Drugs Across the Placenta-Apgar and Papper

(-Transmission of Drugs Across the Placenta3

Virginiia(Apgar, M.D. and E. M.kapper, New York, N. Y.

  Department of Anesthesiology of the College of Physicians
and Surgeons, Columbia Hospital, and the Anesthesia Service of the
  Presbyterian Hospital and the Sloane Hospital for Women

NOWLEDGE REGARDING the transmission of sub-
stances across the human placenta to the fetus has been
gained in several ways. Clinical impressions constitutk by
far the largest group of observations and have only a
limited value because of their purely qualitative nature.

The estimation of depression of the newborn infant after various
sedatives, analgesic and anesthetic agents have been administered to
the mother varies considerably with the interpreter.  The exact mean-
ing of "breathing time" and "crying time" is indefinite although varia-
tions in interpretation are minimized by having only one or two
observers.

Reliance upon clinical impressions alone has accounted for the
unhappy life history of many new drugs and techniques used in obstet-
ric analgesia. The cycle of enthusiastic introduction and subsequent
optimistic reports, followed by a quiet disappearance of such papers
from the literature, and finally a slow death of the new method because
of adverse experiences spread by word of mouth rather than the
printed page, is all too familiar.

  The need for resuscitation of the newborn infant has been used as
a method of evaluation of transplacental passage of potent analgesic
drugs and anesthetic agents1 However, the quality of the administra-
tion of anesthesia, familiarity with resuscitative measures and the
availability of appropriate equipment often are limiting factors which
may vitiate attempts at quantitative interpretation of the effects of
anesthetic agents on the newborn.

In a clinical sense, a long range program of follow-up visits of
severely depressed babies, as well as healthy active infants, alone can
determine the extent of cerebral and other organic damage.  Regin-
nings in this direction have been made.2

Observation of the fetus in utero is a method applicable to animal
experimentation and has been used extensively by Barcroft3 and by
Snyder and R~senfeld.~ Abnormal factors, however, are always intro-
duced, such as a transected cord, administration of labor-arresting
drugs, and opening of the abdominal cavity and uterus in a saline
bath. Despite these difficulties, valuable information can be gained
concerning the effect upon the fetus of analgesic and anesthetic drugs.

Chemical analysis of specific substances in the maternal blood
and placental blood simultaneously may also yield knowledge of the
mechanisms of placental transmission as well as the production and

`Presented before the Twenty-Sixth Annual Congress of Anaesthetists, London, England,

September 3-8, 1951.

309

Current Researches in Anesthesia and Analgesia-Sept.-Oct., 1952

circulation of amniotic fluid. Several pitfalls exist in the collection
of fetal blood for analysis. Eastman6 in 1930 used twelve-inch lengths
of umbilical cord, doubly clamped at the vulva and at the umbilicus,
and took samples from the umbilical arteries and vein by direct punc-
ture. He assumed that no essential change in oxygen or carbon dioxide
tensions took place over several hours. This assumption of the chemi-
cal stability of cord blood may be questionable since Smith` found a
definite loss of ether from blood samples drawn from the isolated cord
in one, two and three hours. He calculated the .loss and devised a
mathematical constant. to correct for the gradual loss of ether.  The
physical state of the blood in such isolated cords can change over a
period of hours. Changes in viscosity, clotting, and development of
a tendency to sludge may interfere with chemical analysis.  Barcroft
has written a masterly description6 of the difficulties encountered in
obtaining blood fcom the umbilical vessels of the intact sheep cord.
The vessels showed immediate "resentment" by going into spasm
whenever they were touched with a needle, which surely interfered
with the normal rate of exchange of gases and nonvolatile compounds.

  The method of catheterization of the umbilical vein to obtain
blood samples in the newborn infant probably provides the least
abnormal values. This method has been popularized by its use for
exchange transfusions in infants with hemolytic disease, and has been
used for blood sampling by Hellman et al.'

Analysis of the organs of the mother, fetus, placenta and amniotic
fluid has been used in animal studies for determining quantitatively
the presence of nonvolatile drugs, such as barbital and amytal.6

  In 2 human full-term cases of fatal self-administered overdosage
with barbiturates, Martland and Martlande studied brain samples of
equal weight from the mother and the fetus and combined equivalent
samples of kidney, liver and spleen of each to determine the relative
content of barbituric acid ester. In both cases fetal tissues con-
tained one and one-half times the barbiturate contents of maternal
tissues.

  Isotopic tracers have been employed recently in studies of placen-
tal transmission of water and electrolytes, the rate of extraction of
substances by the fetus from the maternal circulation, the relation of
such rates to growth of the fetus, and formation and circulation of
apniotic fluid. Flexner and Gelhorn,lo Vosburghl' and others have
reported studies of the rate of exchange of amniotic fluid and placental
permeability to water, with the aid of heavy water and sodium 24.
They found in the guinea pig that the water of the amniotic fluid
was changed 33 per cent in an hour and the sodium content at
one-fifth that rate.

There are many factors concerned with the transport of sub-
stances to and from the placenta. Circulatory changes are important,
although exceedingly difficult to measure, especially in the human

310

Drugs Across the Placenta-Apgar and Papper

patient. liffective placental blood pressure has been estitnatetl to be
the difference between the systemic arterial 1    re and the intra-
11 t erin e pressure.  In the un 111 ed ica t ed human    t the pressure in
tlie resting uterus at term is in the range of 5 to 20 nini. Hg. During
uterine contractions. tlie intrauterine pressure rises to 60 or 70 inn;.
Hg, while during the active bearing down phase, the added work of
the a1)doniinal muscles hrings the total intrauterine pressure to 160
nini. Hg." Since tlie systemic I~lood pressure rise is considerably'less
pronounced, there are periods, especially early in labor, during which
the effective placental blood pressure is loiv. The fetus, at these times,
ex per i en c e s t e ni por ar y i n t e rru 1) ti on in t 11 e t ran sf e r of all s ti 11 stances
in both directions. Clinically, this is often evidenced by fetal llrady-
cardia or other cardiac arrhythmias.

  It is unlikely that all the placental blood, estimated to be 1000 cc.
at term, is squeezed out of the placenta with.each contraction, since
the subsequent rise in matpriial venous pressure is not enough to
account for an autotransfusion of that size, From the anatomical
studies of Grosser,13 S11anne1-l~ and Falkiner,]' it is evident that inter-
villous blood drains into peripherally placed marginal sinusoids and
thence into marginal veins which empty into the uterine veins. As the
intrauterine pressure rises to 20 or 30 mm. Hg, these sinusoids are
compressed conipletely so that no further emptying of placental blood
can occur. The fetus is thus left in contact with much of the placental
blood even during a contraction.

  It is possible to separate the contributions of the uterine muscula-
ture and the abdominal muscles to total intrauterine pressure with
the aid of a differential manometer recording from intragastric (intra-
peritoneal) and intrauterine balloons. Woodbury, Hamilton and Tor-

  found that all anesthetic agents and pentobarbital and morphine
depressed the power of the abdominal muscles to contract.  These
compounds, except for ether and chloroform, had no significant effect
on uterine contractions. The various regional methods of anesthesia
were not studied. Hecaiise the depression caused by anesthetic agents
affects t h e ab doni in a 1 ni II s c 1 e s pr edom in an t 1 y , the effective pl ac en t a1
blood pressure is actually improved, for the total intrauterine pres-
sure is lessened. More blood remains in the placenta during contrac-
tions. The ultimate survival of the fetus during labor, however, is
dependent upon many other factors and not upon the effective
placental blood pressure alone.  These must also be evaluated in the
attempt to understand fetal physiology in the birth process.

  The only substances which' regularly increase the uterine com-
ponent of intrauterine pressure are the oxytoxic drugs and norepineph-
rine.  A negative effective placental blood pressure was not infre-
quently registered. From these facts one would expect a higher inci-
dence of intrapartum fetal death from interference with oxygen trans-
fer when oxytocic drugs are administered. Clinically this does not
seem to be the case, as evidenced by over 2,500 pitocin infusions

311

Current Researches in Anesthesia and Analgesia-Sept.-Oct., 1952
given at the Sloane Hospital for Women, with an actual diminution
in the stillbirth and neonatal death rates.ls

  The blood flow through the uterus has intrigued many workers
and remains difficult to study in the human subject. The changes in
flow during various periods of gestation in the rabbit have been
satisfactorily 0ut1ined.l~ In the middle of the gestation period, the
uterus contains 8 cc. of blood with a flow of 5 cc. per minute. By the
beginning of the third trimester, the volume has doubled to 16 cc.
and the flow increased decidedly to 29 cp. per minute. Then follows a
reduction in flow to 19 cc. per minute, and a final increase back to
29 cc. per minute with a volume of 32 cc. The decrease in flow coin-
cides with the slowing of uterine growth and the increase in fetal
growth.

While studying the oxygenation of the umbilical venous blood in
the human newborn whose mothers received ether, nitrous oxide or
cyclopropane, Smith noted a small peripheral arterial-venous oxygen
difference in the mothers who received cyclopropane and implied that
the high oxygen venous content was due to increased blood flow.  It
was assumed further that this increased blood flow was present in
the placental as well as the peripheral circulation.

The placenta structurally is comparable to a large arterio-venous
fistula. The blood in the intervillous spaces is both arterial and
venous in composition. The surface area of the villi which is exposed
to this blood has been estimated to be between 9 and 16 square meters.
Eastman has stated graphically that this surface is at least as large
as a 9x12 foot living room rug.'s  Mos~man~~ was the first to con-
clude that the direction of flow of blood in the intervillous space was
opposite in direction from that in the fetal villi. The umbilical arteries
bring blood from the fetus to the more venous end of the intervillous
space, where metabolic products are discharged, and the umbilical
vein carries blood back to the fetus from the more arterial end of this
arteriovenous fistula. As much oxygen as the placental blood has to
offer is thus carried to the fetus. At best, the placental blood has a
relatively low oxygen content. From umbilical vein determinations,
Eastman estimated that the highest oxygen tension in the intervillous
spaces is only 40 mm. Hg, as compared with the normal peripheral
arterial tension of 100 mm. Hg.5 Because of the high capacity of
fetal blood for oxygen, it is probable that the infant is normally
cyanotic in utero, for the saturation of oxygen is about 50 per cent.
Fortunately, the oxygen dissociation curve characteristics of fetal
blood favors relatively great increases in oxygen saturation with
smaller changes in tension. If the placental blood oxygen tension is
lower than 40 mm. Hg, the administration of oxygen to the mother
can be expected to provide improvement. At the same time the fetal
blood saturation will profit more by a small increase in  oxygen
tension than the maternal blood would under similar conditions of
desaturation. These facts are of great importance in situations where
effective placental blood pressure is probably low, such as peripheral

312

Drugs Across the Placenta-Apgar and Papper

hypotension from spinal or epidural anesthesia, a tonic contraction of
the titerus from unwise administration of pitocin, or the presence of
Severe anemia in the mother.

  Quantitative estimations of drug levels in the human mother and
newborn infant taken simultaneously are few in number. In 1930,
Eastman deplored the lack of definite information about the transfer
of oxygen and carbon dioxide between mother and child.5  A series of
studies was initiated and extended by I<astman and his students5 20   l1
to include the effect of anesthetic agents on tlie oxygenation of the
baby, the placental transmission of thiopental, and the exchange of
body water and sodium.  In 1939, Smith became interested in the
effect of anesthetic agents on oxygenation of the newborn infant and
performed quantitative studies with cyclopropane, ether and nitrous
oxide.' 22 In 1940, Gardner, Levine and Bodansky analyzed the blood
of the mother and newborn infant for paraldehyde levels after oral
and rectal administration for amnesic and analgesic purposes.23
Studies on the transmission of meperidine (denierol) across the
placenta are in progress with the aid of a specific quantitative method
of analysis devised by Brodie and Burns.24  Lack of suitable methods
of analysis for morphine, heroin and curare have delayed tlie study
of the behavior of these compounds with respect to the placenta and
relative maternal and fetal distributions.

  The information obtained from the studies described above will
be summarized briefly.

  Oxygen Transfer: (16 cases) The oxygen capacity of infant's
blood at birth is distinctly greater than that of the mother's blood,
averaging 20.8 volumes per cent compared with the maternal capacity
of 15.4 volumes per cent.5 The oxygen saturation of fetal arterial
blood in utero (cesarean section-local anesthesia) was 63 per cent
in one subject and 50 per cent at birth, while the mother's venous
saturation was 71 per cent with an estimated arterial saturation of
95 per cent.` The oxygen content of the baby's arterial blood at birth
is 10.5 volumes per cent and the maternal arterial content 14.7 volumes
per cent. The osygen &pacity and content of the blood of the preg-
nant female are less than those of the nongravid female because of
an increased blood volume and proportionately larger increase in
plasma volume during pregnancy. Apparently the red cell mass is
stationary. Eastnian found that the oxygen capacity of 18 nonpreg-
nant women averaged 18.9 volumes per cent while that of 16 pregnant
women was 15.4 volumes per cent.  He also studied the effect of vari-
ous anesthetic methods on the oxygen saturation of the fetus at the
time of birth. With 15 infants as controls, he described 40 newborn
infants whose mothers had been anesthetized with chloroform (4
cases) ether (8 cases) and nitrous oxide and oxygen (28 cases).
Inhaled gas concentrations were estimated from the flow of gases as
registered on the flowmeter of the anesthetic machine, a method which
is subject to error and considerable variation.23 In all cases the oxygen
content of newborn blood was lower than expected.  There was no

JIJ

Current Researches in Anesthesia and Analgesia-Sept.-Oct., 1952

lowering of oxygen saturation of arterial or venous blood of the
infant with chloroform, little change with ether, more with 80 per
cent nitrous oxide and 20 per cent oxygen, and a decided drop with
90 per cent nitrous oxide and 10 per cent oxygen mixture. No analysis
of the concentration of the anesthetic agent in the blood stream was
reported.

In a recent study at the Sloane Hospital for Women the oxygen
content of heel blood taken one to five minutes after birth in 239
infants averaged 8.0 volumes per cent, with a range of 1.1 per cent to
15.5 volumes per cent.26 No correlation was made with the type of
anesthetic agent used or with the maternal blood contents.

Large volumes of water traverse the placenta as determined by
the use of deuterium oxide.'l From the fourteenth to the fortieth
week, there is a five-fold increase in transfer of water per unit of
weight of placenta. At the fourteenth week, the human fetus receives
700 times as much water as is incorporated into his tissues, and at
thirty-one weeks he receives 3800 times more than he retains.  Hell-
man defined the excess of a substance delivered to the fetus and not
retained by it but returned to the mother as the "safety fa~tor."~ The
placenta of the guinea pig is twice as p'ermeable to water as the human
placenta, though they are of the same anatomic type (hemochorial).
The peak in water transfer occurs at thirty-six weeks, with a pro-
nounced fall until birth at the fortieth week.

By injecting deuterium oxide intravenously into a maternal vein
and sampling amniotic fluid for the appearance of the isotope, the rate
of renewal of the water of amniotic fluid was found to be 34.5 per
cent per hour, with a range of 17 to 74 per cent in five subjects.  If
the amniotic fluid is present in usual amounts, averaging 1000 cc.,
this finding indicates that the entire water content changes every three
hours. From the experimental work of Davis and who
injected thorotrast into the amniotic sac of the mother at varying
times in gestation with resu!ting x-ray visualization of the fetus's
lungs and intestinal tract, it is possible that one major route for
removal of this volume of amniotic fluid is by reabsorption into the
fetus by way of his respiratory and intestinal tracts.

The transfer of sodium in amniotic fluid is less rapid.  Using
radioactive sodium, the rate of transfer per hour was determined in
20 patients. It was found that 6.9 per cent of sodium was renewed
each hour.28

  Lactic acid determinations of maternal and fetal blood were made
by Bell in 1928.29 He found the highest values in fetal venous blood,
while even the fetal arterial blood contained almost twice as much
as the maternal arterial or venous blood. Wilson recently30 has sum-
marized the latest `data on acid-base balance in the newborn infant
and corroborates the presence of a mechanism of anaerobic oxidation
at birth and for several days of life. An uncompensated acidosis of
mild degree apparently is normal for the newborn infant, especially a

2

314

Drugs Across the Placenta-Apgar and Papper

premature infant. A low blood hydrogen ion concentration, low total
carbon dioxide content and tension, and end products of metabolism
other than carbonic acid, such as lactic and pyruvic acid, all indicate
the presence of this accessory mechanism of oxidation.

  The transmission of thiopental has been determined in 7 cases.21
Before seven minutes and after twelve minutes, minimal amounts of
thiopental were found in the blood of the newborn infant. Between
these two intervals, the fetal level was 50 per cent or more of the
maternal level. The physiologic fate of thiopental or its distribution
in the newborn infant have not yet been studied.

  Ten patients at term were given paraldehyde by nasal gastric
tube and 10 by the rectal route, and blood levels for paraldehyde were
determined.23 Thirteen cord blood determinations were made also.
The oral route produced higher blood levels three hours after ad-
ministration. At the time of delivery, several hours after the .initial
dose, the cord blood samples averaged 15.5 mg. per cent, while the
maternal average was 16.6 per cent.  In several cases the fetal level
was higher than the maternal.  There was no correlation between
onset of respiration and the fetal blood level of paraldehyde.  The 3
infants with the highest levels all cried lustily, while the 3 apneic
babies, 2 of whom were premature, had levels well below the average.
One of the mothers of the 3 infants had received a small amount of
nitrous oxide, while the other 2 had only local anesthesia for
episiotomy.

  During his study of blood oxygen in the infant, Smith made many
determinations for nitrous oxide, cyclopropane and ether in maternal
and fetal arterial and venous blood. 22 Cyclopropane and ether
traversed the placenta almost quantitatively, while only 60 per cent
of the nitrous oxide in maternal blood reached the fetus.  When the
infants were classified as to promptness of respiration, there was no
correlation with the oxygen content of fetal arterial blood, but with
the 66 ether cases, there was a direct correlation of ether levels with
the depression of respiration.

  Meperidine is transmitted by the placenta to the fetus.  Plasma
levels in the mother and infant taken simultaneously show that 60
to 70 per cent of the maternal blood concentration is present in the
blood of the newborn infant.31 Comparison of maternal and newborn
infant urinary excretion of meperidine after one or two doses of 100
mg. of drug given intramuscularly to 9 mothers showed that at the
most 1 per cent of the drug was recovered in the infant's urine, while
10 per cent was found in maternal urine.34

  The clinical impression exists and is growing that d-tubocurarine
does not pass the placental barrier. Reports of its use, along with light
general anesthesia for both cesarean section32 and for vaginal de-
liveries,33 36 suggest that respiration of the infant is not unfavor-
ably influenced. Quantitative proof of these clinical observations has
not been presented in human subjects. Br~die~~ suggests that the

315

Current Researches in Anesthesia and Analgesia-Sept.-Oct., 1952

rapid binding of curare with maternal proteins may be a possible.
explanation for this phenomenon.

  Harroun and Fisher studied the problem of placental transfer
of curare in 10 pregnant     The animals were made apneic with
d-tubocurarine. Artificial respiration was carried out with oxygen
through an endotracheal airway by manual pressure on the breathing
bag. General anesthesia was induced and the litters of pups delivered
by cesarean section. All 67 pups were lively, active and breathed
well. One pup was subsequently given curare intravenously and
promptly became apneic. The authors concluded that curare did not
traverse the placenta of the pregnant dog.

  Observations on transmission of decamethonium iodide (C 10)
have been made by Young44 in the guinea pig and the rabbit.  She
found the fetal circulatory and respiratory responses were normal
after intravenous injection of the drug into the mother, and conversely,
injection of the drug into the umbilical arteries of the fetus while
still in utero produced no changes in the mother. Sc~rr~~ from clinical
observations on human patients concurs that the drug does not pass
into the placental circulation.

  In 1949, Helliwell and H~tton~~ performed quantitative estima-
tions of trichlorethylene on the fetuses of the ewe and the goat. They
found that the drug appeared almost immediately after its administra-
tion to the mother. In vitro, fetal blood of the ewe had a higher capacity
for trichlorethylene than did the maternal blood.

  Dillies 37 studied the effect of small and large doses of barbiturates
on the rabbit embryo when administered to the mother.  Pregnant
rabbits were given spinal anesthesia with spinocain, and placed in
the supine position. Barbital 75 to 100 mg./kg. were then given intra-
venously. Portions of the uterus were delivered and a fetus removed
without disturbing the rest of the uterus which was returned to the
abdominal cavity. Fetuses were removed at varying intervals after
the barbital injection. The amniotic fluid, the placenta, and the fetus
were analyzed separately for barbital content.

  After five minutes, the drug was identified in all three materials.
All animals breathed spontaneously and reacted to stimuli but barbital
content of the fetus suggests that some central nervous system depres-
sion was present.

1 With large single doses in 9 rabbits, 1 guinea pig and 1 cat, the
placental transmission of amytal and barbital was proved. Large
anesthetic doses administered intravenously could be detected in the
amniotic fluid, placenta and in fetal organs within fifteen minutes.
Repeated daily doses of barbital for 5 to 32 days in 7 dogs resulted
in abortion or resorption of the fetuses. In a single animal, which
received barbital for five days before delivery, the drug level in blood
and liver of the mother and the newborn pups was the same.

316

Drugs Across the Placenta-Apgar and Papper

The folliwing substances are known to traverse the placenta :
oxygen, carbon dioxide, all anesthetic gases and vapors, morphine,
meperidine, barbiturates, bismuth, iron, sodium chloride, magnesium,
water, urea, uric acid, creatine, creatinine, phosphorus, calcium, free
ammonia nitrogen, nucleic acid, sulphanilamide. penicillin, strepto-
mycin, thiamine, vitamin C, lipoids, glucose, fructose, cholestrol,
estrogens, copper, thyroxin, epinephrine, progesterone and certain
antibodies which are gamma globulins of molecular weights of ap-
proximately 103,000.1s 41 Vitamins A and K traverse slowly, I'f at all.
Carbon monoxide, parathyroid hormone, polypeptides, plasma pro-
teins, phospholipids, gonadotropins and the virus of poliomyelitis
apparently do not cross the placental barrier.  It remains to he shown
whether curare and procaine and related local anesthetic agents are
present in fetal blood.

  Amniotic fluid as a vehicle for transmission of many substances,
including drugs, to the fetus is probably more important than was
previously realized.  Heretofore, the umbilical vein has been con-
sidered the only route of transfer. The origin of the large volume of
amniotic fluid, from 600 to 2500 cc., is still mysterious.  Although
fetal urine contributes some volume, it is indeed small.  Vosburgh
and his associates have recently proved that the entire water content
of the amniotic fluid changes at the rate of 350 cc. per hour, so that
an average volume of 1000 cc. is changed every three hours." Whether
its source is partially secretory from the cells of the amnion, as de-
scribed by Polano in 1905,38 or wholly a transudation from the mother
is unknown. It is likely that increased plasma volume of the mother
would allow enough volume for such transudation but this thesis
has not been proved. Transudation through the cord itself is another
possibility but would not account for such a rapid production of fluid.
What becomes of the 350 cc. per hour? Davis and Potter have demon-
strated that the gastrointestinal tract and the lungs of the human
fetus, after the age of 4 months at least, normally contain large
amounts of amniotic fluid.27 If a radiopaque medium is introduced
into the amniotic sac and left there over one hour, an excellent radio-
graph is obtained of the respiratory and gastrointestinal tracts, includ-
ing the rectum. It is possible that deglutition and respiration in utero
account at least partially for the rapid turnover of amniotic fluid.
Obviously, this also affords another route for absorption of drugs into
the fetus, in addition to blood coming via the umbilical cord.

  Dillie, in his work on barbital and amytal in rabbits, guinea pigs
and cats, analyzed fetal blood, amniotic fluid and the placentas separ-
ately. In over half the experiments which included amniotic fluid
determinations, the level of barbituric acid esters was higher in this
fluid than in the fetal blood or the placenta.

  Further evidence of the removal of amniotic fluid by way of the
fetus and thence back to the mother was adduced by Lell, Liber and
Snyder.40 They injected phenolsulfonphthalein into the muscles of the

317

Current Researches in Anesthesia and Analgesia-Sept.-Oct., 1952

back of rabbit fetuses and analyzed the maternal urine for the pres-
ence of dye. In another experiment the dye was placed in amniotic
fluid rather than into the fetus itself. At term, 40 per cent of the dye
was found in maternal urine when it had been placed in amniotic
fluid, while only 13 per cent was recovered when it had been injected
into the paraspinal muscles.

  The citing of 2 cases of hydramnios in which the infants had
duodenal atresia, one proved at autopsy, the other at operation, sug-
gests that the gastrointestinal route of absorption of amniotic fluid is
more important than the respiratory route.32 No cases of hydramnios
accompanying complete laryngeal stenosis have been reported to our
knowledge.

The surprisingly frequent association of anencephaly and hy-
dramnios suggests that deficient innervation may prevent intrauterine
fetal deglutition and respiration so that the circulation of amniotic
fluid is seriously obstructed.

Whether or not the fetus excretes drugs or metabolic products
into amniotic fluid, other than by the urinary route, remains to be
demonstrated.

  In future experimental work with transmission of drugs across
the placenta, it would seem advisable to take samples from amniotic
fluid, as well as from the umbilical vein, for both routes transport
substances to the fetus.

Summary

NFORMATION REGARDING transmission of drugs across the
placenta has been gained in various ways; by rough clinical esti-
mates of the condition of the infant and its need for resuscitation;
by observation of the animal fetus in utero and observing the effect
of drugs administered to the mother on fetal respiration; by analyses
of maternal and fetal brain, liver, kidneys and spleen for drug content;
and by quantitative simultaneous chemical analyses of maternal and
fetal blood. The new method of using isotopic tracer substances
should be as applicable to studies of drug transmission as it is to
studies on transfer of water and electrolytes. Anesthetic gases, vapors,
barbital, amytal, thiopental, paraldehyde and meperidine have been
shown by quantative studies to pass through the placenta.  It is
probable that d-tubocurarine and similar relaxants and drugs used

for regional anesthesia are not transmitted.

The amount of information regarding many physiologic factors
related to maternal uterine circulation is growing slowly.  The net
effective placental blood pressure has been studied during various
periods of gestation and during the course of labor.  It has shown
improvement during light planes of general anesthesia, and diminu-
tion to dangerous levels following the use of oxytocics during the
ante-partum perio?l. A recent clinical series of pitocin infusions, how-

318

Drugs Across the Placenta-Apgar and Papper

ever, was not accompanied by any increased stillbirth or neonatal
mortality.

  The tension of oxygen offered to the fetus in the uterus at term
is less than half the maternal arterial level.  The maternal decreased
oxygen capacity, probably related to an increased plasma volume,
necessitates more frequent administration of oxygen to the mother
during periods of hypotension, or of uterine hypertonicity.  Fetal
factors which tend to make efficient use of the low oxygen tensions
offered to it in the intervillous spaces are the direction of flow of
blood in the villi which is opposite to that of the mother's, a high
oxygen capacity, a shift to the left of the oxygen dissociation curve,
and the existence of a reserve mechanism for anaerobic oxidation.
Further understanding of transmission of water, electrolytes and
metabolic products will aid in the study of drug transmission, dis-
tribution and metabolism.

  The circulation of amniotic fluid is becoming clarified, except for
its origin. Its rate of change is approximately 350 cc. per hour and
its route of removal is related to fetal deglutition and respiration.
Amniotic fluid as well as the umbilical vein should be considered a
route for drug transmission from mother to fetus.  Its relative im-
portance remains to be determined.

References

1. Smith, C. A. and Barker, R. H.: Ether in Blood of Newborn Infants, Am. I. Obst. 6.

2.
3.
4.

Gynec. 43:763-744, 1942.

Babies Hospital, New York City, Personal communication.
Barcroft, J.: Researches on Prenatal Life, Springfield, Ill., C. C. Thomas, 1947.
Snyder, F. F.: Obstetrical Analgesia and Anesthesia, Philadelphia, Pa., W. B. Saunders Co.,

177".

8. Dillie, J. M.: Studies. on Barbiturates: IX. Effect of Barbiturate on Embryo and on

9. Martland H. S. and Martland H. S. Jr.: Placental Barrier in Carbon Monoxide Barbitu-

10.  Flexner, L. B. a;d Gelhorn, A,: The Comparative Ph;siology of Placental Transfer, Am. I.
11.  Vosburg, G. J. et al.: Rate of Renewal of Water and Sodium in Amniotic Fluid as Deter-
12. Woodbury, R. k., Hamilton, W. F. and Torpin, R.: Relationship Between Abdominal

13. Grosser, 0.: Fruhentwicklung, Eihautbilding und plazentation des menschen und der

14. Spanner R. : Mutterlicher und kindlicher Kreislauf der menschlichen placenta und seine

15.

16.
17.
18.

Pregnancy, I. Pharmarol. & Exper. Therap. 52:129-136, 1934.
rate and Radium 'Poisonine: Original Observajion on Humans Am. J. Sxrg. 80:270-279, i950.

Obst. 6. Gvnec. 43:965-974, 1942.

mined by Tracer Technics Am. I. Obst. & Gynrc. 56:1156-1159, 1948.

Uterine and Arterial Pressures During Labor, Am. I. Physiol. 121 :640-649, 1938.

saugetiere, Miinchen, 1927.
Strombahnen Zed Anat. Entu. gesch. 105:(ii) 163  1935.

Fafkiner,' K. McI. : Placental Circulation, $roc. Royal Sor. Med. 37:417-425, 1943-1944.
Sloane Hospital for Women, New York City, Personal communication.
Reynolds, S. R. M.: The Physiology of the Uterus, New York, Hoeber, ed. 2, 1949.
Eastman, N. J.: William's Obstetrics, New York, Appleton, Century Crafts, ed. 10, p. 185,

i9w

  19 Mossman H. W.: The Rabbit Placenta and the Problem of Placental Transmission,
.Am. I.' Anat. 37:433-497, 1926.
  20. Eastman, N. J.: Foetal Blood Studies, 5. Role of Anesthesia in Producing Asphyxia
Neonatorum Am. J. Obst. 6. Gynec. 31:563-572 1936.
  21. Hlllman L. M  Shettles L. B. Manigan C. P. and Eastman, N. J.: Sodium Pentothal

in Obstetrics, Am: J. Obit. 6. Cy&. 48h51-860, lb44.
  22. Smith, C. A,: Cyclopropane in Obstetrics, Surg., Gynec. 6. Obst. 69:584-593, 1939.
  23. Gardner H. L. Levine H. and Bodansky M.: Concentration of Paraldehyde in Blood
After Administraiion Duhng Labdr Am. I. Obst. 6. kynec. 40:435-439, 1940.
  24. Brodie B. B. and Burns,' J. R. : Personal communication.
  25. Depdment of Anesthesiology, Presbyterian Hospital, New York: Personal communication.

319

Current Researches in Anesthesia and Analgesia-Sept.-Oct., 1952

26  Apgar V.: Oxygen as a Supportive Therapy in Fetal Anoxia, Bull. N. Y. Acad. Med.

26:474:478, 195'0.
  27.  Davis, M. E. and Potter, E. L.: Intrauterine Respiration, I. A. M. A. 131:1194-1201  1946.
  28. Flexner, L. B. et al.: Permeability of Human Placenta to Sodium in Normal and Abhormal

Pregnancies and Supply of Sodium to Human Fetus as Determined by Radioactive Sodium, Am. I.
Obst. 6. Gynec. 55:469-480, 1948.
  29. Bell. W. B. et al.: Metabolism and Acidity of Fetal Tissues and Fluids, Brit. M. I. 1:126.
131, 1928.
30. Wilson J. L Reardon H. S. and Murayana, M.: Anaerobic Metabolism in the Newborn

Infant, Pediafrics 1 :58i-592, 194k..
  31. Department of Anesthesiology, Presbyterian Hospital, New York: Personal communication.
  32.  Gray, T. Cecil: d-Tubocurarine in Cesarean Sections; Brit. M. I. 1:444-445  1947.
  33.  McMann W.: Curare and General Anesthesia in Vaginal Deliveries, Am: I. Obst. 6.

Gynec. 60:1366-13&3, 1950.
34. Way, E. L. et al.: The Absorption, Distribution and Excretion of Isonipecaine, I.
Pharmacol. 6. Exper. Therap. 96:477-484, 1949.
  35.  Austin B: and Mering T. W.: Use of Muscle Relaxing Drugs in Complicated Deliveries,
Am. J. Obst. &'Gynec. 62:143-149, 1951.
  36.  Harroun P. and Fisher, C. W.: The Physiological Effects of Curare, Srrg., Gyec. 6.
Obst. 89:73-75, 19k9.
  37. Dillie, J. M.: Placental Transmission of Nonanesthetic Doses of Barbital, Am. I. Obst.
6. Gynec. 32:328-330, 1936.
  38. Polano, 0. : Experimentelle beitrag zur Biologie der Schwangerschaft: Habilitationscrift,
Wurzburg, Sturtz, 1904.
  39. Mengert, W. F. and Baurland, J. W.: The Circulation of Amniotic Fluid, Am. 1. Obst.
6. Gynec. 50:79-83, 1945.
  40. Lell, W. A., Liber, K. E. and Snyder, F. F.: Quantitative Study of Placental Transmission,

Am. I. Physiol. 100:21-31, 1932.
  41.  Needham, J: Chemical Embryology, Vol. 3, Cambridge Univ. Press, 1930.
  42. Brodie, B. B.: Personal communication. -
  43. Helliwell, P. J. and Hutton, A. M.: Analgesia in Obstetrics, Anaesthesia 4:18-21, 1949.
44. Young, I. M. : Abdominal Relaxation with Decamethonium Iodide During Caesarian

45. Scurr, C. F.: Comparative Review of Relaxants, Brit. I. Anaes. 23:102-116, 1951.

Section, Lancet 1 :1052-1053, 1949.