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Effect of maternal exposure to high altitude upon fetal oxygenation
Effect of maternal exposure to high altitude upon fetal oxygenation EDGAR L. MAKOWSKI, M.D. FREDERICK C. BATTAGLIA, M.D. GIACOMO MESCHIA, M.D. RICHARD E. BEHRMAN, M.D.* JOHN SCHRUEFER, M.D.* A. ELMORE SEEDS, M.D.* PAUL D. BRUNS, M.D. Denver, Colorado Acute exposure to high altitude of 6 pregnant ewes in the last third of pregnancy produced a significant decrease in oxygen content in the umbilical vein in the first 48 hours. With continued exposure to high altitude there was an increase in oxygen content in the umbilical vein toward normal values. Two of 6 animals attained normal values in about 2 wnks. This process of adaptation was detectable as early as the fourth day of exposure to low barometric pressure. The rise in oxygen content in the umbilical vein was due in part to an increased umbilical vein oxygen tension and in part to an increased oxygen capacity. The rise of oxygen tension in the umbilical vein was parallel to a rise of oxygen tension in the uterine vein.
T HIS STU 0 Y was carried out to determine whether fetal hypoxia occurred in nonacclimatized pregnant ewes exposed acutely to high altitude during the last third of gestation. If fetal hypoxia occurred, it was hoped that any fetal adaptation to altitude could be described. Catheters were inserted into the umbilical vein and artery, uterine vein and maternal femoral artery of 6 ewes of known breeding dates, in Denver (elevation 5,280 feet above sea level). After recovery from the operation the animals were transported to Mount Evans (elevation 14,260 feet above sea level) and kept at high altitude for several days (7
to 18 days). Maternal and fetal blood samples were drawn at the two different altitudes and analyzed for their oxygen content, oxygen combining capacity, oxygen pressure and hydrogen ion concentration.
Materials and methods The animals were bred on a farm in Oklahoma (altitude 1,250 feet) and brought to Denver about the eightieth day of gestation. Prior to operation, the presence and size of the fetus were detected radiographically in the Roentgen Diagnostic Research Laboratory, University of Colorado Medical Center, which is supported by Grant No. HE 0911003. The ewes were kept off feed for 48 hours prior to operation and given 125 mg. Proluton (Schering) intramuscularly on the morning of the operation. The animal was sedated with pentobarbital and given a spinal anesthesia (6 mg. of Pontocaine). Polyvinyl catheters, I.D. 0.55 mm., were inserted into the umbilical vein and artery, uterine vein,
From the Departments of Obstetrics and Gynecology, Pediatrics, and Physiology, the University of Colorado Medical Center. This work supported by United Cerebral Palsy Grant No. R-196-67C and United States Public Health Service Grant No. HD 00781-03. *Visiting Scientist, United Cerebral Palsy Foundation.
852
Volume 100 Number 6
Effect of high altitude on fetal oxygenation
and maternal femoral artery. At the conclusion of the operation and daily thereafter the catheters were filled with a heparin solution (1,000 units per milliliter in 0.9 per cent NaCI). In addition, the ewes received one million units of aqueous penicillin and 0.75 Gm. of streptomycin intramuscularly for 3 days following the operation. On the first postoperative day in Denver, blood samples of 1.0 ml. were obtained from each catheter with the animal standing quietly in the stall. The samples were drawn into oiled syringes in which the dead space was filled with a solution consisting of 1,000 units of heparin and 30 mg. NaF per milliliter. The samples were stored in ice water prior to analysis. The oxygen content and the oxygen capacity were determined by gas chromatography (Beckman Model GC-2). The oxygen capacity determination was done by equilibrating blood with air in a glass syringe. The p02 was measured with a Clark electrode (macroelectrode Beckman Model 325812) and the pH with a glass electrode (Radiometer Model G297/G2). The types of hemoglobin in maternal and fetal blood were determined by paper electrophoresis 1 and by alkali denaturation. 2 Within 24 hours following the control samples in Denver, the animals were transported to the crest of Mount Evans-elevation 14,260 feet-and housed there in a van. The van had straw on the floor and ad libitum supply of hay, grain, and water. The temperature in the van was subject to large fluctuations from below freezing to comfortably warm. Samples were drawn from each catheter every other day until the cathe-
ter stopped functioning. The samples were stored in ice and brought to Denver for analysis. This trip imposed a minimum delay between sampling and analysis of 2Y:z hours. Table I shows the gestational age of the 6 fetuses which were studied, the number of days at high altitude, and the mode of delivery. Result, The maternal blood of all sheep contained a single slow-moving hemoglobin, type B (1). Alkali denaturation studies of fetal blood showed 100 per cent hemoglobin F and this was confirmed by elution studies on the red cells which demonstrated 93 to lOOper cent hemoglobin F in all fetuses. Twenty-four hours after operation the maternal oxygen capacity ranged from 4.94 to 6.53 mM. per liter with an average of 5.69 mM. per liter. While the ewes were exposed to an altitude of 14,260 feet, the oxygen capacity rose in four and fell in 2 ewes (Fig. 1). These 2 ewes had the highest oxygen capacities 24 hours postoperatively in the group-6.53 and 6.35 mM. per liter, respectively. Animal No. 270 shows what might be considered a typical response, i.e., a rise of oxygen capacity at high altitude followed by a slow decrease after the animal was returned to Denver. By contrast, the oxygen capacity of Ewe No. 0005 shows a progressive drop throughout the period of observation (36 days). The oxygen capacity in the 6 fetuses (Fig. 2) at the start of the experiment in Denver ranged from 4.09 to 5.40 mM. per liter with an average of 4.76 mM. per liter. On the
Table I Sh"p No. 0005
117
32
34
270 115
C.s'ational a6. th, first day at
Days at
14,260 /,.,
14,260 /,.,
9495 95
18
97 97 98
10
12
7
10
15
853
141
117 119 115 143 118
"One of twI... Weltht of other fetua at _ _ _ -'IoD 1,410 arama.
Vaginal Cesarean Ceaarean Cesarean Vaginal Cesarean
aec:tion aec:tion lection Metion
Alive AliWl Alive Alive Alive Alive
2,348 1,625 1,518 1,443 3,555 1,619-
Oxygen Capacity Maternal Artery
140 %
To Denver
40 20%
4
2
6 8 ID ~ M Day. at altitude 14,260 feet
re
18
2
4
6
8
10
12
14
16
18
Fig. 1. Per cent variation of maternal oxygen capacity. On the abscissa are the number of days the animals were observed at high altitude followed by the number of days the animals were observed at Denver. On the ordinate is plotted the percentage of oxygen capacity in the maternal artery. The oxygen capacity in Denver prior to high altitude exposure is referred to as 100 per cent. A, Animal No. 270; b., Animal No. 32; . , Animal No. 34; 0, Animal No. 115; 0, Animal No. 117; e, Animal No. 0005.
Oxygen Capacity Fetus
~ ~-=--=.
I~~~~~__ ~ __________________________________________ _
80
60 To Denvw-
40
2
4
8
10
U
14
re
18
2
4
6
10
U
M
Days at altitude 14,260 feet
Fig. 2. Per cent variation of fetal oxygen capacity. Symbols and abscissa as in Fig. 1. On the ordinate is plotted the percentage of oxygen capacity in the fetus. The values in Denver prior to high altitude exposure are referred to as 100 per cent.
Volume 100 Number 6
Effect of high altitude on fetal oxygenation
eighth day at high altitude the fetal oxygen capacity was about 20 per cent higher than in Denver in Fetuses No. 32 and No. 270. In Fetus No. 0005 the oxygen capacity showed an initial drop and a subsequent rise above Denver level on the fourteenth day. The remaining 3 fetuses showed no significant changes. Umbilical vein catheters continued to function in 2 animals (Nos. 0005 and 270) after their return to Denver. In these 2 fetuses the oxygen capacity did not return to the control values measured prior to high altitude exposure. In Denver, prior to high altitude exposure, the oxygen content of arterial blood ranged from 4.27 to 6.26 mM. per liter with an average of 4.96 mM. per liter and the oxygen content in uterine venous blood ranged from 3.57 to 4.08 mM. per liter with an average of 3.79 mM. per liter. At Mount Evans the maternal arterial
140 'Y.
855
oxygen content fell significantly in 4 of the 6 animals on the second to fourth day of exposure to high altitude. The oxygen content in the uterine vein fell in all animals, from an average control value of 3.79 ± 0.17 to 2.45 ± 0.47 mM. per liter on the second and third day of exposure to high altitude. The difference is statistically significant (p < 0.01). After one week at high altitude the uterine vein oxygen content was about 75 per cent of the control value. Upon returning to Denver, the few samples obtained suggest an abrupt rise in the oxygen content followed by a slower decrease. The oxygen content in the umbilical vein showed an initial fall below Denver values and then a return toward prealtitude levels (Fig. 3). Two of the 5 fetuses showed a complete return to control values on the tenth and sixteenth days, respectively. After the ewes were returned to Denver, No. 0005
Oxygen Content Umbilical Vein
130 120 110 100
90
eo 70
80 To Denver
80 40
,..
0.88
o
2
4
12 14 Day. at altitude 14,280 feet.
18
2
4
8
8
10
1
14
16
Fig. S. Per cent variation of oxygen content in the umbilical vein. SymboJa and abacia. u in Fig. 1. On the ordinate is plotted the percentage of oxygen content in the umbilical vein. The lowest oxygen content at high altitude is given in millimols per liter next to each curve. The values in Denver prior to high altitude eXpoIure are referred to u 100 per cent.
8
856 Makowski et 01.
Am.
showed an umbilical vein oxygen content which was 35 per cent above control value. This returned to control value after 18 days in Denver. The umbilical artery catheter continued to function in only 3 animals from 7 to 12 days following the operation. The oxygen content in the umbilical artery at Denver ranged from 1.73 to 3.23 mM. per liter (average 2.59 mM. per liter). On the second day at high altitude the oxygen content in the umbilical artery was 26 to 60 per cent of the values obtained in Denver, with the same trend toward prealtitude values with continued exposure to high altitude. The average per cent oxygen saturation of the maternal arterial blood was 87.0 ± 5.31 on the first postoperative day in Denver (Fig. 4) and, at altitude, 67.6 ± 6.88. When the animals were brought back to Denver the saturation returned to control values. The pH of the blood in the maternal artery
March 15. 1968
J. Obot. I: Craec.
averaged 7.42 in Denver, 7.41 at high altitude and 7.40 on return to Denver, those in the uterine vein 7.38, 7.38, and 7.37, respectively. The differences are not significant. On exposure to high altitude the saturation in the uterine vein showed a drop from 66.4 to 40 per cent on the second day and 50 per cent thereafter (Fig. 5 ) . On return to Den\'er, the saturations returned to control values. The oxygen saturations in the umbilical vessels are shown in Figs. 6 and 7. The per cent saturation of the umbilical vein blood in the control samples ranged from 54.5 to 88.1 per cent, average 73.6 per cent. The lowest saturations in the umbilical vein were obtained between the second and fourth days at high altitude and then a tendency toward recovery was observed in three ewes (Nos. 0005, 34, and 115). A remarkable recovery was observed in Sheep No. 0005. On the sixteenth day the saturation had almost
Percent Saturation Matemel Artery
•
•
•
I
•
•
•
0
a
~
•
•• • •
,
DO·
• • •• 0
2
•
•
• To Denver
30 20%
2
12 14 4 Deya at altitude 14.:zeo feet
16
4
8
Fig. 4. Per cent saturation maternal artery. Symbola and absciua as in Fig. 1. On the ordinate it plotted the per cent saturation in the maternal artery.
••
Percent Saturation Uterine Vein
I
~~
_..&_"2!::;~;;-.~
To Denver
o
2
4
6 8 10 12 14 Days lit altitude 14,260 feet
16
18
2
4
6
8
10
12
14
16
18
Fig. 5. Per cent saturation uterine vein. Symbols and abscissa as in Fig. 1. On the ordinate is plotted the per cent saturation in the uterine vein.
Percent Saturation
Umbilical Vein
Too.tver
o
2
4
8
8
1
14
Days .t altitude 14,260 feet
4
8
18
FI,. 6. Per cent aaturation umbilical vein. Symbol. and abaciasa at in Fig. 1. On the ordinate il plotted the per cent aaturation in the umbilical vein.
18
858 Makowski et al.
Am.
J.
March 15. 1968 Obst. "Gynec.
Percent Saturation Umbilical Artery
80 ""
70
To Denver 10
ct. 024681012141618 Days at altitude 14.260 feet
246810
12141818
Fig. 7. Per cent saturation umbilical artery. Symbols and abscissa as in Fig. 1. On the ordinate is plotted the per cent saturation in the umbilical artery.
reached the control value in Denver-79.1 and 81.5 per cent, respectively. Samples obtained from the umbilical vein of 2 pregnant ewes when returned to Denver showed saturations almost identical to the values prior to high altitude exposure. The pH of umbilical vein blood averaged 7.30 in Denver (range, 7.243 to 7.358), 7.28 at high altitude (range, 7.225 to 7.366), and 7.32 upon return to Denver (range, 7.290 to 7.372) . The oxygen saturation of the umbilical artery in Denver ranged from 59.8 to 62.0 per cent, average 61.0 per cent. The lowest umbilical arterial saturation was obtained on the second day at high altitude; 2 of the 3 fetuses had a saturation of about 15 per cent. The pH of the umbilical arterial blood averaged 7.26 in Denver (range 7.195 to 7.318) and 7.27 at high altitude (range, 7.178 to 7.295). The oxygen tension data are presented in Figs. 8 and 9. The maternal arterial pOz in the control samples varied between 62.0 and 75.0 mm. Hg, average 69.4 mm. Hg. At high
altitude the maternal arterial pOz averaged 46.3 mm. Hg. The average uterine vein pOz was 45.6 ± 2.83 mm. Hg in Denver and at high altitude 36.0 ± 1.87 mm. Hg. The average umbilical vein p02 was 29.2 ± 5.52 mm. Hg in Denver and at high altitude 20.0 ± 3.88 mm. Hg. The data show a fall in oxygen tension in the uterine and umbilical veins to a minimum between the second and fourth days at high altitude followed by a recovery. Animal No. 0005, which was followed the longest, had an oxygen tension in the umbilical vein which went from 31 mm. Hg in Denver to a minimum of 16 mm. Hg on the fourth day and then back to 25.4 mm. Hg on the sixteenth day of high altitude. The oxygen tension in the uterine vein showed a similar pattern, i.e., an oxygen tension of 45.0 mm. Hg in Denver to a minimum of 31.5 mm. Hg on the second day and then 37.8 mm. Hg on the ninth day of high altitude. The oxygen tension in the umbilical artery averaged 21.1 mm. Hg in Denver and 14.4 ± 2.11 mm. Hg at high altitude. Upon returning the pregnant ewes to
Volume 100 Number 6
Effect of high altitude on fetal oxygenation
859
• Maternal Artery o Umbilical Artery
mm Hg.
J_.•
I , •
•• • " "0
0
g
0
''0- __ .0.--.0........ -
.• : _-0._
• •
•
•
•
•
•
.
---.................................-.
To Denver
---"0
o
10
12
14
18
2
8
10
Days lit altitude 14.280 ' . .t
Fig. 8. Oxygen tension in maternal and umbilical arteries. Abscissa as in Fig. 1. The oxygen tensions in the maternal and umbilical arteries of 6 animal. are plotted against time. Closed circles maternal artery. Open circles umbilical artery. The solid line connects the oxygen tensions in the maternal artery in Animal No. 0005 and the broken line connects the oxygen tensions in the umbilical artery of that same animal.
=
=
Denver, the average oxygen tensions in the maternal artery and uterine vein of Sheep No. 0005 and No. 270 were 67.8 and 44.8 mm. Hg, respectively. These were essentially unchanged from the control values obtained in Denver prior to exposure to high altitude, which were 69.4 and 45.6 mm. Hg, respectively. The average oxygen tension in the umbilical vein was 25.6 nun. Hg, 3.6 mm. Hg below the average control oxygen tension in the umbilical vein. Comment
Earlier studies in fetal physiology at high altitudeS were carried out on sheep which were bred at about 12,000 feet and pastured in the last third of pregnancy at an elevation of 14,000 feet. In these studies the oxygen tensions and saturations found in the umbilical blood were not significantly different from sea level values despite a marked re-
duction oC oxygen pressure in the maternal artery and uterine vein. These studies at high altitude and the sea level control experiments with which they are compared were done prior to the development of a sheep preparation with indwelling plastic catheters in the umbilical circulation. Thus, these experiments had the drawback of comparing single observations per fetus. Furthennore, the sampling was done while the animal was under the stress of surgical procedures. It was possible, therefore, that high altitude brought about changes in fetal oxygenation which were too subtle or too labile to be observed under those experimental conditions. The use of a preparation which allows multiple sampling of fetal blood obviates these reservations. In addition, it extends our range of observations from fuUy acclimatized pregnant animals to those exposed acutely to high altitude.
860 Makowski et al.
• Uterine
mm
Am.
J.
March 15, 1968
Obat. &: Gynec •
Vein
o Umbilical Vein
Hg.
8
70 60
• •
•
•
•• o
To Denver
10
o~~~~__~~__~~~~__~~~~__~~~~__~~~~~~~
0246 10121416182468 Days at altitude 14,260 feet
12141818
Fig. 9. Oxygen tension in uterine and umbilical veins. Abscissa as in Fig. I. On the ordinate is plotted the oxygen tension (mm. Hg) in both the uterine and umbilical veins of all 6 animals. Closed circles = uterine vein. Open circles umbilical vein. The solid line connects the oxygen tensions in the uterine vein of Animal No. 0005 and the broken line connects the oxygen tensions in the umbilical vein of that same animal.
=
The present study has shown that acute exposure to high altitude involves a marked reduction in p02' O 2 saturation, and O2 content in the umbilical vessels. Presumably, the fall in fetal pOz is a direct consequence of a lowered oxygen pressure in the maternal placental blood. With prolonged exposure to low barometric pressure there is an adaptation characterized by a rise of O 2 content in the umbilical circulation. The umbilical vein O 2 content is already rising in some animals at the sixth day of exposure to high altitude and it may return to the level observed prior to high altitude exposure in about 2 weeks. This increase of O 2 content in the umbilical vein was due to a combination of increased O 2 saturation and hemoglobin content. The increase in oxygen saturation was due primarily to an increased umbilical vein pOz. The increase in umbilical vein p02 followed the increase in uterine vein pOa. In this respect Animal No. 0005, which was observed the longest, is particularly instructive
(Fig. 9). This observation suggests that an increase in uterine blood flow may be an important factor in the over-all adaptation of the fetus. The results of the 1958 experiments led to the tentative conclusion that adaptation was in fact due to an increase in oxygen "diffusing capacity" of the placenta. s This interpretation was based on the assumption that the sheep placenta is a countercurrent exchange system and that concentration differ-, ences between uterine and umbilical veins are necessarily the consequence of a limited permeability of the placenta. In the light of present knowledge 4 • 5 this assumption appears incorrect. In addition, the present study does not show any evidence of a narrower uterine vein to umbilical vein oxygen tension difference after acclimatization. This finding contradicts the hypothesis of a greater oxygen "diffusing capacity" as the principal mechanism of fetal adaptation to high altitude.
Volume 100 Number 6
REFERENCES
1. Naughton, M . A., Meschia. G., Battaglia, F., Hellegers, A., Hagopian, H., and Barron, D. H.: Quart. J. Exper. Physiol. 48: 313, 1963. 2. Breathnach, C. S. : Quart. J, Exper. Physiol. 49: 277, 1964. 3. Barron, Donald H ., Metcalfe, J" Melchia, G., Huckabee, W., Hellegers, A., and Prystowsky, H.: The Symposium on the Physiological Ef· fecll of High Altitude, Interlaken, Switzerland, Oxford, 1962, Pergamon Press, Ltd., p. 115.
Effect of high altitude on fetal oxygenation 861
4. Meschia, Giacomo, Cotter, J. R., Makowski, E. L., and Barron, D. H.: Quart. J. Exper. Physiol. 50: 1, 1967. 5. Meschia, Giacomo, Battaglia, F. C., and Bruns, P. D.: J. Appl. Physiol. In press.
4200 East Ninth Avenue D,nver, Colorado 80220
T HIS STU 0 Y was carried out to determine whether fetal hypoxia occurred in nonacclimatized pregnant ewes exposed acutely to high altitude during the last third of gestation. If fetal hypoxia occurred, it was hoped that any fetal adaptation to altitude could be described. Catheters were inserted into the umbilical vein and artery, uterine vein and maternal femoral artery of 6 ewes of known breeding dates, in Denver (elevation 5,280 feet above sea level). After recovery from the operation the animals were transported to Mount Evans (elevation 14,260 feet above sea level) and kept at high altitude for several days (7
to 18 days). Maternal and fetal blood samples were drawn at the two different altitudes and analyzed for their oxygen content, oxygen combining capacity, oxygen pressure and hydrogen ion concentration.
Materials and methods The animals were bred on a farm in Oklahoma (altitude 1,250 feet) and brought to Denver about the eightieth day of gestation. Prior to operation, the presence and size of the fetus were detected radiographically in the Roentgen Diagnostic Research Laboratory, University of Colorado Medical Center, which is supported by Grant No. HE 0911003. The ewes were kept off feed for 48 hours prior to operation and given 125 mg. Proluton (Schering) intramuscularly on the morning of the operation. The animal was sedated with pentobarbital and given a spinal anesthesia (6 mg. of Pontocaine). Polyvinyl catheters, I.D. 0.55 mm., were inserted into the umbilical vein and artery, uterine vein,
From the Departments of Obstetrics and Gynecology, Pediatrics, and Physiology, the University of Colorado Medical Center. This work supported by United Cerebral Palsy Grant No. R-196-67C and United States Public Health Service Grant No. HD 00781-03. *Visiting Scientist, United Cerebral Palsy Foundation.
852
Volume 100 Number 6
Effect of high altitude on fetal oxygenation
and maternal femoral artery. At the conclusion of the operation and daily thereafter the catheters were filled with a heparin solution (1,000 units per milliliter in 0.9 per cent NaCI). In addition, the ewes received one million units of aqueous penicillin and 0.75 Gm. of streptomycin intramuscularly for 3 days following the operation. On the first postoperative day in Denver, blood samples of 1.0 ml. were obtained from each catheter with the animal standing quietly in the stall. The samples were drawn into oiled syringes in which the dead space was filled with a solution consisting of 1,000 units of heparin and 30 mg. NaF per milliliter. The samples were stored in ice water prior to analysis. The oxygen content and the oxygen capacity were determined by gas chromatography (Beckman Model GC-2). The oxygen capacity determination was done by equilibrating blood with air in a glass syringe. The p02 was measured with a Clark electrode (macroelectrode Beckman Model 325812) and the pH with a glass electrode (Radiometer Model G297/G2). The types of hemoglobin in maternal and fetal blood were determined by paper electrophoresis 1 and by alkali denaturation. 2 Within 24 hours following the control samples in Denver, the animals were transported to the crest of Mount Evans-elevation 14,260 feet-and housed there in a van. The van had straw on the floor and ad libitum supply of hay, grain, and water. The temperature in the van was subject to large fluctuations from below freezing to comfortably warm. Samples were drawn from each catheter every other day until the cathe-
ter stopped functioning. The samples were stored in ice and brought to Denver for analysis. This trip imposed a minimum delay between sampling and analysis of 2Y:z hours. Table I shows the gestational age of the 6 fetuses which were studied, the number of days at high altitude, and the mode of delivery. Result, The maternal blood of all sheep contained a single slow-moving hemoglobin, type B (1). Alkali denaturation studies of fetal blood showed 100 per cent hemoglobin F and this was confirmed by elution studies on the red cells which demonstrated 93 to lOOper cent hemoglobin F in all fetuses. Twenty-four hours after operation the maternal oxygen capacity ranged from 4.94 to 6.53 mM. per liter with an average of 5.69 mM. per liter. While the ewes were exposed to an altitude of 14,260 feet, the oxygen capacity rose in four and fell in 2 ewes (Fig. 1). These 2 ewes had the highest oxygen capacities 24 hours postoperatively in the group-6.53 and 6.35 mM. per liter, respectively. Animal No. 270 shows what might be considered a typical response, i.e., a rise of oxygen capacity at high altitude followed by a slow decrease after the animal was returned to Denver. By contrast, the oxygen capacity of Ewe No. 0005 shows a progressive drop throughout the period of observation (36 days). The oxygen capacity in the 6 fetuses (Fig. 2) at the start of the experiment in Denver ranged from 4.09 to 5.40 mM. per liter with an average of 4.76 mM. per liter. On the
Table I Sh"p No. 0005
117
32
34
270 115
C.s'ational a6. th, first day at
Days at
14,260 /,.,
14,260 /,.,
9495 95
18
97 97 98
10
12
7
10
15
853
141
117 119 115 143 118
"One of twI... Weltht of other fetua at _ _ _ -'IoD 1,410 arama.
Vaginal Cesarean Ceaarean Cesarean Vaginal Cesarean
aec:tion aec:tion lection Metion
Alive AliWl Alive Alive Alive Alive
2,348 1,625 1,518 1,443 3,555 1,619-
Oxygen Capacity Maternal Artery
140 %
To Denver
40 20%
4
2
6 8 ID ~ M Day. at altitude 14,260 feet
re
18
2
4
6
8
10
12
14
16
18
Fig. 1. Per cent variation of maternal oxygen capacity. On the abscissa are the number of days the animals were observed at high altitude followed by the number of days the animals were observed at Denver. On the ordinate is plotted the percentage of oxygen capacity in the maternal artery. The oxygen capacity in Denver prior to high altitude exposure is referred to as 100 per cent. A, Animal No. 270; b., Animal No. 32; . , Animal No. 34; 0, Animal No. 115; 0, Animal No. 117; e, Animal No. 0005.
Oxygen Capacity Fetus
~ ~-=--=.
I~~~~~__ ~ __________________________________________ _
80
60 To Denvw-
40
2
4
8
10
U
14
re
18
2
4
6
10
U
M
Days at altitude 14,260 feet
Fig. 2. Per cent variation of fetal oxygen capacity. Symbols and abscissa as in Fig. 1. On the ordinate is plotted the percentage of oxygen capacity in the fetus. The values in Denver prior to high altitude exposure are referred to as 100 per cent.
Volume 100 Number 6
Effect of high altitude on fetal oxygenation
eighth day at high altitude the fetal oxygen capacity was about 20 per cent higher than in Denver in Fetuses No. 32 and No. 270. In Fetus No. 0005 the oxygen capacity showed an initial drop and a subsequent rise above Denver level on the fourteenth day. The remaining 3 fetuses showed no significant changes. Umbilical vein catheters continued to function in 2 animals (Nos. 0005 and 270) after their return to Denver. In these 2 fetuses the oxygen capacity did not return to the control values measured prior to high altitude exposure. In Denver, prior to high altitude exposure, the oxygen content of arterial blood ranged from 4.27 to 6.26 mM. per liter with an average of 4.96 mM. per liter and the oxygen content in uterine venous blood ranged from 3.57 to 4.08 mM. per liter with an average of 3.79 mM. per liter. At Mount Evans the maternal arterial
140 'Y.
855
oxygen content fell significantly in 4 of the 6 animals on the second to fourth day of exposure to high altitude. The oxygen content in the uterine vein fell in all animals, from an average control value of 3.79 ± 0.17 to 2.45 ± 0.47 mM. per liter on the second and third day of exposure to high altitude. The difference is statistically significant (p < 0.01). After one week at high altitude the uterine vein oxygen content was about 75 per cent of the control value. Upon returning to Denver, the few samples obtained suggest an abrupt rise in the oxygen content followed by a slower decrease. The oxygen content in the umbilical vein showed an initial fall below Denver values and then a return toward prealtitude levels (Fig. 3). Two of the 5 fetuses showed a complete return to control values on the tenth and sixteenth days, respectively. After the ewes were returned to Denver, No. 0005
Oxygen Content Umbilical Vein
130 120 110 100
90
eo 70
80 To Denver
80 40
,..
0.88
o
2
4
12 14 Day. at altitude 14,280 feet.
18
2
4
8
8
10
1
14
16
Fig. S. Per cent variation of oxygen content in the umbilical vein. SymboJa and abacia. u in Fig. 1. On the ordinate is plotted the percentage of oxygen content in the umbilical vein. The lowest oxygen content at high altitude is given in millimols per liter next to each curve. The values in Denver prior to high altitude eXpoIure are referred to u 100 per cent.
8
856 Makowski et 01.
Am.
showed an umbilical vein oxygen content which was 35 per cent above control value. This returned to control value after 18 days in Denver. The umbilical artery catheter continued to function in only 3 animals from 7 to 12 days following the operation. The oxygen content in the umbilical artery at Denver ranged from 1.73 to 3.23 mM. per liter (average 2.59 mM. per liter). On the second day at high altitude the oxygen content in the umbilical artery was 26 to 60 per cent of the values obtained in Denver, with the same trend toward prealtitude values with continued exposure to high altitude. The average per cent oxygen saturation of the maternal arterial blood was 87.0 ± 5.31 on the first postoperative day in Denver (Fig. 4) and, at altitude, 67.6 ± 6.88. When the animals were brought back to Denver the saturation returned to control values. The pH of the blood in the maternal artery
March 15. 1968
J. Obot. I: Craec.
averaged 7.42 in Denver, 7.41 at high altitude and 7.40 on return to Denver, those in the uterine vein 7.38, 7.38, and 7.37, respectively. The differences are not significant. On exposure to high altitude the saturation in the uterine vein showed a drop from 66.4 to 40 per cent on the second day and 50 per cent thereafter (Fig. 5 ) . On return to Den\'er, the saturations returned to control values. The oxygen saturations in the umbilical vessels are shown in Figs. 6 and 7. The per cent saturation of the umbilical vein blood in the control samples ranged from 54.5 to 88.1 per cent, average 73.6 per cent. The lowest saturations in the umbilical vein were obtained between the second and fourth days at high altitude and then a tendency toward recovery was observed in three ewes (Nos. 0005, 34, and 115). A remarkable recovery was observed in Sheep No. 0005. On the sixteenth day the saturation had almost
Percent Saturation Matemel Artery
•
•
•
I
•
•
•
0
a
~
•
•• • •
,
DO·
• • •• 0
2
•
•
• To Denver
30 20%
2
12 14 4 Deya at altitude 14.:zeo feet
16
4
8
Fig. 4. Per cent saturation maternal artery. Symbola and absciua as in Fig. 1. On the ordinate it plotted the per cent saturation in the maternal artery.
••
Percent Saturation Uterine Vein
I
~~
_..&_"2!::;~;;-.~
To Denver
o
2
4
6 8 10 12 14 Days lit altitude 14,260 feet
16
18
2
4
6
8
10
12
14
16
18
Fig. 5. Per cent saturation uterine vein. Symbols and abscissa as in Fig. 1. On the ordinate is plotted the per cent saturation in the uterine vein.
Percent Saturation
Umbilical Vein
Too.tver
o
2
4
8
8
1
14
Days .t altitude 14,260 feet
4
8
18
FI,. 6. Per cent aaturation umbilical vein. Symbol. and abaciasa at in Fig. 1. On the ordinate il plotted the per cent aaturation in the umbilical vein.
18
858 Makowski et al.
Am.
J.
March 15. 1968 Obst. "Gynec.
Percent Saturation Umbilical Artery
80 ""
70
To Denver 10
ct. 024681012141618 Days at altitude 14.260 feet
246810
12141818
Fig. 7. Per cent saturation umbilical artery. Symbols and abscissa as in Fig. 1. On the ordinate is plotted the per cent saturation in the umbilical artery.
reached the control value in Denver-79.1 and 81.5 per cent, respectively. Samples obtained from the umbilical vein of 2 pregnant ewes when returned to Denver showed saturations almost identical to the values prior to high altitude exposure. The pH of umbilical vein blood averaged 7.30 in Denver (range, 7.243 to 7.358), 7.28 at high altitude (range, 7.225 to 7.366), and 7.32 upon return to Denver (range, 7.290 to 7.372) . The oxygen saturation of the umbilical artery in Denver ranged from 59.8 to 62.0 per cent, average 61.0 per cent. The lowest umbilical arterial saturation was obtained on the second day at high altitude; 2 of the 3 fetuses had a saturation of about 15 per cent. The pH of the umbilical arterial blood averaged 7.26 in Denver (range 7.195 to 7.318) and 7.27 at high altitude (range, 7.178 to 7.295). The oxygen tension data are presented in Figs. 8 and 9. The maternal arterial pOz in the control samples varied between 62.0 and 75.0 mm. Hg, average 69.4 mm. Hg. At high
altitude the maternal arterial pOz averaged 46.3 mm. Hg. The average uterine vein pOz was 45.6 ± 2.83 mm. Hg in Denver and at high altitude 36.0 ± 1.87 mm. Hg. The average umbilical vein p02 was 29.2 ± 5.52 mm. Hg in Denver and at high altitude 20.0 ± 3.88 mm. Hg. The data show a fall in oxygen tension in the uterine and umbilical veins to a minimum between the second and fourth days at high altitude followed by a recovery. Animal No. 0005, which was followed the longest, had an oxygen tension in the umbilical vein which went from 31 mm. Hg in Denver to a minimum of 16 mm. Hg on the fourth day and then back to 25.4 mm. Hg on the sixteenth day of high altitude. The oxygen tension in the uterine vein showed a similar pattern, i.e., an oxygen tension of 45.0 mm. Hg in Denver to a minimum of 31.5 mm. Hg on the second day and then 37.8 mm. Hg on the ninth day of high altitude. The oxygen tension in the umbilical artery averaged 21.1 mm. Hg in Denver and 14.4 ± 2.11 mm. Hg at high altitude. Upon returning the pregnant ewes to
Volume 100 Number 6
Effect of high altitude on fetal oxygenation
859
• Maternal Artery o Umbilical Artery
mm Hg.
J_.•
I , •
•• • " "0
0
g
0
''0- __ .0.--.0........ -
.• : _-0._
• •
•
•
•
•
•
.
---.................................-.
To Denver
---"0
o
10
12
14
18
2
8
10
Days lit altitude 14.280 ' . .t
Fig. 8. Oxygen tension in maternal and umbilical arteries. Abscissa as in Fig. 1. The oxygen tensions in the maternal and umbilical arteries of 6 animal. are plotted against time. Closed circles maternal artery. Open circles umbilical artery. The solid line connects the oxygen tensions in the maternal artery in Animal No. 0005 and the broken line connects the oxygen tensions in the umbilical artery of that same animal.
=
=
Denver, the average oxygen tensions in the maternal artery and uterine vein of Sheep No. 0005 and No. 270 were 67.8 and 44.8 mm. Hg, respectively. These were essentially unchanged from the control values obtained in Denver prior to exposure to high altitude, which were 69.4 and 45.6 mm. Hg, respectively. The average oxygen tension in the umbilical vein was 25.6 nun. Hg, 3.6 mm. Hg below the average control oxygen tension in the umbilical vein. Comment
Earlier studies in fetal physiology at high altitudeS were carried out on sheep which were bred at about 12,000 feet and pastured in the last third of pregnancy at an elevation of 14,000 feet. In these studies the oxygen tensions and saturations found in the umbilical blood were not significantly different from sea level values despite a marked re-
duction oC oxygen pressure in the maternal artery and uterine vein. These studies at high altitude and the sea level control experiments with which they are compared were done prior to the development of a sheep preparation with indwelling plastic catheters in the umbilical circulation. Thus, these experiments had the drawback of comparing single observations per fetus. Furthennore, the sampling was done while the animal was under the stress of surgical procedures. It was possible, therefore, that high altitude brought about changes in fetal oxygenation which were too subtle or too labile to be observed under those experimental conditions. The use of a preparation which allows multiple sampling of fetal blood obviates these reservations. In addition, it extends our range of observations from fuUy acclimatized pregnant animals to those exposed acutely to high altitude.
860 Makowski et al.
• Uterine
mm
Am.
J.
March 15, 1968
Obat. &: Gynec •
Vein
o Umbilical Vein
Hg.
8
70 60
• •
•
•
•• o
To Denver
10
o~~~~__~~__~~~~__~~~~__~~~~__~~~~~~~
0246 10121416182468 Days at altitude 14,260 feet
12141818
Fig. 9. Oxygen tension in uterine and umbilical veins. Abscissa as in Fig. I. On the ordinate is plotted the oxygen tension (mm. Hg) in both the uterine and umbilical veins of all 6 animals. Closed circles = uterine vein. Open circles umbilical vein. The solid line connects the oxygen tensions in the uterine vein of Animal No. 0005 and the broken line connects the oxygen tensions in the umbilical vein of that same animal.
=
The present study has shown that acute exposure to high altitude involves a marked reduction in p02' O 2 saturation, and O2 content in the umbilical vessels. Presumably, the fall in fetal pOz is a direct consequence of a lowered oxygen pressure in the maternal placental blood. With prolonged exposure to low barometric pressure there is an adaptation characterized by a rise of O 2 content in the umbilical circulation. The umbilical vein O 2 content is already rising in some animals at the sixth day of exposure to high altitude and it may return to the level observed prior to high altitude exposure in about 2 weeks. This increase of O 2 content in the umbilical vein was due to a combination of increased O 2 saturation and hemoglobin content. The increase in oxygen saturation was due primarily to an increased umbilical vein pOz. The increase in umbilical vein p02 followed the increase in uterine vein pOa. In this respect Animal No. 0005, which was observed the longest, is particularly instructive
(Fig. 9). This observation suggests that an increase in uterine blood flow may be an important factor in the over-all adaptation of the fetus. The results of the 1958 experiments led to the tentative conclusion that adaptation was in fact due to an increase in oxygen "diffusing capacity" of the placenta. s This interpretation was based on the assumption that the sheep placenta is a countercurrent exchange system and that concentration differ-, ences between uterine and umbilical veins are necessarily the consequence of a limited permeability of the placenta. In the light of present knowledge 4 • 5 this assumption appears incorrect. In addition, the present study does not show any evidence of a narrower uterine vein to umbilical vein oxygen tension difference after acclimatization. This finding contradicts the hypothesis of a greater oxygen "diffusing capacity" as the principal mechanism of fetal adaptation to high altitude.
Volume 100 Number 6
REFERENCES
1. Naughton, M . A., Meschia. G., Battaglia, F., Hellegers, A., Hagopian, H., and Barron, D. H.: Quart. J. Exper. Physiol. 48: 313, 1963. 2. Breathnach, C. S. : Quart. J, Exper. Physiol. 49: 277, 1964. 3. Barron, Donald H ., Metcalfe, J" Melchia, G., Huckabee, W., Hellegers, A., and Prystowsky, H.: The Symposium on the Physiological Ef· fecll of High Altitude, Interlaken, Switzerland, Oxford, 1962, Pergamon Press, Ltd., p. 115.
Effect of high altitude on fetal oxygenation 861
4. Meschia, Giacomo, Cotter, J. R., Makowski, E. L., and Barron, D. H.: Quart. J. Exper. Physiol. 50: 1, 1967. 5. Meschia, Giacomo, Battaglia, F. C., and Bruns, P. D.: J. Appl. Physiol. In press.
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