shq. I .\ .. and Kkitl.

M. D ... hL

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CJil.

(J9. ]flO. I (I].

I fle'. ](J'\.

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\09.

\Ill. Ill.

I I~II :l.

16: l-:29, Ul95.

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J. ( Jh..,t.

Ill.

L.

J. ( )BST.

&

S ..

and

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J

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71:

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pharmacological basis of therapt·utics, ,.cJ. '1. ;\j,•w York. 196), The Macmillan C:ompan' Cordon. R. R .. ~md De,Lil. T · Fll'il. M. ) 2: 719. 195:i.

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IJH.

IlyrJI<
19+iL

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125. l2t:i. !27. l2H.

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~~1.: ~A,.rr1.

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459

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460

193. 19+. 195. 196. 197. 19B. 199. :COU.

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