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Placental transport of alcohol and its effect on maternal and fetal acid-base balance
FETUS,PLACENTA, ANDNEWBORN Placental transport of alcohol and its effect on maternal and fetal acid-base balance LEON
I.
MANN,
.4MRUTHA
M.D.
BHAKTHAVATHSALAN,
MAIDA
LIU,
PHILIP
MAKOWSKI,
Enst Meadow
M.D
B.S.
and Stony
M.D. Brook,
New
York
The placentul transport of alcohol and its effect on maternal and fetal acid-base balance studied in 10 sheep experiments by the maternal infusion of a 9.75 per cent solution of alcohol-dextrose at a rate of 15 C.C. per kilogram for I or 2 hours. Serial maternal and fetal blood .sampling during and following the alcohol infusion revealed rapid placental diffusion of alcohol. a highly significant correlation between maternal and fetal blood alcohol concentrations, and a similar peak concentration of approximately 0.230 Gm. per 100 ml. in maternal and fetal blood that ditered only in time of onset during the I and 2 hour infusion periods. Blood alcohol concentrations remained hi.qh for seueral hours during the postinfusion pried. A significant maternal hypcrlactacidemia and hyper,glycemia were noted but did not r.e.\ult in significant alterations in maternal acid-base balance. An initial fetal metabolic acidosis and later mixed acidosis were observed during the alcohol infusion and worsened during the po.,tinfusion period.
From
the Department of Obstetrics and Nassau County Medical Center, East Meadow, and the Health Sciences Center, State llnioersity of New York at Stony Brook.
M E T I-I o D s to prevent premature labor represent a major challenge in obstetrics. A prerequisite for any successful method is that it be safe for mother and fetus. While the results of clinical studies of alcohol infusion seen] encouraging,*’ ’ there is little understanding of the acute and long-term effects of alcohol on the fetus. In published animal studies of the effect of maternal alcohol infusion on uterine and fetal hemodynamics and metabolism, experimenters have disagreed in terms of their observations and conclusions.“-’ In this report observations from a sheep model on the placental transport of alcohol and its effect on maternal and fetal systems are presented. A future report will present the effects of alrohol on fetal cerebral function and metabolistn.
c,ynecology,
Supported in part by a grant from the United Cprebral Palsy Research and Education Foundation 237-71 and the Meadowbrook Medical Research and Education Foundation. Inc. Receir:ed Revised Accepted
for publication January January
October
31, 1974.
9, 1975. 9. 1975.
Reprint requests: Leon I. Mann, and Co-Chairman, Department Gynecology, State University of Stony Brook; Director, Department and Gynecology. Nassau County 2201 Hempstead Turnpike, East New York 115.54.
M.D., Professor of Obstetrics and New York at of Obstetrics Medical Center, Meadow,
837
838
Mann
035
1
I
August 1, 1975
et al.
Am. J. Obstet.
Maternal Artery Fetal Comtid Artery
15cc/kg/lhr --
- T I
025-
,
+ 1
I JOI
0’
I 60’
I 105’
Time
Fig. 1A. Mean (? concentrations at infusion of 9.75 CL. per kilogram
Materials
and
S.E.M.) maternal and fetal blood alcohol intervals during and following maternal per cent alcohol-dextrose solution at 15 of total maternal weight for 1 hour.
methods
Experiments were conducted on 10 Dorset ewes and their fetuses which ranged in gestational age from 121 to 138 days (term is approximately 145 days). The ewes were prepared for operation by withholding food for 24 hours and water for 12 hours. Progesterone in oil (Proluton, Schering Corporation, Union, New Jersey), 150 mg., was administered intramuscularly twice daily for 2 days before and on the day of operation. Anesthesia was induced with halothane (Fluothane, Ayerst Laboratories, Division American Home Products Corporation, New York, New York) 2 to 4 per cent delivered by nose cone and anesthesia was maintained with a 0.6 to 1.2 per cent halothane, 30 per cent oxygenbalanced nitrogen mixture delivered by means of a cuffed endotracheal tube, a positive-negative respirator (Bird, Palm Springs, California) and an anesthetic apparatus. Polyvinyl catheters were placed into the maternal jugular vein and maternal ventral aorta by a surgical cut-down procedure over the neck and femoral triangle, respectively. The maternal jugular catheter was used for alcohol infusion. The distal ventral aorta catheter was connected to a three-way stopcock and a pressure transducer (Statham P23 Db) was used for intermittent blood sampling and continuous blood pressure recordings. The fetal head was delivered through an abdomi-
Gynecol.
nal and myometrial incision and placed into a stereotaxic device (David Kopf Instruments, Tujunga, California) that was modified for sheep. The technique of catheterization of the carotid artery and sagittal vein has been previously presented in detail.” A perivascular ultrasonic flow transducer (Ward Associates, La Jolla, California) was placed high on the carotid artery after its tributaries had been ligated. The output of the flow transducer was calibrated for volume flow in vivo during the experiment by the technique that has been previously described.” Pressure in the cerebral vessels was monitored continuously via pressure transducers. All electrophysiologic parameters were displayed by direct write-out on an eight-channel dynograph (Type RM, Beckman Instruments, Inc., Fullerton, California) through appropriate couplers. Each ewe was weighed prior to the experiment and a total dose of 15 C.C. per kilogram of total body weight of 9.75 per cent solution of alcohol in 5 per cent dextrose was infused by means of a constant infusion pump (Harvard Pump) for 1 or 2 hours. Blood samples were drawn simultaneously from the maternal and fetal circulations at 30 minute intervals throughout the infusion period and at 15 minute intervals after infusion for as long as the fetus was viable. A portion of the blood sample was deproteinated immediately with cold perchloric acid, frozen, and determined at a later date for glucose and lactate by enzymatic methods (Boehringer Mannheim Corp., New York, New York). A second part of the blood sample was evaluated immediately for pH, Pco2, and PO, on an IL1 13 pH blood-gas analyzer. Oxygen content was calculated from the determination of the per cent of saturation of hemoglobin with oxygen and the concentration of hemoglobin as determined by means of an I.L. Co-Oximeter. Base excess (mmEq./L.) was calculated for nomograms. Blood alcohol determinations were made by gas chromat0graphy.r The fetal heart rate was calculated from the carotid pressure recording. The mean pressure in the maternal ventral aorta and carotid artery was calculated as diastolic plus one-third pulse pressure. Group values are expressed as mean plus or minus one standard error. Statistical significance of changes from baseline was calculated by Student’s t test. Significance is presented in terms of p values. Results
Maternal-fetal alcohol concentrations. In four experiments the infusion of the 9.75 per cent alcohol-dextrose solution was completed in 1 hour (Fig.
Volume Number
Placental
122 7
transport
of alcohol
839
15cc/kgllhr. 0.35-
= E : 2 J z c
0.30-
T
0.25-
y : - 0.0062
+0.9007x
,D : 0.20E
O.l5-
O.lO-
0.05
-
0.00
1 0.0.0
Hofcrnol Pl
I
I
0.10
0.15
I
ETOH
Fig. 1B. Correlation
of maternal
with
fetal
I
0.20
0.25
I 0.35
I 0.40
(go/d
blood
1A). The highest concentration of alcohol in both the maternal (0.230 & 0.054 Gm. per 100 ml.) and fetal (0.222 ? 0.052 Gm. per 100 ml.) circulation occurred at 60 minutes. Approximately 45 minutes following the termination of the infusion of the alcohol-dextrose solution, both the maternal and fetal values were still 70 per cent of the peak value. The correlation between maternal aorta and fetal carotid blood concentrations of alcohol was highly significant (Fig. 1B; r = 0.87; p < 0.001). Infusion of the same total dose of alcohol over a 2 hour period was accomplished in six experiments (Figs. 2A and 2B). Infusion over 2 hours resulted in a peak concentration in the maternal circulation at 90 minutes of 0.237 t 0.022 Gm. per 100 ml. The concentration of alcohol in the fetal blood reached its maximum at 120 minutes following the start of infusion (0.222 + 0.019 Gm. per 100 ml.), but was not significantly higher than the concentration in the maternal circulation at that time. Both the maternal and fetal concentrations of alcohol were 90 per cent of their peak concentrations 30 minutes after infusion. In the single experiment shown in Fig. 3A the maternal and fetal blood alcohol concentrations were still approximately 75 per cent of the peak concentration 1 hour following the infusion. In two additional experiments where the fetus was viable 2 hours following the cessation of the infusion of the alcohol-dextrose solution the blood alcohol concentrations were 50 and 60 per cent of the peak concentration. A highly significant
I 0.30
alcohol
concentrations
during
1 hour
infusion.
correlation (Fig. 2B; r = 0.7196; p < 0.01) was found for the simultaneously obtained maternalfetal blood samples during the 2 hour infusion experiments. Maternal and fetal cardiovascular and metabolic observations. Observations of cardiovascular and metabolic changes in the mother and fetus were similar during both the 1 hour and 2 hour infusion periods. Therefore, the results (Tables I and II) are shown for the mother and fetus during the 2 hour infusion only. There was no significant change in maternal heart rate, blood pressure, Pou, oxygen content, Pco2, or pH during or following the infusion of the alcohol solution. The concentration of glucose in the maternal artery showed a significant elevation throughout and following the period of infusion although it was returning toward baseline 30 minutes following the infusion. The concentration of lactate in the maternal circulation increased significantly by 90 minutes when it was almost double the baseline concentration. While the lactate concentration continued to increase during and following infusion the increase was not significantly different from the 90 minute concentration. The fetal heart rate showed an insignificant increase during the infusion, which returned toward baseline rates 30 minutes following the infusion (Table II). The mean blood pressure in the carotid artery decreased during the infusion and was significantly lower than the baseline (p < 0.05) 30
840
Mann
et al.
Auglst
Am. J. Obstvt.
0 35
Moiernol Fetal Carotid
1, 1973
(:ynecol.
15cc/kg12hrs. Artery - - - -
!
, 000
y
-or-60’
I 30’
0’
--
1 --I 90’
150’
120’
Tlnw
Fig. 2A. Mean (? S.E.M.) maternal and fetal blood alcohol concentrations and following maternal infusion of 9.75 per cent alcohol4extrose solution gram of total maternal weight for 2 hours.
0.35-
f m 5
at intervals during at 15 C.C. per kilo-
15cclkg/2hn.
0.30-f s 1 B
0.25T -D 5 o.eoL
r :0.7196 y=O.OOM
+0.6362x
0.15-
O.lO-
0.05 i 0.00
Mot*md *rt.ry , I 0.00 0.05
. I
0 IO
I 0.15
I 0.20 ETOH
Fig.
2B. Correlation
of maternal
with
fetal
blood
minutes after infusion. Oxygen tension in the carotid artery was unaffected by the alcohol infusion. However, oxygen content decreased during the period of infusion and was significantly different from baseline 30 minutes following the infusion when the pH was at its lowest value. In the carotid artery pH had decreased significantly from baseline by 90 minutes and progressively decreased to a value 30 minutes following infusion of 7.188 + 0.056 (p < 0.0025). The initial fall in the pH at 90 minutes was due primarily to the metabolic component as lactate had almost doubled from 35.36 k 2.98 to
I
I
I
I
0.25
0.30
0.35
0.40
(q%)
alcohol
concentrations
during
2 hour
infusion.
53.26 + 5.58 mg. per 100 ml. (p < 0.001) at that time. Lactate continued to rise throughout the infusion and recovery periods and associated with a significant increase in the Pco? resulted in a further decrease in pH. The significant increase in base excess throughout the infusion and recovery period confirmed the primary metabolic etiology of the acidosis. Glucose concentration in the fetal artery increased to a maximum at 120 minutes of 69.8 f 4.02 mg. per 100 ml. Oxygen tension and acid-base consideration are shown for a single experiment in Fig. 3B. At the
Volume Number
122 7
Placental
transport
of
alcohol
841
Ewe # 122 Gest. Age 126days IScc/kg/2hrs. Moternol Artery Fetal Carotid Artery - - - -
0.25
-
2 p 0.20I 0 0 15L O.lO0.050.00
r
I
I
0’
30’
60’
I
I
I
I
90’
120’
150’
180
I
Time
Fig. 3A. Absolute blood alcohol 9.75 per cent alcohol-dextrose of the fetus was 126 days (term
t220 t2 IO + 200
concentrations at intervals during and following infusion solution at 15 C.C. per kilogram per 2 hours. Gestational approximately 145 days).
pco2
‘%b‘xAd
Ewe
B.E.
-
15cc/kg/2hrs
+ 300
Loctote***** PO2 . . . . .
f
I I I’
Gest.
*
of a age
122 Age
126 doys
+ 150
+
100
% +50 +40 +30 +20 + IO - lo” -20 -30 -40 -50
-
100
7.445 I
1.450 I
7.450 I
2410 I
7.370
7.170
6.950
I
I
I
0’
30’
60’
90’
120’
I 50’
160’
Fig. 3B. Acid-base observations obtained at intervals during and following ( 15 cc. per kilogram per 2 hours). Blood alcohol concentrations are shown points represent per cent change from the baseline value taken as zero.
end of the 2-hour infusion in this experiment oxygen tension was insignificant from baseline, Pcoz showed only a slight percentage increase from the baseline value, while the concentration of lactate reflected in the base excess was increased by some 65%. At the 2 hour point the pH was decreased by only 0.075. In the hour following the 2 hour
PH
Time
alcohol infusion in Fig. 3A. Serial
infusion the pH fell significantly to 6.950 lactate and Pco? increased markedly.
as the
Comment
In view of the serious medical and social aspects of acute or chronic alcohol ingestion, a vast literature has accumulated on the subject of the effect
842
Mann
et al.
Table I. Maternal per kilogram
cardiovascular, per 2 hours
I Heart rate (beats/ min.) Blood pressure (mm. Hg) PO? (mm. Hg) Or Content (vol. %I Pco? (mm. Hg) PH Glucose (mg./lOO ml.) Lactate (mg./lOO ml. )
metabolic,
Baseline 97.50
90 min.
+ 5.74
65.22 111.67
+ 3.09 * 14.34
/
P
observations
1
120
min.
following
/
f
8.39
N.S.
103.50
k 10.38
N.S.
70.55 144.17
+ 6.39 + 19.73
N.S. N.S.
64.66 161.60
+ 7.36 f 21.40
N.S.
f + -t
N.S. N.S. N.S.
2 + 5
N.S. N.S. N.S.
k ? 2
0.55 0.94 0.015
11.82 22.50 7.605
43.39
f
3.84
226.32
14.34
f
2.28
29.43
0.44 2.40 0.036
11.69 19.60 7.6’9
2 10.87
< 0.0005
246.51
+
< 0.0005
33.65
and acid-base
1.59
observations
0.05
0.55 0.83 0.030
alcohol
P
106.66
11.16 21.00 7.660
Table II. Fetal cardiovascular,
and acid-base
150
infusion
min.
15 C.C.
/
P
101.88
2 13.53
N.S.
57.50 169.00
+ 6.17 + 28.30
N.S. N.S.
2 0.39 5 0.74 -c 0.034
N.S. N.S. N.S.
11.15 20.25 7.6075
i 12.97
< 0.0005
175.44
2
7.29
< 0.0005
t-
0.89
< 0.0005
34.86
f
1.74
< 0.0005
alcohol
infusion,
15 cc. per kilogram
following
per
2 hours I Heart rate (beats/ min.) Blood pressure (mm. Hg) PO? (FA) (mm. Hs) 0% content (FA) (vol. %) PH (FA) Pcoz (FA) (mm. Hg) Lactate (FA) (mg. %) Base excess (FA) mEq./L.) Glucose (FA)
Baseline 141
* 9.05
/
90 min. 164
1
2 9.45
N.S.
P
1
120 154
min.
/
P
2 10.65
N.S.
1
150 149
min.
/
P
t 6.97
N.S.
41.72
* 2.39
36.28
* 2.88
N.S.
36.86
t
2.66
N.S.
35.41
+ 2.17
< 0.05
15.8
t 0.87
17.5
+ 0.94
N.S.
18.0
+
1.10
N.S.
17.8
+ 0.96
N.S.
+ 1.13 t 0.058
N.S. < 0.05
1.10 0.052
N.S. < 0.01
5.39 7.188
9.52 7.438
f 1.17 + 0.029
7.93 7.310
7.98 + 7.2702
30.33
+ 1.54
38.17
+ 4.47
N.S.
35.36
2 2.98
53.26
25.58
< 0.01
59.45
-2.08 11.82
f 1.17 + 2.00
-6.75 53.78
t 2.06 f 4.41
< 0.05 < 0.0005
-8.16 69.83
of alcohol on cellular, organ, and total body functioning. Most of the reports, however, have dealt with the effect of alcohol on the adult human or animal model. As a result of the successful application of alcohol infusion in the inhibition of premature labor, interest in the effects of alcohol on the fetus was stimulated. The original investigative work of Fuchs1 was performed on a rabbit model and primarily concerned with proving the effectiveness of alcohol in inhibiting myometrial contractility and its mechanism of action. The effects of alcohol on maternal and fetal cardiovascular, metabolic, and acid-base parameters have only recently been evaluated in primate” and sheep32 4 studies. Unfortunately, there is disagreement in the observations and conclusions. Alcohol is predominantly metabolized by the
39.20
C 3.68 +
*
6.82
_+ 1.57 4.02
i 0.73 2 0.056
< 0.01 < 0.0025
< 0.05
45.00
+ 4.86
< 0.0125
< 0.01
68.87
+ 9.00
< 0.005
-12.00 65.62
k 2.28 + 6.14
< 0.0025 < 0.0005
< 0.01 < 0.0005
liver with probably no more than 20 per cent of alcohol metabolism occurring in extrahepatic sites.“, ’ The first step in the metabolism of alcohol is its oxidation to acetaldehyde which is catalyzed by at least three different enzyme systems. Alcohol dehydrogenase (ADH) is the most important enzyme. The second step in the metabolism of alcohol involves the conversion of acetaldehyde into acetate by the aldehyde dehydrogenase enzyme system primarily. The carbon skeleton of alcohol becomes incorporated into a variety of metabolic products. The ratio of DPNH to DPN is increased in the cytoplasm of the liver as a result of the conversion of alcohol to acetaldehyde. This conversion results in a number of significant effects on cellular metabolism, one of which is the reduction of pyruvate to lactate and an increase in the normal lactate/py-
Volume Number
122 7
ruvate ratio. A mild metabolic acidosis might ensue under these conditions. In the experiments presented here in sheep and those of Horiguchi and a~sociates’ in primates, a hyperlactacidemia and mild compensated metabolic acidosis, as reflected in the base excess or base deficit calculations, was observed in the mother during alcohol infusion. Dilt?! 4 recorded an insignificant decrease in pH and increase in base excess in the mother during alcohol infusion under spinal anesthesia but not under pentobarbital anesthesia. Because the equilibrium of the conversion of acetaldehyde to acetate is far to the right, little acetaldehyde is detectable in the blood following alcohol acetaldehyde has been impliinfusion. However, cated as the cause for a number of effects that cannot be attributed to alcohol aIone, such as peripheral vasodilatation and tachycardia which is commonly recorded following alcohol infusion.!’ An insignificant increase in maternal heart rate and decrease in maternal blood pressure was noted in the present experiments. Alcohol’s small molecular size and weak properties of dissociation and polarization result in its being freely miscible with water and relatively soluble in lipoid solvents. It would, therefore, be expected that alcohol would diffuse across cellular membranes with relative ease and would be rapidly and readily diffusable throughout body fluids and tissues. Kapid diffusion of alcohol across the placenta was evident from the present experiments, as has been reported previously by others.“, “’ There was no difference in the peak concentration of alcohol in the mother or fetus in the present experiments whether the calculated dose of 15 C.C. per kilogram of body weight (1.5 Gm. of alcohol per kilogram) was infused for 1 or 2 hours. The mean concentration of alcohol in the fetal circulation at 2 hours following a 2 hour infusion was somewhat higher than that reported by Dilts but within the range of concentrations presented. The mean and range of values presented by Horiguchi, where an infusion of 2 to 4 Gm. per kilogram of body weight was conducted for 1 hour, are somewhat higher than the values obtained with the 1 hour infusion in this series. These concentrations of alcohol must be considered consistent with intoxication or stuporous levels of alcohol. The observations reported here support those of Horigurhi that the fetal concentration at the end of the infusion period may actuaIly be greater than the maternal concentration and this level may per-
Placental
transport
of alcohol
843
sist for several hours following discontinuation of the alcohol infusion. The observations presented by Dilts were terminated at the end of the 2 hour infusion period. Reports of maternal and fetal blood concentrations of alcohol in human subjects have varied, with the highest values being those presented by Fuchs from a case of twins where a maternal level of 0.15 Gm. per 100 ml. was associated with a twin A value of 0.18 Gm. per 100 ml. and a twin B value of 0.17 Gm. per 100 ml. The effect of alcohol on cardiovascular and acidbase parameters discussed above for the adult animal seem to be exaggerated for the fetus. This is particularly true for the observations made during the last 30 minutes of infusion and for the halfto one-hour period following infusion. An insignificant increase in the fetal heart rate was recorded. Fetal blood pressure decreased as a result of the infusion of alcohol. The significant decrease in pH at 90 minutes of infusion was primarily metabolic in type due to a hyperlactacidemia. During the last 30 minutes of infusion and into the recovery period the fetal pH decreased further as a result of a mixed metabolic-respiratory acidosis at which time the maternal Pcos had decreased. These results are similar to those presented by Horiguchi in the primate but differ significantly from those presented by Dilts, who did not record a significant acidosis during alcohol infusion. Unexplained by Dilts, however, was the observation that under pentobarbital anesthesia and alcohol infuison acidosis was not noted in the face of a marked decrease in umbilical blood flow and oxygen transferred to the fetus. Postinfusion values which were not presented in that paper might have revealed the development of a fetai acidosis. While fetal oxygen consumption was not measured in the present series or that reported by Horiguchi, oxygen tension did not change during or after infusion in the present experiments. The significant decrease in oxygen content reported here in the face of insignificant changes in oxygen tension lvould be explained by a right shift in the oxygenhemogloblin dissociation curve as a result of the fall in pH (Bohr effect). The acid-base observations, however, would tend to suggest that fetal oxygen consumption had decreased as the metabolic acidosis effected a decrease in cardiac output and/or redistribution of cardiac output to vital organs at the expense of a decrease in umbilical blood flow. The accumulation of CO, within the fetal circulation wold support this pathophysiology. The significant increase in fetal glucose concentration dur-
844
Mann
ing
infusion
served
et al.
of
and
glucose
discussed
Correlation conditions
of to the
drome
in
infantile
delivered
during at
inhibiting
be
expected
by
the
transient
in
the
motor
this
component
prepared
the that
the
observaat-
with
alcohol
incidence be
of
unanswered the
effect
of
the
1. Fuchs, F.: J. Obstet. Gynaecol. Br. Commonw. 72: 1011, 1965. 2. Fuchs, F., Fuchs, A-R., Poblete, V. F., Jr., and Risk, A.: AM. J. OBSTET. GYNECOL. 99: 627, 1967. 3. Dilts, P. V., Jr.: AM. J. OBSTET. GYNECOL. 107: 1018, 1970. 4. Dilts, P. V., Jr.: AM. J. OBSTET. GYNECOL. 108: 221, 1970. 5. Horiguchi, T., Suzuki, K., Comas-Urrutia, A. C., Mueller-Heubach, E., Boyer-Milic, A. M., Baratz, R. A., Morishima, H. D., James, L. S., and Adamson, K.: AM. J. OBSTET. GYNECOL. 109: 910, 1971. 6. Mann, L. I., Carmichael, A., and Duchin, S.: AM. J. OBSTET. GYNECOL. 114:549, 1972.
7.
inhibition
of premature
labor
on
inhibit
acidosis
The unit
neonatal to
less
be
alerted
in
these
immediate
in-
than
the
disease
team
should
seem
alcohol
are
acidosis
Until
would
rnembrane
perinatal
initiate
infant. it
labor
hyaline
death.
the
following
premature
prematurity,
of
of available,
and to infants
resuscitative
and
neonatal the
possiand
be mea-
of
The authors wish to acknowledge the cooperation and assistance of Mr. Peter Lorenzo and staff of the Animal Kesearch Division of the Nassau County Medical Center in the performance of these experiments, and Dr. J. Bidouset and Mr. Tom Manning of the Toxicology Division, Nassau County Medical Examiner’s Office, for
a
successful
as a result
are
sures.
newborns
unsuccessful
functioning
of fetal
intensive-care
to
question acidosis
of
neonatal
analogous study,
would
fetal
risk
bility
a higher
observations
syn-
risks to
While
labor
have
the
fusion
induced
mental
observations
solutions.‘”
an
A further of
and
that
drawn
alcohol
alcohol
premature
episodes
have
fetal
impression
following to
depression. present
the
exactly
the
or
could neonatal
to
not
support
tempt
ob-
clinical
intravenously
alimentation
are
do
been
with
reports
of
due
infused
studies
and
performed
here
has
further
Recent
infancy’”
conditions
mother
animal
intoxication
experiments
the
recognition
early
of parentally
tions
these
is hazardous.
attention
these
to
previously.‘l
performance
of the
alcohol
determinations.
eventual
REFERENCES
Note
to
authors:
Change
in
reference
8. 9. 10. 11. 12. 13.
Goldbaum, L. R., and Schlaegel, E. L.: J. Forensic Sci. 9: 63, 1964. Lieber, C. S.: Gastroenterology 65: 821, 1973. Myerson, R. M.: Med. Clin. N. Am. 57: 925, 1973. Dilts, P. V., Jr.: AM. J. OBSTET. GYNECOL. 107: 1195, 1970. Mann, L. I., Prichard, J., and Symmes, D.: AM. J. OBSTET. GYNECOL. 107: 610, 1970. Jones, K. L., and Smith, D. W.: Lancet 11: 999, 1973. Peden, V. H., and Downey, D. A.: J. Pediatr. 83: 490. 1973.
style
The Editors and Publisher have agreed to add the article title to references in the AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY. References will now conform to the style of the Cumulated Index Medicus, viz., name of author, title of article, name of periodical, volume, page, and year. Authors are always encouraged to limit references t9 sixteen for the following JOURNAL sections: Obstetrics, Gynecology, and Fetus, Placenta, andNewborn.
I.
MANN,
.4MRUTHA
M.D.
BHAKTHAVATHSALAN,
MAIDA
LIU,
PHILIP
MAKOWSKI,
Enst Meadow
M.D
B.S.
and Stony
M.D. Brook,
New
York
The placentul transport of alcohol and its effect on maternal and fetal acid-base balance studied in 10 sheep experiments by the maternal infusion of a 9.75 per cent solution of alcohol-dextrose at a rate of 15 C.C. per kilogram for I or 2 hours. Serial maternal and fetal blood .sampling during and following the alcohol infusion revealed rapid placental diffusion of alcohol. a highly significant correlation between maternal and fetal blood alcohol concentrations, and a similar peak concentration of approximately 0.230 Gm. per 100 ml. in maternal and fetal blood that ditered only in time of onset during the I and 2 hour infusion periods. Blood alcohol concentrations remained hi.qh for seueral hours during the postinfusion pried. A significant maternal hypcrlactacidemia and hyper,glycemia were noted but did not r.e.\ult in significant alterations in maternal acid-base balance. An initial fetal metabolic acidosis and later mixed acidosis were observed during the alcohol infusion and worsened during the po.,tinfusion period.
From
the Department of Obstetrics and Nassau County Medical Center, East Meadow, and the Health Sciences Center, State llnioersity of New York at Stony Brook.
M E T I-I o D s to prevent premature labor represent a major challenge in obstetrics. A prerequisite for any successful method is that it be safe for mother and fetus. While the results of clinical studies of alcohol infusion seen] encouraging,*’ ’ there is little understanding of the acute and long-term effects of alcohol on the fetus. In published animal studies of the effect of maternal alcohol infusion on uterine and fetal hemodynamics and metabolism, experimenters have disagreed in terms of their observations and conclusions.“-’ In this report observations from a sheep model on the placental transport of alcohol and its effect on maternal and fetal systems are presented. A future report will present the effects of alrohol on fetal cerebral function and metabolistn.
c,ynecology,
Supported in part by a grant from the United Cprebral Palsy Research and Education Foundation 237-71 and the Meadowbrook Medical Research and Education Foundation. Inc. Receir:ed Revised Accepted
for publication January January
October
31, 1974.
9, 1975. 9. 1975.
Reprint requests: Leon I. Mann, and Co-Chairman, Department Gynecology, State University of Stony Brook; Director, Department and Gynecology. Nassau County 2201 Hempstead Turnpike, East New York 115.54.
M.D., Professor of Obstetrics and New York at of Obstetrics Medical Center, Meadow,
837
838
Mann
035
1
I
August 1, 1975
et al.
Am. J. Obstet.
Maternal Artery Fetal Comtid Artery
15cc/kg/lhr --
- T I
025-
,
+ 1
I JOI
0’
I 60’
I 105’
Time
Fig. 1A. Mean (? concentrations at infusion of 9.75 CL. per kilogram
Materials
and
S.E.M.) maternal and fetal blood alcohol intervals during and following maternal per cent alcohol-dextrose solution at 15 of total maternal weight for 1 hour.
methods
Experiments were conducted on 10 Dorset ewes and their fetuses which ranged in gestational age from 121 to 138 days (term is approximately 145 days). The ewes were prepared for operation by withholding food for 24 hours and water for 12 hours. Progesterone in oil (Proluton, Schering Corporation, Union, New Jersey), 150 mg., was administered intramuscularly twice daily for 2 days before and on the day of operation. Anesthesia was induced with halothane (Fluothane, Ayerst Laboratories, Division American Home Products Corporation, New York, New York) 2 to 4 per cent delivered by nose cone and anesthesia was maintained with a 0.6 to 1.2 per cent halothane, 30 per cent oxygenbalanced nitrogen mixture delivered by means of a cuffed endotracheal tube, a positive-negative respirator (Bird, Palm Springs, California) and an anesthetic apparatus. Polyvinyl catheters were placed into the maternal jugular vein and maternal ventral aorta by a surgical cut-down procedure over the neck and femoral triangle, respectively. The maternal jugular catheter was used for alcohol infusion. The distal ventral aorta catheter was connected to a three-way stopcock and a pressure transducer (Statham P23 Db) was used for intermittent blood sampling and continuous blood pressure recordings. The fetal head was delivered through an abdomi-
Gynecol.
nal and myometrial incision and placed into a stereotaxic device (David Kopf Instruments, Tujunga, California) that was modified for sheep. The technique of catheterization of the carotid artery and sagittal vein has been previously presented in detail.” A perivascular ultrasonic flow transducer (Ward Associates, La Jolla, California) was placed high on the carotid artery after its tributaries had been ligated. The output of the flow transducer was calibrated for volume flow in vivo during the experiment by the technique that has been previously described.” Pressure in the cerebral vessels was monitored continuously via pressure transducers. All electrophysiologic parameters were displayed by direct write-out on an eight-channel dynograph (Type RM, Beckman Instruments, Inc., Fullerton, California) through appropriate couplers. Each ewe was weighed prior to the experiment and a total dose of 15 C.C. per kilogram of total body weight of 9.75 per cent solution of alcohol in 5 per cent dextrose was infused by means of a constant infusion pump (Harvard Pump) for 1 or 2 hours. Blood samples were drawn simultaneously from the maternal and fetal circulations at 30 minute intervals throughout the infusion period and at 15 minute intervals after infusion for as long as the fetus was viable. A portion of the blood sample was deproteinated immediately with cold perchloric acid, frozen, and determined at a later date for glucose and lactate by enzymatic methods (Boehringer Mannheim Corp., New York, New York). A second part of the blood sample was evaluated immediately for pH, Pco2, and PO, on an IL1 13 pH blood-gas analyzer. Oxygen content was calculated from the determination of the per cent of saturation of hemoglobin with oxygen and the concentration of hemoglobin as determined by means of an I.L. Co-Oximeter. Base excess (mmEq./L.) was calculated for nomograms. Blood alcohol determinations were made by gas chromat0graphy.r The fetal heart rate was calculated from the carotid pressure recording. The mean pressure in the maternal ventral aorta and carotid artery was calculated as diastolic plus one-third pulse pressure. Group values are expressed as mean plus or minus one standard error. Statistical significance of changes from baseline was calculated by Student’s t test. Significance is presented in terms of p values. Results
Maternal-fetal alcohol concentrations. In four experiments the infusion of the 9.75 per cent alcohol-dextrose solution was completed in 1 hour (Fig.
Volume Number
Placental
122 7
transport
of alcohol
839
15cc/kgllhr. 0.35-
= E : 2 J z c
0.30-
T
0.25-
y : - 0.0062
+0.9007x
,D : 0.20E
O.l5-
O.lO-
0.05
-
0.00
1 0.0.0
Hofcrnol Pl
I
I
0.10
0.15
I
ETOH
Fig. 1B. Correlation
of maternal
with
fetal
I
0.20
0.25
I 0.35
I 0.40
(go/d
blood
1A). The highest concentration of alcohol in both the maternal (0.230 & 0.054 Gm. per 100 ml.) and fetal (0.222 ? 0.052 Gm. per 100 ml.) circulation occurred at 60 minutes. Approximately 45 minutes following the termination of the infusion of the alcohol-dextrose solution, both the maternal and fetal values were still 70 per cent of the peak value. The correlation between maternal aorta and fetal carotid blood concentrations of alcohol was highly significant (Fig. 1B; r = 0.87; p < 0.001). Infusion of the same total dose of alcohol over a 2 hour period was accomplished in six experiments (Figs. 2A and 2B). Infusion over 2 hours resulted in a peak concentration in the maternal circulation at 90 minutes of 0.237 t 0.022 Gm. per 100 ml. The concentration of alcohol in the fetal blood reached its maximum at 120 minutes following the start of infusion (0.222 + 0.019 Gm. per 100 ml.), but was not significantly higher than the concentration in the maternal circulation at that time. Both the maternal and fetal concentrations of alcohol were 90 per cent of their peak concentrations 30 minutes after infusion. In the single experiment shown in Fig. 3A the maternal and fetal blood alcohol concentrations were still approximately 75 per cent of the peak concentration 1 hour following the infusion. In two additional experiments where the fetus was viable 2 hours following the cessation of the infusion of the alcohol-dextrose solution the blood alcohol concentrations were 50 and 60 per cent of the peak concentration. A highly significant
I 0.30
alcohol
concentrations
during
1 hour
infusion.
correlation (Fig. 2B; r = 0.7196; p < 0.01) was found for the simultaneously obtained maternalfetal blood samples during the 2 hour infusion experiments. Maternal and fetal cardiovascular and metabolic observations. Observations of cardiovascular and metabolic changes in the mother and fetus were similar during both the 1 hour and 2 hour infusion periods. Therefore, the results (Tables I and II) are shown for the mother and fetus during the 2 hour infusion only. There was no significant change in maternal heart rate, blood pressure, Pou, oxygen content, Pco2, or pH during or following the infusion of the alcohol solution. The concentration of glucose in the maternal artery showed a significant elevation throughout and following the period of infusion although it was returning toward baseline 30 minutes following the infusion. The concentration of lactate in the maternal circulation increased significantly by 90 minutes when it was almost double the baseline concentration. While the lactate concentration continued to increase during and following infusion the increase was not significantly different from the 90 minute concentration. The fetal heart rate showed an insignificant increase during the infusion, which returned toward baseline rates 30 minutes following the infusion (Table II). The mean blood pressure in the carotid artery decreased during the infusion and was significantly lower than the baseline (p < 0.05) 30
840
Mann
et al.
Auglst
Am. J. Obstvt.
0 35
Moiernol Fetal Carotid
1, 1973
(:ynecol.
15cc/kg12hrs. Artery - - - -
!
, 000
y
-or-60’
I 30’
0’
--
1 --I 90’
150’
120’
Tlnw
Fig. 2A. Mean (? S.E.M.) maternal and fetal blood alcohol concentrations and following maternal infusion of 9.75 per cent alcohol4extrose solution gram of total maternal weight for 2 hours.
0.35-
f m 5
at intervals during at 15 C.C. per kilo-
15cclkg/2hn.
0.30-f s 1 B
0.25T -D 5 o.eoL
r :0.7196 y=O.OOM
+0.6362x
0.15-
O.lO-
0.05 i 0.00
Mot*md *rt.ry , I 0.00 0.05
. I
0 IO
I 0.15
I 0.20 ETOH
Fig.
2B. Correlation
of maternal
with
fetal
blood
minutes after infusion. Oxygen tension in the carotid artery was unaffected by the alcohol infusion. However, oxygen content decreased during the period of infusion and was significantly different from baseline 30 minutes following the infusion when the pH was at its lowest value. In the carotid artery pH had decreased significantly from baseline by 90 minutes and progressively decreased to a value 30 minutes following infusion of 7.188 + 0.056 (p < 0.0025). The initial fall in the pH at 90 minutes was due primarily to the metabolic component as lactate had almost doubled from 35.36 k 2.98 to
I
I
I
I
0.25
0.30
0.35
0.40
(q%)
alcohol
concentrations
during
2 hour
infusion.
53.26 + 5.58 mg. per 100 ml. (p < 0.001) at that time. Lactate continued to rise throughout the infusion and recovery periods and associated with a significant increase in the Pco? resulted in a further decrease in pH. The significant increase in base excess throughout the infusion and recovery period confirmed the primary metabolic etiology of the acidosis. Glucose concentration in the fetal artery increased to a maximum at 120 minutes of 69.8 f 4.02 mg. per 100 ml. Oxygen tension and acid-base consideration are shown for a single experiment in Fig. 3B. At the
Volume Number
122 7
Placental
transport
of
alcohol
841
Ewe # 122 Gest. Age 126days IScc/kg/2hrs. Moternol Artery Fetal Carotid Artery - - - -
0.25
-
2 p 0.20I 0 0 15L O.lO0.050.00
r
I
I
0’
30’
60’
I
I
I
I
90’
120’
150’
180
I
Time
Fig. 3A. Absolute blood alcohol 9.75 per cent alcohol-dextrose of the fetus was 126 days (term
t220 t2 IO + 200
concentrations at intervals during and following infusion solution at 15 C.C. per kilogram per 2 hours. Gestational approximately 145 days).
pco2
‘%b‘xAd
Ewe
B.E.
-
15cc/kg/2hrs
+ 300
Loctote***** PO2 . . . . .
f
I I I’
Gest.
*
of a age
122 Age
126 doys
+ 150
+
100
% +50 +40 +30 +20 + IO - lo” -20 -30 -40 -50
-
100
7.445 I
1.450 I
7.450 I
2410 I
7.370
7.170
6.950
I
I
I
0’
30’
60’
90’
120’
I 50’
160’
Fig. 3B. Acid-base observations obtained at intervals during and following ( 15 cc. per kilogram per 2 hours). Blood alcohol concentrations are shown points represent per cent change from the baseline value taken as zero.
end of the 2-hour infusion in this experiment oxygen tension was insignificant from baseline, Pcoz showed only a slight percentage increase from the baseline value, while the concentration of lactate reflected in the base excess was increased by some 65%. At the 2 hour point the pH was decreased by only 0.075. In the hour following the 2 hour
PH
Time
alcohol infusion in Fig. 3A. Serial
infusion the pH fell significantly to 6.950 lactate and Pco? increased markedly.
as the
Comment
In view of the serious medical and social aspects of acute or chronic alcohol ingestion, a vast literature has accumulated on the subject of the effect
842
Mann
et al.
Table I. Maternal per kilogram
cardiovascular, per 2 hours
I Heart rate (beats/ min.) Blood pressure (mm. Hg) PO? (mm. Hg) Or Content (vol. %I Pco? (mm. Hg) PH Glucose (mg./lOO ml.) Lactate (mg./lOO ml. )
metabolic,
Baseline 97.50
90 min.
+ 5.74
65.22 111.67
+ 3.09 * 14.34
/
P
observations
1
120
min.
following
/
f
8.39
N.S.
103.50
k 10.38
N.S.
70.55 144.17
+ 6.39 + 19.73
N.S. N.S.
64.66 161.60
+ 7.36 f 21.40
N.S.
f + -t
N.S. N.S. N.S.
2 + 5
N.S. N.S. N.S.
k ? 2
0.55 0.94 0.015
11.82 22.50 7.605
43.39
f
3.84
226.32
14.34
f
2.28
29.43
0.44 2.40 0.036
11.69 19.60 7.6’9
2 10.87
< 0.0005
246.51
+
< 0.0005
33.65
and acid-base
1.59
observations
0.05
0.55 0.83 0.030
alcohol
P
106.66
11.16 21.00 7.660
Table II. Fetal cardiovascular,
and acid-base
150
infusion
min.
15 C.C.
/
P
101.88
2 13.53
N.S.
57.50 169.00
+ 6.17 + 28.30
N.S. N.S.
2 0.39 5 0.74 -c 0.034
N.S. N.S. N.S.
11.15 20.25 7.6075
i 12.97
< 0.0005
175.44
2
7.29
< 0.0005
t-
0.89
< 0.0005
34.86
f
1.74
< 0.0005
alcohol
infusion,
15 cc. per kilogram
following
per
2 hours I Heart rate (beats/ min.) Blood pressure (mm. Hg) PO? (FA) (mm. Hs) 0% content (FA) (vol. %) PH (FA) Pcoz (FA) (mm. Hg) Lactate (FA) (mg. %) Base excess (FA) mEq./L.) Glucose (FA)
Baseline 141
* 9.05
/
90 min. 164
1
2 9.45
N.S.
P
1
120 154
min.
/
P
2 10.65
N.S.
1
150 149
min.
/
P
t 6.97
N.S.
41.72
* 2.39
36.28
* 2.88
N.S.
36.86
t
2.66
N.S.
35.41
+ 2.17
< 0.05
15.8
t 0.87
17.5
+ 0.94
N.S.
18.0
+
1.10
N.S.
17.8
+ 0.96
N.S.
+ 1.13 t 0.058
N.S. < 0.05
1.10 0.052
N.S. < 0.01
5.39 7.188
9.52 7.438
f 1.17 + 0.029
7.93 7.310
7.98 + 7.2702
30.33
+ 1.54
38.17
+ 4.47
N.S.
35.36
2 2.98
53.26
25.58
< 0.01
59.45
-2.08 11.82
f 1.17 + 2.00
-6.75 53.78
t 2.06 f 4.41
< 0.05 < 0.0005
-8.16 69.83
of alcohol on cellular, organ, and total body functioning. Most of the reports, however, have dealt with the effect of alcohol on the adult human or animal model. As a result of the successful application of alcohol infusion in the inhibition of premature labor, interest in the effects of alcohol on the fetus was stimulated. The original investigative work of Fuchs1 was performed on a rabbit model and primarily concerned with proving the effectiveness of alcohol in inhibiting myometrial contractility and its mechanism of action. The effects of alcohol on maternal and fetal cardiovascular, metabolic, and acid-base parameters have only recently been evaluated in primate” and sheep32 4 studies. Unfortunately, there is disagreement in the observations and conclusions. Alcohol is predominantly metabolized by the
39.20
C 3.68 +
*
6.82
_+ 1.57 4.02
i 0.73 2 0.056
< 0.01 < 0.0025
< 0.05
45.00
+ 4.86
< 0.0125
< 0.01
68.87
+ 9.00
< 0.005
-12.00 65.62
k 2.28 + 6.14
< 0.0025 < 0.0005
< 0.01 < 0.0005
liver with probably no more than 20 per cent of alcohol metabolism occurring in extrahepatic sites.“, ’ The first step in the metabolism of alcohol is its oxidation to acetaldehyde which is catalyzed by at least three different enzyme systems. Alcohol dehydrogenase (ADH) is the most important enzyme. The second step in the metabolism of alcohol involves the conversion of acetaldehyde into acetate by the aldehyde dehydrogenase enzyme system primarily. The carbon skeleton of alcohol becomes incorporated into a variety of metabolic products. The ratio of DPNH to DPN is increased in the cytoplasm of the liver as a result of the conversion of alcohol to acetaldehyde. This conversion results in a number of significant effects on cellular metabolism, one of which is the reduction of pyruvate to lactate and an increase in the normal lactate/py-
Volume Number
122 7
ruvate ratio. A mild metabolic acidosis might ensue under these conditions. In the experiments presented here in sheep and those of Horiguchi and a~sociates’ in primates, a hyperlactacidemia and mild compensated metabolic acidosis, as reflected in the base excess or base deficit calculations, was observed in the mother during alcohol infusion. Dilt?! 4 recorded an insignificant decrease in pH and increase in base excess in the mother during alcohol infusion under spinal anesthesia but not under pentobarbital anesthesia. Because the equilibrium of the conversion of acetaldehyde to acetate is far to the right, little acetaldehyde is detectable in the blood following alcohol acetaldehyde has been impliinfusion. However, cated as the cause for a number of effects that cannot be attributed to alcohol aIone, such as peripheral vasodilatation and tachycardia which is commonly recorded following alcohol infusion.!’ An insignificant increase in maternal heart rate and decrease in maternal blood pressure was noted in the present experiments. Alcohol’s small molecular size and weak properties of dissociation and polarization result in its being freely miscible with water and relatively soluble in lipoid solvents. It would, therefore, be expected that alcohol would diffuse across cellular membranes with relative ease and would be rapidly and readily diffusable throughout body fluids and tissues. Kapid diffusion of alcohol across the placenta was evident from the present experiments, as has been reported previously by others.“, “’ There was no difference in the peak concentration of alcohol in the mother or fetus in the present experiments whether the calculated dose of 15 C.C. per kilogram of body weight (1.5 Gm. of alcohol per kilogram) was infused for 1 or 2 hours. The mean concentration of alcohol in the fetal circulation at 2 hours following a 2 hour infusion was somewhat higher than that reported by Dilts but within the range of concentrations presented. The mean and range of values presented by Horiguchi, where an infusion of 2 to 4 Gm. per kilogram of body weight was conducted for 1 hour, are somewhat higher than the values obtained with the 1 hour infusion in this series. These concentrations of alcohol must be considered consistent with intoxication or stuporous levels of alcohol. The observations reported here support those of Horigurhi that the fetal concentration at the end of the infusion period may actuaIly be greater than the maternal concentration and this level may per-
Placental
transport
of alcohol
843
sist for several hours following discontinuation of the alcohol infusion. The observations presented by Dilts were terminated at the end of the 2 hour infusion period. Reports of maternal and fetal blood concentrations of alcohol in human subjects have varied, with the highest values being those presented by Fuchs from a case of twins where a maternal level of 0.15 Gm. per 100 ml. was associated with a twin A value of 0.18 Gm. per 100 ml. and a twin B value of 0.17 Gm. per 100 ml. The effect of alcohol on cardiovascular and acidbase parameters discussed above for the adult animal seem to be exaggerated for the fetus. This is particularly true for the observations made during the last 30 minutes of infusion and for the halfto one-hour period following infusion. An insignificant increase in the fetal heart rate was recorded. Fetal blood pressure decreased as a result of the infusion of alcohol. The significant decrease in pH at 90 minutes of infusion was primarily metabolic in type due to a hyperlactacidemia. During the last 30 minutes of infusion and into the recovery period the fetal pH decreased further as a result of a mixed metabolic-respiratory acidosis at which time the maternal Pcos had decreased. These results are similar to those presented by Horiguchi in the primate but differ significantly from those presented by Dilts, who did not record a significant acidosis during alcohol infusion. Unexplained by Dilts, however, was the observation that under pentobarbital anesthesia and alcohol infuison acidosis was not noted in the face of a marked decrease in umbilical blood flow and oxygen transferred to the fetus. Postinfusion values which were not presented in that paper might have revealed the development of a fetai acidosis. While fetal oxygen consumption was not measured in the present series or that reported by Horiguchi, oxygen tension did not change during or after infusion in the present experiments. The significant decrease in oxygen content reported here in the face of insignificant changes in oxygen tension lvould be explained by a right shift in the oxygenhemogloblin dissociation curve as a result of the fall in pH (Bohr effect). The acid-base observations, however, would tend to suggest that fetal oxygen consumption had decreased as the metabolic acidosis effected a decrease in cardiac output and/or redistribution of cardiac output to vital organs at the expense of a decrease in umbilical blood flow. The accumulation of CO, within the fetal circulation wold support this pathophysiology. The significant increase in fetal glucose concentration dur-
844
Mann
ing
infusion
served
et al.
of
and
glucose
discussed
Correlation conditions
of to the
drome
in
infantile
delivered
during at
inhibiting
be
expected
by
the
transient
in
the
motor
this
component
prepared
the that
the
observaat-
with
alcohol
incidence be
of
unanswered the
effect
of
the
1. Fuchs, F.: J. Obstet. Gynaecol. Br. Commonw. 72: 1011, 1965. 2. Fuchs, F., Fuchs, A-R., Poblete, V. F., Jr., and Risk, A.: AM. J. OBSTET. GYNECOL. 99: 627, 1967. 3. Dilts, P. V., Jr.: AM. J. OBSTET. GYNECOL. 107: 1018, 1970. 4. Dilts, P. V., Jr.: AM. J. OBSTET. GYNECOL. 108: 221, 1970. 5. Horiguchi, T., Suzuki, K., Comas-Urrutia, A. C., Mueller-Heubach, E., Boyer-Milic, A. M., Baratz, R. A., Morishima, H. D., James, L. S., and Adamson, K.: AM. J. OBSTET. GYNECOL. 109: 910, 1971. 6. Mann, L. I., Carmichael, A., and Duchin, S.: AM. J. OBSTET. GYNECOL. 114:549, 1972.
7.
inhibition
of premature
labor
on
inhibit
acidosis
The unit
neonatal to
less
be
alerted
in
these
immediate
in-
than
the
disease
team
should
seem
alcohol
are
acidosis
Until
would
rnembrane
perinatal
initiate
infant. it
labor
hyaline
death.
the
following
premature
prematurity,
of
of available,
and to infants
resuscitative
and
neonatal the
possiand
be mea-
of
The authors wish to acknowledge the cooperation and assistance of Mr. Peter Lorenzo and staff of the Animal Kesearch Division of the Nassau County Medical Center in the performance of these experiments, and Dr. J. Bidouset and Mr. Tom Manning of the Toxicology Division, Nassau County Medical Examiner’s Office, for
a
successful
as a result
are
sures.
newborns
unsuccessful
functioning
of fetal
intensive-care
to
question acidosis
of
neonatal
analogous study,
would
fetal
risk
bility
a higher
observations
syn-
risks to
While
labor
have
the
fusion
induced
mental
observations
solutions.‘”
an
A further of
and
that
drawn
alcohol
alcohol
premature
episodes
have
fetal
impression
following to
depression. present
the
exactly
the
or
could neonatal
to
not
support
tempt
ob-
clinical
intravenously
alimentation
are
do
been
with
reports
of
due
infused
studies
and
performed
here
has
further
Recent
infancy’”
conditions
mother
animal
intoxication
experiments
the
recognition
early
of parentally
tions
these
is hazardous.
attention
these
to
previously.‘l
performance
of the
alcohol
determinations.
eventual
REFERENCES
Note
to
authors:
Change
in
reference
8. 9. 10. 11. 12. 13.
Goldbaum, L. R., and Schlaegel, E. L.: J. Forensic Sci. 9: 63, 1964. Lieber, C. S.: Gastroenterology 65: 821, 1973. Myerson, R. M.: Med. Clin. N. Am. 57: 925, 1973. Dilts, P. V., Jr.: AM. J. OBSTET. GYNECOL. 107: 1195, 1970. Mann, L. I., Prichard, J., and Symmes, D.: AM. J. OBSTET. GYNECOL. 107: 610, 1970. Jones, K. L., and Smith, D. W.: Lancet 11: 999, 1973. Peden, V. H., and Downey, D. A.: J. Pediatr. 83: 490. 1973.
style
The Editors and Publisher have agreed to add the article title to references in the AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY. References will now conform to the style of the Cumulated Index Medicus, viz., name of author, title of article, name of periodical, volume, page, and year. Authors are always encouraged to limit references t9 sixteen for the following JOURNAL sections: Obstetrics, Gynecology, and Fetus, Placenta, andNewborn.