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Placental oxygen consumption in vitro
volume 107 number 1 May 1, 1970
American Journal of
Obstetrics and Gynecology
OBSTETRICS
Placental oxygen consumption in vitro IV. Variations with Apgar score
EMANUEL A. FRIEDMAN, M.D., MEn.Sc.D.* MARTIN B. KASS, M.D. MARLENE R. SACHTLEBEN, B.S. ELIZABETH M. ST. JOHN Chicago, Illinois Placental oxygen consumption was studied by Warburg respirometric techniques in 617 placentas obtained at delivery. Correlations between Apgar score, gestational age, and infant weight were analyzed. Elevated oxygen consumption was encountered among placentas from infants with low Apgar scores, short gestational age, and low birth weight when these factors were examined separately. When corrections were applied for fetal size, the correlation between placental oxygen consumption and Apgar score disappeared.
T H E C 0 M P E T I T I 0 N for available oxygen between the fetus and the placenta, interposed between the fetus and its oxygen source, has been suggested as an important area for investigation.3 If such competition does indeed exist, the interposition of an
From th11 Department of Obstetrics and Gynecology, Michael Reese Hospital and Medical Center. *Present address: Department of Obstetrics and Gynecology, Harvard Medical School, Beth Israel Hospital, Boston, Massachusetts.
actively metabolizing organ between mother and fetus in utero may, under certain hypoxic conditions, contribute significantly and in a deleterious manner to fetal welfare. Preliminary studies3 showed infants depressed at birth on the basis of Apgar score to be associated with placentas with diminished relative oxygen consumption. Total absolute consumption of such placentas, moreover, was found 2 to be depressed when compared with the strikingly uniform values for placentas in the third trimester. With regard to this uniformity, it was conjectured that
May I, 1970
2 Friedman et al.
compensatory adjustments appear to maintain adequate, stable placental metabolic activity and fetal oxygenation up to a point; beyond this point, compensatory changes may not be adequate to maintain gaseous exchange, resulting in fetal hypoxia. The latter is manifest by intrauterine fetal distress (bradycardia) and depressed Apgar scores. A clear-cut relationship exists between placental oxygen consumption and gestational age."· 4 • 7 Furthermore, gestational age plays a role in fetal outcome, particularly with regard to the known correlation between prematurity and neonatal depression." This rdationship has been shown to hold regardless of other coexisting anoxigenic phenomen
Amcr.
J. Obstet. Gyncc.
Table I. Placental oxygen consumption according to neonatal Apgar score Corrected* Apgar score
0 1 2 3 4
5 6
7 8 9 10
Mean QO,
No. 67 8 9 1+ 15 18 35 73 183 149 40
I(11-l/mg./hr.) 3.37 2.22 2.37 2.04 1.92 2.04 2.01 2.11 2.09 2.03 2.09
± ± ± ±
± ± ± ± ± ± ±
0.14 0.27 0.24 O.o7 0.10 0.09 0.08 0.04 0.02 0.03 0.06
QO, (Ji.l/mg./hr.)
1.95 1.86 2.10 2.00 1.90 2.03 2.00 2.06 2.04 2.02 2.07
± 0.11
± 0.15 ± 0.19 ± 0.05
± 0.09 ± 0.08 ± 0.06
± 0.03 ± 0.02 ± 0.03
± 0.05
Total 611 2.21 ± 0.03 2.06 ± 0.02 •·Qo, based on placentas from infants weighing 1,500 grams or more only.
002~--------------------------------~
3
Material and methods
Details of technique have previously been presented. 3 • 6 • 8 Oxygen uptake of aliquots of placental tissue slices was determined by standard W arburg respirometric techniques under aerobic conditions. Fluid phase consisted of physiologic Ringer's solution buffered at pH 7.4 with 15M phosphate and gas phase of 100 per cent oxygen maintained at a constant temperature of 37° C. Oxygen uptake (Q0 2 ) was quantitated in microliters per milligram dry weight of placenta per hour as determined by calculating the volume of gas necessary to change the pressure a measured amount within the manometric system under known constant conditions of temperature and volume. A seri.es of 617 nearly consecutive placentas obtained at delivery were studied. Maternal
2
0 ~~0~~~2~_g~4~~~6-Y~~8~~~10~ APGAR SCORE
Fig. 1. Placental oxygen consumption trends by Apgar score. QO, in microliters per milligram per hour. White bars represent raw data; black bars data from placentas of infants weighing 1,500 grams or more. The apparent increase in QO, among depressed infants with low Apgar scores is erased when corrected for infant weight.
Volume 107 Number I
Placental oxygen consumption
actuarial data of age, parity, gravidity, gestational age, fetal weight, delivery frequencies, and incidences of maternal and fetal complications. Additionally, there were included 52 placentas obtained from first and second trimester therapeutic abortions. Of prime importance, infants were evaluated for Apgar score. 1 The newborn infant was graded at 60 seconds after birth on the basis of heart rate, respiratory effort, muscle tone, reflex irritability, and color, 2 points being assigned to each of these 5 factors. Scores of 4 or less at age 1 minute were indicative of neonatal depression. Therapeutic abortions aside, there were
3
11 stillborn infants and 4 neonatal deaths. Complications noted among infants born in a severely depressed state (Apgar score 0 to 2) included 5 mothers with pre-eclampsia, 2 with diabetes, 3 Rh isoimmunization, 2 pyelonephritis, and 1 abruptio placentae. There were 22 in all with Apgar scores of 2 or less born without apparent maternal or labor complications. Results
In the original study group, there were 611 vvith recorded Apgar scores. Breakdown by score showed an incidence of neonatal depression of 18.5 per cent ( 113 infants with
002 4~-----------------------------------------,
0~--------------------------------------------~ 3.5 .ol+ 2.5 1.5 3 <.5 .5 2 Kilograms Jiig. 2. Relationship between QO, and infant weight showing progressive diminution with increasing birth weight to 1,500 grams.
4
Friedman et al.
Amer.
Score 4 or less) . The average Q0 2 for the entire series was 2.21 ± 0.03 fLl per milligrams per hour. This figure is distinctly higher than that which might be expected from unselected term placentas (2.02 ± 0.03) .3 When one examines the Q0 2 data by Apgar score (Table I, Fig. 1) , one finds significant elevation of oxygen uptake with Scores 0 to 2. If th'~ data are retallied for infants scoring 3 or better, the average Q0 2 becomes 2.06 ± 0.02, a figure quite comparable with that expected for normal term placentas.
J.
May 1, 1970 Obstet. Gyncc.
The relationship between placental oxygen consumption and infant weight was readily verified by subdividing the 594 infants with precisely recorded birth weights into 500 gram increment groups. The trend is illustrated in Fig. 2. The linear regression curve previously found to describe the relationship between Q0 2 and menstrual age of pregnancy3 was also reconfirmed (Fig. 3) utilizing the grouped data for the 602 patients in this series with v\ell documented gestational durations. The slow, almcst constantly pro-
0~--------------------------------------~ <8
8
12
16
20
24
28
32
36
38
40
42
44+
WEEKS Fig. 3. Gestational age versus placental oxygen consumption. Linear regression between 16 and 38 weeks is demonstrated.
Volume 107
Placental oxygen consumption 5
l\'umber 1
gressive diminution in Q0 2 with advancing gestational age from 16 through 38 weeks is apparent and closely follows the mathematical expression y 5.47 - 0.092x. Changes with infant weight, on the other hand, .are not quite so clear-cut, linear progression being seen up to 1,500 grams, but not beyond. The average Q02 over-all for this group was 2.19 ± 0.02, whereas for infants over 1,500 grams only it was 2.06 ± 0.01 (as compared with 2.02 at term). On the basis of these latter findings, it seemed reasonable to reconsider the Apgar score data on the basis of 2 major infant weight subdivisions of more or less than 1,500 grams. It was found that placentas of 63 depressed infants at birth (Apgar scores 0 to 2) with low birth weights (under 1,500 grams) consumed 3.55 ± 0.09 ,ul per milligrams per hour. Placentas from the 21 similarly depressed infants weighing 1,500 grams or more consumed 1.95 ± 0.11, a significant difference (p < 0.001). Neither of these figures was determined to be statistically different from Q0 2 averages for normal infants (Apgar 3 to 10) of comparable weights. These data, "corrected" for infant weight, are shown in Fig. 1. The aforementioned trends have disappeared. Con1ment
The previously encountered depression of placental oxygen consumption among infants '.vith low Apgar scores 3 has not been verified. On the contrary, our initial results in this rather extensive series showed the opposite trend, namely, quite significantly ele-
REFERENCES
1. Apgar, V.: Anesth. Analg. 32:260, 1953. 2. Friedman, E. A .. Little, W. A., and Sachtleben, M. R.: AMER. J. 0BsTET. GYNEC. 84: 561, 1962. 3. Friedman, E. A., and Sachtleben, M. R.: AMER. J. 0BSTET. GYNEC. 79: 1058, 1960. 4. MacKay, R. B.: J. Obstet. Gynaec. Brit. Emp. 65: 791, 1958. 5. Niswander, K. R., Friedman, E. A., Hoover,
vated Q0 2 among placentas from depressed infants. Closer inspection of these data, however, has shown rather cogently that the effect seen was that attributable to fetal weight and gestational age, rather than to infant depression per se. This study is a portion of a large prospective clinical correlative investigation attempting to define as specifically as feasible those factors among the many acting upon the placenta and the infant that may affect outcome. Because of the numerous possible variations in factors of maternal health and gestational complications, large numbers have been required for adequate statistical evaluation. Subdivision of the case material according to pertinent clinical features that may influence placental metabolism allows us to examine the potential effects of these factors. The likelihood that several agents or conditions may be acting concomitantly in either an additive or compensatory manner makes it essential that substratification of the data, such as illustrated here, be undertaken where possible. Since ideal laboratory-type experimental design is not possible under available clinical circumstances, the less satisfactory approach we have used was required. The negative findings notwithstanding, it is still possible that other factors, as yet unknown, may be acting to mask an underlying trend in placental oxygen consumption as it relates to the immediate outcome of the newborn infant. At this time, we are obligated to state that we cannot uncover any meaningful tendencies in this regard.
D. B., Pietrowski, H., and Westphal, M. C.: AMER. J. 0BSTET. GYNEC. 95: 838, 1966. 6. Umbreit, W. W., Burris, R. H., and Stauffer, J. F.: Manometric Techniques and Related Methods for the Study of Tissue Metabolism, Minneapolis, 1944, Burgess Publishing Company. 7. Villee, C. A.: J. Bioi. Chern. 205: 113, 1953. 8. Warburg, 0.: Dber den Stoffwechsel der Tumoren, Berlin, 1926, Springer-Verlag.
American Journal of
Obstetrics and Gynecology
OBSTETRICS
Placental oxygen consumption in vitro IV. Variations with Apgar score
EMANUEL A. FRIEDMAN, M.D., MEn.Sc.D.* MARTIN B. KASS, M.D. MARLENE R. SACHTLEBEN, B.S. ELIZABETH M. ST. JOHN Chicago, Illinois Placental oxygen consumption was studied by Warburg respirometric techniques in 617 placentas obtained at delivery. Correlations between Apgar score, gestational age, and infant weight were analyzed. Elevated oxygen consumption was encountered among placentas from infants with low Apgar scores, short gestational age, and low birth weight when these factors were examined separately. When corrections were applied for fetal size, the correlation between placental oxygen consumption and Apgar score disappeared.
T H E C 0 M P E T I T I 0 N for available oxygen between the fetus and the placenta, interposed between the fetus and its oxygen source, has been suggested as an important area for investigation.3 If such competition does indeed exist, the interposition of an
From th11 Department of Obstetrics and Gynecology, Michael Reese Hospital and Medical Center. *Present address: Department of Obstetrics and Gynecology, Harvard Medical School, Beth Israel Hospital, Boston, Massachusetts.
actively metabolizing organ between mother and fetus in utero may, under certain hypoxic conditions, contribute significantly and in a deleterious manner to fetal welfare. Preliminary studies3 showed infants depressed at birth on the basis of Apgar score to be associated with placentas with diminished relative oxygen consumption. Total absolute consumption of such placentas, moreover, was found 2 to be depressed when compared with the strikingly uniform values for placentas in the third trimester. With regard to this uniformity, it was conjectured that
May I, 1970
2 Friedman et al.
compensatory adjustments appear to maintain adequate, stable placental metabolic activity and fetal oxygenation up to a point; beyond this point, compensatory changes may not be adequate to maintain gaseous exchange, resulting in fetal hypoxia. The latter is manifest by intrauterine fetal distress (bradycardia) and depressed Apgar scores. A clear-cut relationship exists between placental oxygen consumption and gestational age."· 4 • 7 Furthermore, gestational age plays a role in fetal outcome, particularly with regard to the known correlation between prematurity and neonatal depression." This rdationship has been shown to hold regardless of other coexisting anoxigenic phenomen
Amcr.
J. Obstet. Gyncc.
Table I. Placental oxygen consumption according to neonatal Apgar score Corrected* Apgar score
0 1 2 3 4
5 6
7 8 9 10
Mean QO,
No. 67 8 9 1+ 15 18 35 73 183 149 40
I(11-l/mg./hr.) 3.37 2.22 2.37 2.04 1.92 2.04 2.01 2.11 2.09 2.03 2.09
± ± ± ±
± ± ± ± ± ± ±
0.14 0.27 0.24 O.o7 0.10 0.09 0.08 0.04 0.02 0.03 0.06
QO, (Ji.l/mg./hr.)
1.95 1.86 2.10 2.00 1.90 2.03 2.00 2.06 2.04 2.02 2.07
± 0.11
± 0.15 ± 0.19 ± 0.05
± 0.09 ± 0.08 ± 0.06
± 0.03 ± 0.02 ± 0.03
± 0.05
Total 611 2.21 ± 0.03 2.06 ± 0.02 •·Qo, based on placentas from infants weighing 1,500 grams or more only.
002~--------------------------------~
3
Material and methods
Details of technique have previously been presented. 3 • 6 • 8 Oxygen uptake of aliquots of placental tissue slices was determined by standard W arburg respirometric techniques under aerobic conditions. Fluid phase consisted of physiologic Ringer's solution buffered at pH 7.4 with 15M phosphate and gas phase of 100 per cent oxygen maintained at a constant temperature of 37° C. Oxygen uptake (Q0 2 ) was quantitated in microliters per milligram dry weight of placenta per hour as determined by calculating the volume of gas necessary to change the pressure a measured amount within the manometric system under known constant conditions of temperature and volume. A seri.es of 617 nearly consecutive placentas obtained at delivery were studied. Maternal
2
0 ~~0~~~2~_g~4~~~6-Y~~8~~~10~ APGAR SCORE
Fig. 1. Placental oxygen consumption trends by Apgar score. QO, in microliters per milligram per hour. White bars represent raw data; black bars data from placentas of infants weighing 1,500 grams or more. The apparent increase in QO, among depressed infants with low Apgar scores is erased when corrected for infant weight.
Volume 107 Number I
Placental oxygen consumption
actuarial data of age, parity, gravidity, gestational age, fetal weight, delivery frequencies, and incidences of maternal and fetal complications. Additionally, there were included 52 placentas obtained from first and second trimester therapeutic abortions. Of prime importance, infants were evaluated for Apgar score. 1 The newborn infant was graded at 60 seconds after birth on the basis of heart rate, respiratory effort, muscle tone, reflex irritability, and color, 2 points being assigned to each of these 5 factors. Scores of 4 or less at age 1 minute were indicative of neonatal depression. Therapeutic abortions aside, there were
3
11 stillborn infants and 4 neonatal deaths. Complications noted among infants born in a severely depressed state (Apgar score 0 to 2) included 5 mothers with pre-eclampsia, 2 with diabetes, 3 Rh isoimmunization, 2 pyelonephritis, and 1 abruptio placentae. There were 22 in all with Apgar scores of 2 or less born without apparent maternal or labor complications. Results
In the original study group, there were 611 vvith recorded Apgar scores. Breakdown by score showed an incidence of neonatal depression of 18.5 per cent ( 113 infants with
002 4~-----------------------------------------,
0~--------------------------------------------~ 3.5 .ol+ 2.5 1.5 3 <.5 .5 2 Kilograms Jiig. 2. Relationship between QO, and infant weight showing progressive diminution with increasing birth weight to 1,500 grams.
4
Friedman et al.
Amer.
Score 4 or less) . The average Q0 2 for the entire series was 2.21 ± 0.03 fLl per milligrams per hour. This figure is distinctly higher than that which might be expected from unselected term placentas (2.02 ± 0.03) .3 When one examines the Q0 2 data by Apgar score (Table I, Fig. 1) , one finds significant elevation of oxygen uptake with Scores 0 to 2. If th'~ data are retallied for infants scoring 3 or better, the average Q0 2 becomes 2.06 ± 0.02, a figure quite comparable with that expected for normal term placentas.
J.
May 1, 1970 Obstet. Gyncc.
The relationship between placental oxygen consumption and infant weight was readily verified by subdividing the 594 infants with precisely recorded birth weights into 500 gram increment groups. The trend is illustrated in Fig. 2. The linear regression curve previously found to describe the relationship between Q0 2 and menstrual age of pregnancy3 was also reconfirmed (Fig. 3) utilizing the grouped data for the 602 patients in this series with v\ell documented gestational durations. The slow, almcst constantly pro-
0~--------------------------------------~ <8
8
12
16
20
24
28
32
36
38
40
42
44+
WEEKS Fig. 3. Gestational age versus placental oxygen consumption. Linear regression between 16 and 38 weeks is demonstrated.
Volume 107
Placental oxygen consumption 5
l\'umber 1
gressive diminution in Q0 2 with advancing gestational age from 16 through 38 weeks is apparent and closely follows the mathematical expression y 5.47 - 0.092x. Changes with infant weight, on the other hand, .are not quite so clear-cut, linear progression being seen up to 1,500 grams, but not beyond. The average Q02 over-all for this group was 2.19 ± 0.02, whereas for infants over 1,500 grams only it was 2.06 ± 0.01 (as compared with 2.02 at term). On the basis of these latter findings, it seemed reasonable to reconsider the Apgar score data on the basis of 2 major infant weight subdivisions of more or less than 1,500 grams. It was found that placentas of 63 depressed infants at birth (Apgar scores 0 to 2) with low birth weights (under 1,500 grams) consumed 3.55 ± 0.09 ,ul per milligrams per hour. Placentas from the 21 similarly depressed infants weighing 1,500 grams or more consumed 1.95 ± 0.11, a significant difference (p < 0.001). Neither of these figures was determined to be statistically different from Q0 2 averages for normal infants (Apgar 3 to 10) of comparable weights. These data, "corrected" for infant weight, are shown in Fig. 1. The aforementioned trends have disappeared. Con1ment
The previously encountered depression of placental oxygen consumption among infants '.vith low Apgar scores 3 has not been verified. On the contrary, our initial results in this rather extensive series showed the opposite trend, namely, quite significantly ele-
REFERENCES
1. Apgar, V.: Anesth. Analg. 32:260, 1953. 2. Friedman, E. A .. Little, W. A., and Sachtleben, M. R.: AMER. J. 0BsTET. GYNEC. 84: 561, 1962. 3. Friedman, E. A., and Sachtleben, M. R.: AMER. J. 0BSTET. GYNEC. 79: 1058, 1960. 4. MacKay, R. B.: J. Obstet. Gynaec. Brit. Emp. 65: 791, 1958. 5. Niswander, K. R., Friedman, E. A., Hoover,
vated Q0 2 among placentas from depressed infants. Closer inspection of these data, however, has shown rather cogently that the effect seen was that attributable to fetal weight and gestational age, rather than to infant depression per se. This study is a portion of a large prospective clinical correlative investigation attempting to define as specifically as feasible those factors among the many acting upon the placenta and the infant that may affect outcome. Because of the numerous possible variations in factors of maternal health and gestational complications, large numbers have been required for adequate statistical evaluation. Subdivision of the case material according to pertinent clinical features that may influence placental metabolism allows us to examine the potential effects of these factors. The likelihood that several agents or conditions may be acting concomitantly in either an additive or compensatory manner makes it essential that substratification of the data, such as illustrated here, be undertaken where possible. Since ideal laboratory-type experimental design is not possible under available clinical circumstances, the less satisfactory approach we have used was required. The negative findings notwithstanding, it is still possible that other factors, as yet unknown, may be acting to mask an underlying trend in placental oxygen consumption as it relates to the immediate outcome of the newborn infant. At this time, we are obligated to state that we cannot uncover any meaningful tendencies in this regard.
D. B., Pietrowski, H., and Westphal, M. C.: AMER. J. 0BSTET. GYNEC. 95: 838, 1966. 6. Umbreit, W. W., Burris, R. H., and Stauffer, J. F.: Manometric Techniques and Related Methods for the Study of Tissue Metabolism, Minneapolis, 1944, Burgess Publishing Company. 7. Villee, C. A.: J. Bioi. Chern. 205: 113, 1953. 8. Warburg, 0.: Dber den Stoffwechsel der Tumoren, Berlin, 1926, Springer-Verlag.