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The significance of meconium staining
FETUS,PLACENTA, ANDNEWBORN
The significance of meconium staining TOSHIO
FUJIKURA,
BERNARD
M.D.
KLIONSKY,
Pittsburgh,
Pennsylvania
Meconium
staining
M.D.
of the
placenta
and/or
fetal
body
was present
at birth
in 10.3
per
cent
42,000 live-born infants, but was present disproportionately in 18.1 per cent of 788 neonatal deaths. The neonatal mortality rate was 3.3 per cent in the stained group and 1.7 per cent in the nonstained group. Among infants who died, the incidence of erythroblastosis was quadrupled and that of cardiovascular malformation was doubled in the stained group. Meconium staining was associated with a decrease in the expected frequency of hyaline membranes and atelectasis even in premature infants; hypotheses for this phenomenon wtre presented. Meconium staining of the fetus or placenta requires several hours of exposure. of
As a hypothesis, the stresses of cumulative meconium if delivery
observed increase of deaths or chronic hypoxia which is prolonged.
in stained neonates may occur after
T H E s I G N I F I c A N c E Of meconium-stained amniotic fluid is still a widely debated subject. Meconium staining of the amniotic fluid is one of the From the Department of Pathology, Pittsburgh School of Medicine.
University
classic signs of fetal distress in utero. The stimulus causing passage of meconium before birth is, by tradition, fetal anoxia or hypoxia, yet in 12 to 25 per cent of deliveries complicated by fetal meconium passage, no definite cause of such conditions is found.” However, Desmond and associate? reported that meconium staining of the amniotic fluid, placenta. and umbilical cord is associated with an increase in neonatal morbidity and mortality rates. Walke+ observed a mortality rate between 5 and 8 per cent when a rapid fetal heart rate alone is noted, and 20 per cent-when this is accompanied by the passage of meconium. Such increase of mortality rates indicated the potential seriousness of meconium-stained amniotic fluid at delivery. Undoubtedly many maternal factors contribute to the passage of meconium before birth, among which may be cited maternal age, prolonged gestation, type of labor, obesity, hypertension, toxemia of pregnancy, and anemia.“-” However, knowledge of the fetal factors governing the passage of meconium is still incomplete and should be investigated.
of
The Collaborative Study of Cerebral Palsy, Mental Retardation. and Other Neuroloeical and Sensory Disorders of. Infancy and Childhiod is supportedby the National Institute of Neurological’biseases and Stroke. The following institutions participate: Boston Lying-In Hospital; Brown University; Charity Hospital, New Orleans; Children’s Hospital of Butfalo; Children’s Hospital of Philadelphia; Children’s Medical Center, Boston; Columbia University; The Johns Hopkins Hospital; the University of Minnesota; the University of Oregon; the University of Tennessee and the Perinatal Research Branch, National Institute of Neurological Diseases and Stroke. I
,
Received
for
Accepted
August
publication
May
may be related to the the initial passage of
31, 1974.
8, 1974.
Reprint requests: Dr. Toshio Fujikura, MageeWomens Hospital, Department of Pathology, Forbes Ave. and Halket St., Pittsburgh, Pennsylvania 15261. 45
46
Fujikura
and
January 1, 1975 Am. J. Obstet. Gynecol.
Klionsky
Table I. Neonatal death rate and percentage frequency between stained and nonstained groups
Live Groug
No.
Stained Nonstained Total P <
Neonatal deaths
births )
4,390 38,100
42,490
%
No.
10.3 89.7 100.0
143 645 788
)
% 18.1 81.9 100.0
Neonatal death rate (%) 3.3 1.7 1.8
0.001.
The constituents of meconium are mainly bile pigments, bile salts, fetal hair, squamous cells, mucopolysaccharides, and cholesterol.2 Bile pigments have a strong surface-active action.17 Theoretically, aspirated meconium could reduce surface tension in the pulmonary alveoli and facilitate alveolar expansion with reduction of the viscosity of bronchial secretions. The purpose of this study is to investigate the pathologic findings in autopsies of neonates born with meconium staining and to determine the possible relationship of this condition to a variety of other disorders. Material
and
methods
This report was based on 42,490 live-horn infants delivered of randomly selected Collaborative Study registrants from 12 participating institutions. The bulk of the population consists of approximately an equal number of Caucasians and Negroes, with a small percentage of Puerto Ricans and other ethnic groups. The present study was limited to 788 autopsied neonatal deaths of Collaborative Study cases. The autopsy rate of neonatal deaths was about 89 per cent. Abortions, multiple births, and stillbirths were not included. The Collaborative Study required that, when permission was granted, a detailed autopsy was to be performed according to a standard protocol on all deaths, including gross and microscopic reports. Copies of such protocols and duplicate histologic sections of lungs were reviewed in order to obtain specific information such as hyaline membranes, pneumonia, congenital malformations, etc. The criteria used for congenital malformations and their classification by organ systems were those described in detail in a previous paper.8 Meconium staining of the placenta (membranes and umbilical cord) and/or fetal body was used as the criterion of selection of a meconium-stained case. Meconium staining of the amniotic fluid alone was
not included. The criteria for pre-eclampsia were based on the definition in Williams’ Obstetric? and included cases with or without chronic hypertension. Mothers were considered as diabetic if their glucose tolerance curves met the criteria set forth by Somogyi-Nelsonlo or if, in lieu of glucose tolerance curves, the patient was clearly known to be diabetic and was treated with more than 20 U. of insulin daily. The significance of data presented in Tables I to V was calculated by the chi-square test. Results Table I shows the effect of meconium staining on the survival of the live-born infants. Although 10.3 per cent of all live-born infants had meconium staining, 18.1 per cent of neonates who died were stained by meconium. The stained group was associated with a neonatal mortality rate of 3.3 per cent as opposed to 1.7 per cent in the nonstained group. In Table II the relationship between meconium staining and birth weights of live births is shown. Both the frequency distribution and the incidence of meconium staining increased significantly in babies with birth weights of over 3,501 grams. In babies weighing 2,000 grams or below, the incidence of meconium staining was also slightly elevated. Table III shows the incidence of fetal and maternal conditions in neonatal deaths with or without meconium staining. Cardiovascular malformations (13.9 per cent), erythroblastosis fetalis (22.4 per cent) chorioamnionitis (37.7 per cent), and preeclampsia ( 11.1 per cent) were significantly higher in the stained group; conversely hyaline membranes (13.9 per cent) and atelectasis (37.5 per cent) were lower. In other fetal and maternal conditions the incidence between the two groups was not significantly different. Pneumonia and pulmonary hemorrhage were found just as frequently in the stained group as in the nonstained group, as were conditions associated with anoxia or hypoxia, abruptio placentae, placenta previa, and prolapsed cord. Table IV presents a comparison of the incidence of hyaline membranes according to birth weight between the two groups. The incidence of hyaline membranes in infants weighing 1,500 grams or less at birth was significantly lower in the stained group. The incidence in other birth weight intervals was lower in the stained group, but not significantly so. In Table V a similar trend of reduced incidence of hyaline membranes was also found in the stained group at gestational ages below 27 weeks. The in-
Volume Number
121 1
Significance
of meconium
staining
47
Table II. Meconium staining of live births according to birth weight Group with Birth
1,500 and 1,501-2,000 2,001-2,500 2,501-3,000 3,001-3,500 3,501-4,000 4,001 and Total
Grout
staining
weight (Gm.)
No. less
over
Incidence
Total
No.
%
No.
366 540 2,828 9,856 15,412 7,473 1,625 38,100
0.9 1.4 7.4 25.9 40.5 19.6 4.3 100.0
410 618 3,102 10,775 17,097 8,501 1,987 42,490
70
44 78 274 919 1,685 1,028 362 4,390
without
staining
1.0 1.8 6.2 20.9 38.4 23.4 __ 8.2 100.0
of
staining -% P
70 0.9
10.7 12.6 8.8
:*z 25:4 40.2 20.0 4.7 1oo.o
a.5 9.8 12.0 18.2 10.3
0.841 0.071 0.005 < 0.001 0.009 < 0.001 < 0.001
Table III. Fetal and maternal findings with or without meconium staining in neonatal deaths Group with
Group without staining
staining
Number
cases
of Hyaline
143 (::.9)*
membranes
Atelectasis
(Z.7)
Pneumonia
$6)
Pulmonary
hemorrhages
Congenital
(Z.4)
malformations
Cardiovascular Central
(Z.3)
system
nervous
$9)
Digestive
(;.6) y
system
(6.2)
system
Erythroblastosis
$.7)
fetalis?
Chorioamnionitis,
moderate
13/58 @$.4)
or marked
(37.7) ruptured
membranes $1)
Prolapsed
placentae
(i.3) 44 (5.5) 28 (3.5) 30 (3.8) 25 (3.1) 25/285 (8.7) 207 (26.2) 132 (16.7) 60 (7.6) 31 (3.9) 23 (2.9) 23
(8.0)
JO)
28 (4.3) 19
(i.7)
(2.9)
(:.3) 16 (11.1)
21 (3.2) 38 (5.8)
previa cord
*Numbers in parentheses are per cent of each incidence. +The incidences are based on the number of Caucasians 285.
(i.3) 33 (5.1) 25 (3.8) 21 (3.2) 21 (3.2) 12/227 (5.2) 153 (23.7) 106 (16.4) 52
(i.5)
Diabetes Pre-eclampsia
ii.4)
0.001 0.161 0.484
;;;.3) (19.1) 62 (7.8)
0.271 0.002
0.548 (i.6) 11
system
Unspecified
Placenta
tz.0,
< 0.001
0.133
system
Musculoskeletal
Abruptio
788 212 (26.9) 400 (50.7) 190 (24.1) 184
system
Genitourinary
Prolonged
645 192 (29.7) 346 (53.6) 149 (23.1) 149 (23.1) 119 (18.4) 42 (6.5)
P
system (461)
Respiratory
Total
only:
group
with
staining,
0.230 0.317 0.089 0.841 < 0.001 < 0.001 0.617 0.368 0.230 1 .ooo 0.271
g.9’
0.027
(6.8) 58; group
without
staining,
227;
total,
48
Fujikura
and
Klionsky
Table IV. Incidence
of hyaline
membranes
in neonatal
deaths
according
to birth
weight
and meconium
%
No. of deaths
No. of HM
%
P
29.0 42.5 -18.9 29.7
392 173 223 788
106 69 37 212
27.0 39.8 16.5 __ 26.9
0.016 0.089 0.161 0.001
staining Group
with
Group without staining
staining Birth
weight (Gm.1
No. of deaths
1,500 and less 1,501-2,500 2,500 and over Total
48 25 70 143
Table V. Incidence
of hyaline
No.
with HM
6 6 8 -ii
membranes
%
No. of deaths
12.5 24.0 -11.4 13.9
344 148 -153 645
in neonatal
No.
Total
with HM
100 63 - 29 192
deaths
accordin
g to gestational
age and
meconium
staining
Gestational age (wk.)
27 and less 28-36 37 and over Total
cidence in gestational over was significantly
Group with staining No. of deaths
No. HM
3 9 8 0
7%
8.1 25.0 11.4 13.9
218 277 150 645
age intervals of 37 weeks and lower in the stained group.
Comment
Neonatal
Total
with
37 36 70
143
Group without staining
mortality rate. Meconium staining of the placenta and/or fetal body was present in 10.3 per cent of all live births and in 18.1 per cent of neonatal deaths. The neonatal mortality rate was 3.3 per cent in the stained group and 1.7 per cent in the nonstained group. This is in keeping with the report of Desmond and associates* that intrauterine passage of meconium is associated with an increase in neonatal mortality and morbidity rates. Staining and birth weight. In Table II the incidence of meconium staining is significantly increased in babies of birth weight greater than 3,501 grams. In babies weighing 2,000 grams or less, the incidence was slightly, but not significantly elevated. However, Desmond and associates?, 5 reported that me’conium staining of the amniotic fluid is disproportionately uncommon in premature infants weighing 2,000 grams or less. The exact mechanism of relative failure of the premature infant to pass meconium is still unknown. According to SmithI the explanation may be a smaller accumulation of meconium in the intestine or a lower sensitivity to anoxia or hypoxia. Staining and hyaline membranes. A decrease of hvaline membranes and atelectasis in the stained
50 105 37 192
9%
No. of deaths
22.9 37.9 24.6 F7
255 313 220 788
No.
with HM
53 114 45 212
%
P
20.7 36.4 -20.4 26.9
0.045 0.133 0.027 0.001
group (Table III) can be explained by four hypotheses relating to (1) fetal maturity, (2) surfactant, (3) intestinal enzymes, and (4) chronic stress. 1. The decrease in hyaline membranes and atelectasis could be due to the increased percentage of mature infants in the stained group. In Table V the decrease in hyaline membranes was significant in the stained group at gestational ages above 37 weeks. However, even in the premature infants below 1,500 grams or 27 weeks the frequency of these pulmonary problems was lower in the stained group (Tables IV and V) . 2. Besides the well-known factor of prematurity in hyaline membrane disease, aspirated bile pigments acting as a strong surfactanP7 may prevent the production of atelectasis and hyaline membranes. Although surface-active agents have proved disappointing in the treatment of hyaline membrane disease because of their toxic action, bile pigments which are diluted with amniotic fluid appear to be relatively harmless. 3. It is unlikely that tryptic intestinal enzymes present in meconium-stained amniotic fluid either inhibit the development or speed the lysis of hyaline membranes. Intestinal enzymes from meconium have been reported to be ineffective, or for some reason inactivated.14 4. Chronic intrauterine stress has been demon-
Volume Number
121 1
Significance
strated to decrease the expected incidence of respiratory distress syndrome6; the conditions which lead to meconium staining may represent such chronic stresses. Meconium staining is not prominent with acute obstetric emergencies such as prolapsed cord, abruptio placentae, or placenta previa in this study or in others5; by comparison, meconium staining is prominently associated with chronic maternal stresses such as toxemia, prolonged gestation, and anemia.5 Our findings confirmed the significant association of staining with pre-eclampsia and chorioamnionitis. These maternal complications are more likely to be present in a chronic state of fetal distress than in the acute state. Such chronic stress may trigger hormonal secretion by the fetal adrenal capable of accelerating pulmonary surfactant synthesis. Recently many stressful conditions such as maternal hypertensive disease,’ premature rupture of the membranes,” and maternal narcotic addiction” are reported to have a sparing effect on the development of respiratory distress syndrome. The relationship between respiratory distress syndrome and meconium staining needs further clinical investigation in relation to these hypotheses. Cardiovascular malformations. Cardiovascular malformations in neonatal autopsies were twice as high in the stained group (13.9 per cent) as in the nonstained group (6.5 per cent). Of 62 neonatal deaths with cardiovascular malformations, 20 had meconium staining in this study. These 20 cases included 8 ventricular septal defects, 5 atria1 septal defects, 4 transpositions of the great vessels, 3 preductal coarctations, and one tetralogy of Fallot. Meconium staining may produce a warning sign of fetal anoxia, hypoxia, and distress in the malformed infants. Erythroblastosis. The relationship between erythroblastosis and meconium staining was significantly high among neonatal deaths (22.4 per cent). Out of 391 live-born infants with definite erythroblastosis, 72 (18.4 per cent) were associated with meconium staining. According to Potter,ll fetuses with severe erythroblastosis excrete large amounts of bili-
REFERENCES
1. Abramovici, H., Brandes, J. M., Timor-Tritsch, I.: AM. J. OBSTET. 251,
Fuchs, GYNECOL.
K.,
and 118:
1974.
2. Bourne, G.: The Human Amnion and Chorion, Chicago, 1962, Year Book Medical Publishers, Inc., pp. 3.
143-154.
Clifford,
S. H.: J. Pediatr. 44: 1, 1954.
of
meconium
staining
49
rubin in the urine, and it discolors the placental surface, umbilical cord, and vernix caseosa, giving a false impression of meconium discoloration of the skin. However, the hemolysis and anemia could produce fetal hypoxia and the passage of meconium with erythroblastosis. Since meconium or bilirubin staining of the fetus and placenta are respectively indicators of fetal hypoxia and hyperbilirubinemia, their presence should alert the clinician to the possibility of subsequent bilirubin encephalopathy which is associated with both the level of bilirubin and the extent of hyp0xia.l” The role of time. Time is an important factor in the development of meconium staining. Evidence available from in vivo and in vitro observations’, 4 suggests that a minimum of 4 to 6 hours is required between passage of meconium into the amniotic fluid and staining of the placenta or fetus. There appears to be a critical difference between the presence of meconium in the amniotic fluid and meconium staining. This difference involves time and the probability of exacerbation of the pathologic physiology which leads to passage of meconium. Meconium is infrequently found in normal amniotic fluid and the initial passage of meconium most often occurs as a warning sign late in gestation and very shortly before delivery, presumably from mild or transient degrees of hypoxia that are not harmful to the fetus.’ Many investigators agree that the presence of meconium-stained amniotic fluid is not necessarily a sign of severe hypoxia, acidosis, or acute fetal distress; rather, it may be considered as an indicator of either a previous bout of intrauterine anoxia or a state of compensated fetal distress.’ If, following the initial bout of hypoxia and passage of meconium, delivery is delayed for the substantial length of time required to produce meconium staining, there exists a greater probability that the stresses of cumulative or repeated bouts of chronic hypoxia can produce intrauterine death or the increased neonatal mortality rate observed in this study or in others.4, 5, I3
4. Desmond, M. M., Lindley, J. E., Moore, J., and Brown, C. A.: J. Pediatr. 49: 540, 1956. 5. Desmond, M. M., Moore, J., Lindley, J. E., and Brown, C. A.: Obstet. Gynecol. 9: 91, 1957. 6. Gluck, L., and Kulovich, M. V.: Zn Syndrome, Villee, C. A., Villee, D. B., and Zuckerman, J., editors: Respiratory Diseases Syndrome, New York, 1973, Academic Press, Inc., pp. 183-196.
50
7.
8.
9.
10. 11.
Fujikura
and Klionsky
Hellman, L. H., and Pritchard, J. A.: Williams’ Obstetrics, New York, 1971, Appleton-Century-Crofts, pp. 685-689. Froehlich, L. A., and Fujikura, T.: In Nishimura, H., and Miller, J. R., editors: Methods for Teratological Studies in Experimental Animals and Man, Tokyo, 1969, Igaku Shoin Ltd., pp. 167-194. Naeye, R.: In Villee, C. A., Villee, D. B., and Zuckerman, J., editors: Respiratory Distress Syndrome, New York. 1973. Academic Press. Inc.. DD. 147-156. O’Sullivan,‘J. B., and Mahan, d.‘M.: Diabetes 13: 278, 1964. Potter, E. L.: Pathology of the fetus and the infant, Chicago, 1961, Year Book Medical Publishers, Inc., pp. 613-614.
12.
13. 14.
15. 16. 17.
Richardson, C. J., Pomerance, J. H., Cunningham, M. D., and Gluck, L.: AM. J. OBSTET. GYNECOI.. 118: 1115, 1974. Rooth, G.: J. Perinat. Med. 1: 7, 1973. Smith, C. A.: The physiology of the newborn infant, Springfield, Ill., 1959, Charles C Thomas, Publisher, pp. 244-250. Smith, J. F.: Pediatric neuropathology, New York. 1974, McGraw-Hill Book Company, Inc., page 90. Walker, J.: J. Obstet. Gynecol. Br. Commonw. 61: 162, 1954. West, E. S., Todd, M. R., Mason, H. S., and Van Bruggen, J. T.: Textbook of biochemistry, New York, 1966, MacMillan Co., p. 97.
The significance of meconium staining TOSHIO
FUJIKURA,
BERNARD
M.D.
KLIONSKY,
Pittsburgh,
Pennsylvania
Meconium
staining
M.D.
of the
placenta
and/or
fetal
body
was present
at birth
in 10.3
per
cent
42,000 live-born infants, but was present disproportionately in 18.1 per cent of 788 neonatal deaths. The neonatal mortality rate was 3.3 per cent in the stained group and 1.7 per cent in the nonstained group. Among infants who died, the incidence of erythroblastosis was quadrupled and that of cardiovascular malformation was doubled in the stained group. Meconium staining was associated with a decrease in the expected frequency of hyaline membranes and atelectasis even in premature infants; hypotheses for this phenomenon wtre presented. Meconium staining of the fetus or placenta requires several hours of exposure. of
As a hypothesis, the stresses of cumulative meconium if delivery
observed increase of deaths or chronic hypoxia which is prolonged.
in stained neonates may occur after
T H E s I G N I F I c A N c E Of meconium-stained amniotic fluid is still a widely debated subject. Meconium staining of the amniotic fluid is one of the From the Department of Pathology, Pittsburgh School of Medicine.
University
classic signs of fetal distress in utero. The stimulus causing passage of meconium before birth is, by tradition, fetal anoxia or hypoxia, yet in 12 to 25 per cent of deliveries complicated by fetal meconium passage, no definite cause of such conditions is found.” However, Desmond and associate? reported that meconium staining of the amniotic fluid, placenta. and umbilical cord is associated with an increase in neonatal morbidity and mortality rates. Walke+ observed a mortality rate between 5 and 8 per cent when a rapid fetal heart rate alone is noted, and 20 per cent-when this is accompanied by the passage of meconium. Such increase of mortality rates indicated the potential seriousness of meconium-stained amniotic fluid at delivery. Undoubtedly many maternal factors contribute to the passage of meconium before birth, among which may be cited maternal age, prolonged gestation, type of labor, obesity, hypertension, toxemia of pregnancy, and anemia.“-” However, knowledge of the fetal factors governing the passage of meconium is still incomplete and should be investigated.
of
The Collaborative Study of Cerebral Palsy, Mental Retardation. and Other Neuroloeical and Sensory Disorders of. Infancy and Childhiod is supportedby the National Institute of Neurological’biseases and Stroke. The following institutions participate: Boston Lying-In Hospital; Brown University; Charity Hospital, New Orleans; Children’s Hospital of Butfalo; Children’s Hospital of Philadelphia; Children’s Medical Center, Boston; Columbia University; The Johns Hopkins Hospital; the University of Minnesota; the University of Oregon; the University of Tennessee and the Perinatal Research Branch, National Institute of Neurological Diseases and Stroke. I
,
Received
for
Accepted
August
publication
May
may be related to the the initial passage of
31, 1974.
8, 1974.
Reprint requests: Dr. Toshio Fujikura, MageeWomens Hospital, Department of Pathology, Forbes Ave. and Halket St., Pittsburgh, Pennsylvania 15261. 45
46
Fujikura
and
January 1, 1975 Am. J. Obstet. Gynecol.
Klionsky
Table I. Neonatal death rate and percentage frequency between stained and nonstained groups
Live Groug
No.
Stained Nonstained Total P <
Neonatal deaths
births )
4,390 38,100
42,490
%
No.
10.3 89.7 100.0
143 645 788
)
% 18.1 81.9 100.0
Neonatal death rate (%) 3.3 1.7 1.8
0.001.
The constituents of meconium are mainly bile pigments, bile salts, fetal hair, squamous cells, mucopolysaccharides, and cholesterol.2 Bile pigments have a strong surface-active action.17 Theoretically, aspirated meconium could reduce surface tension in the pulmonary alveoli and facilitate alveolar expansion with reduction of the viscosity of bronchial secretions. The purpose of this study is to investigate the pathologic findings in autopsies of neonates born with meconium staining and to determine the possible relationship of this condition to a variety of other disorders. Material
and
methods
This report was based on 42,490 live-horn infants delivered of randomly selected Collaborative Study registrants from 12 participating institutions. The bulk of the population consists of approximately an equal number of Caucasians and Negroes, with a small percentage of Puerto Ricans and other ethnic groups. The present study was limited to 788 autopsied neonatal deaths of Collaborative Study cases. The autopsy rate of neonatal deaths was about 89 per cent. Abortions, multiple births, and stillbirths were not included. The Collaborative Study required that, when permission was granted, a detailed autopsy was to be performed according to a standard protocol on all deaths, including gross and microscopic reports. Copies of such protocols and duplicate histologic sections of lungs were reviewed in order to obtain specific information such as hyaline membranes, pneumonia, congenital malformations, etc. The criteria used for congenital malformations and their classification by organ systems were those described in detail in a previous paper.8 Meconium staining of the placenta (membranes and umbilical cord) and/or fetal body was used as the criterion of selection of a meconium-stained case. Meconium staining of the amniotic fluid alone was
not included. The criteria for pre-eclampsia were based on the definition in Williams’ Obstetric? and included cases with or without chronic hypertension. Mothers were considered as diabetic if their glucose tolerance curves met the criteria set forth by Somogyi-Nelsonlo or if, in lieu of glucose tolerance curves, the patient was clearly known to be diabetic and was treated with more than 20 U. of insulin daily. The significance of data presented in Tables I to V was calculated by the chi-square test. Results Table I shows the effect of meconium staining on the survival of the live-born infants. Although 10.3 per cent of all live-born infants had meconium staining, 18.1 per cent of neonates who died were stained by meconium. The stained group was associated with a neonatal mortality rate of 3.3 per cent as opposed to 1.7 per cent in the nonstained group. In Table II the relationship between meconium staining and birth weights of live births is shown. Both the frequency distribution and the incidence of meconium staining increased significantly in babies with birth weights of over 3,501 grams. In babies weighing 2,000 grams or below, the incidence of meconium staining was also slightly elevated. Table III shows the incidence of fetal and maternal conditions in neonatal deaths with or without meconium staining. Cardiovascular malformations (13.9 per cent), erythroblastosis fetalis (22.4 per cent) chorioamnionitis (37.7 per cent), and preeclampsia ( 11.1 per cent) were significantly higher in the stained group; conversely hyaline membranes (13.9 per cent) and atelectasis (37.5 per cent) were lower. In other fetal and maternal conditions the incidence between the two groups was not significantly different. Pneumonia and pulmonary hemorrhage were found just as frequently in the stained group as in the nonstained group, as were conditions associated with anoxia or hypoxia, abruptio placentae, placenta previa, and prolapsed cord. Table IV presents a comparison of the incidence of hyaline membranes according to birth weight between the two groups. The incidence of hyaline membranes in infants weighing 1,500 grams or less at birth was significantly lower in the stained group. The incidence in other birth weight intervals was lower in the stained group, but not significantly so. In Table V a similar trend of reduced incidence of hyaline membranes was also found in the stained group at gestational ages below 27 weeks. The in-
Volume Number
121 1
Significance
of meconium
staining
47
Table II. Meconium staining of live births according to birth weight Group with Birth
1,500 and 1,501-2,000 2,001-2,500 2,501-3,000 3,001-3,500 3,501-4,000 4,001 and Total
Grout
staining
weight (Gm.)
No. less
over
Incidence
Total
No.
%
No.
366 540 2,828 9,856 15,412 7,473 1,625 38,100
0.9 1.4 7.4 25.9 40.5 19.6 4.3 100.0
410 618 3,102 10,775 17,097 8,501 1,987 42,490
70
44 78 274 919 1,685 1,028 362 4,390
without
staining
1.0 1.8 6.2 20.9 38.4 23.4 __ 8.2 100.0
of
staining -% P
70 0.9
10.7 12.6 8.8
:*z 25:4 40.2 20.0 4.7 1oo.o
a.5 9.8 12.0 18.2 10.3
0.841 0.071 0.005 < 0.001 0.009 < 0.001 < 0.001
Table III. Fetal and maternal findings with or without meconium staining in neonatal deaths Group with
Group without staining
staining
Number
cases
of Hyaline
143 (::.9)*
membranes
Atelectasis
(Z.7)
Pneumonia
$6)
Pulmonary
hemorrhages
Congenital
(Z.4)
malformations
Cardiovascular Central
(Z.3)
system
nervous
$9)
Digestive
(;.6) y
system
(6.2)
system
Erythroblastosis
$.7)
fetalis?
Chorioamnionitis,
moderate
13/58 @$.4)
or marked
(37.7) ruptured
membranes $1)
Prolapsed
placentae
(i.3) 44 (5.5) 28 (3.5) 30 (3.8) 25 (3.1) 25/285 (8.7) 207 (26.2) 132 (16.7) 60 (7.6) 31 (3.9) 23 (2.9) 23
(8.0)
JO)
28 (4.3) 19
(i.7)
(2.9)
(:.3) 16 (11.1)
21 (3.2) 38 (5.8)
previa cord
*Numbers in parentheses are per cent of each incidence. +The incidences are based on the number of Caucasians 285.
(i.3) 33 (5.1) 25 (3.8) 21 (3.2) 21 (3.2) 12/227 (5.2) 153 (23.7) 106 (16.4) 52
(i.5)
Diabetes Pre-eclampsia
ii.4)
0.001 0.161 0.484
;;;.3) (19.1) 62 (7.8)
0.271 0.002
0.548 (i.6) 11
system
Unspecified
Placenta
tz.0,
< 0.001
0.133
system
Musculoskeletal
Abruptio
788 212 (26.9) 400 (50.7) 190 (24.1) 184
system
Genitourinary
Prolonged
645 192 (29.7) 346 (53.6) 149 (23.1) 149 (23.1) 119 (18.4) 42 (6.5)
P
system (461)
Respiratory
Total
only:
group
with
staining,
0.230 0.317 0.089 0.841 < 0.001 < 0.001 0.617 0.368 0.230 1 .ooo 0.271
g.9’
0.027
(6.8) 58; group
without
staining,
227;
total,
48
Fujikura
and
Klionsky
Table IV. Incidence
of hyaline
membranes
in neonatal
deaths
according
to birth
weight
and meconium
%
No. of deaths
No. of HM
%
P
29.0 42.5 -18.9 29.7
392 173 223 788
106 69 37 212
27.0 39.8 16.5 __ 26.9
0.016 0.089 0.161 0.001
staining Group
with
Group without staining
staining Birth
weight (Gm.1
No. of deaths
1,500 and less 1,501-2,500 2,500 and over Total
48 25 70 143
Table V. Incidence
of hyaline
No.
with HM
6 6 8 -ii
membranes
%
No. of deaths
12.5 24.0 -11.4 13.9
344 148 -153 645
in neonatal
No.
Total
with HM
100 63 - 29 192
deaths
accordin
g to gestational
age and
meconium
staining
Gestational age (wk.)
27 and less 28-36 37 and over Total
cidence in gestational over was significantly
Group with staining No. of deaths
No. HM
3 9 8 0
7%
8.1 25.0 11.4 13.9
218 277 150 645
age intervals of 37 weeks and lower in the stained group.
Comment
Neonatal
Total
with
37 36 70
143
Group without staining
mortality rate. Meconium staining of the placenta and/or fetal body was present in 10.3 per cent of all live births and in 18.1 per cent of neonatal deaths. The neonatal mortality rate was 3.3 per cent in the stained group and 1.7 per cent in the nonstained group. This is in keeping with the report of Desmond and associates* that intrauterine passage of meconium is associated with an increase in neonatal mortality and morbidity rates. Staining and birth weight. In Table II the incidence of meconium staining is significantly increased in babies of birth weight greater than 3,501 grams. In babies weighing 2,000 grams or less, the incidence was slightly, but not significantly elevated. However, Desmond and associates?, 5 reported that me’conium staining of the amniotic fluid is disproportionately uncommon in premature infants weighing 2,000 grams or less. The exact mechanism of relative failure of the premature infant to pass meconium is still unknown. According to SmithI the explanation may be a smaller accumulation of meconium in the intestine or a lower sensitivity to anoxia or hypoxia. Staining and hyaline membranes. A decrease of hvaline membranes and atelectasis in the stained
50 105 37 192
9%
No. of deaths
22.9 37.9 24.6 F7
255 313 220 788
No.
with HM
53 114 45 212
%
P
20.7 36.4 -20.4 26.9
0.045 0.133 0.027 0.001
group (Table III) can be explained by four hypotheses relating to (1) fetal maturity, (2) surfactant, (3) intestinal enzymes, and (4) chronic stress. 1. The decrease in hyaline membranes and atelectasis could be due to the increased percentage of mature infants in the stained group. In Table V the decrease in hyaline membranes was significant in the stained group at gestational ages above 37 weeks. However, even in the premature infants below 1,500 grams or 27 weeks the frequency of these pulmonary problems was lower in the stained group (Tables IV and V) . 2. Besides the well-known factor of prematurity in hyaline membrane disease, aspirated bile pigments acting as a strong surfactanP7 may prevent the production of atelectasis and hyaline membranes. Although surface-active agents have proved disappointing in the treatment of hyaline membrane disease because of their toxic action, bile pigments which are diluted with amniotic fluid appear to be relatively harmless. 3. It is unlikely that tryptic intestinal enzymes present in meconium-stained amniotic fluid either inhibit the development or speed the lysis of hyaline membranes. Intestinal enzymes from meconium have been reported to be ineffective, or for some reason inactivated.14 4. Chronic intrauterine stress has been demon-
Volume Number
121 1
Significance
strated to decrease the expected incidence of respiratory distress syndrome6; the conditions which lead to meconium staining may represent such chronic stresses. Meconium staining is not prominent with acute obstetric emergencies such as prolapsed cord, abruptio placentae, or placenta previa in this study or in others5; by comparison, meconium staining is prominently associated with chronic maternal stresses such as toxemia, prolonged gestation, and anemia.5 Our findings confirmed the significant association of staining with pre-eclampsia and chorioamnionitis. These maternal complications are more likely to be present in a chronic state of fetal distress than in the acute state. Such chronic stress may trigger hormonal secretion by the fetal adrenal capable of accelerating pulmonary surfactant synthesis. Recently many stressful conditions such as maternal hypertensive disease,’ premature rupture of the membranes,” and maternal narcotic addiction” are reported to have a sparing effect on the development of respiratory distress syndrome. The relationship between respiratory distress syndrome and meconium staining needs further clinical investigation in relation to these hypotheses. Cardiovascular malformations. Cardiovascular malformations in neonatal autopsies were twice as high in the stained group (13.9 per cent) as in the nonstained group (6.5 per cent). Of 62 neonatal deaths with cardiovascular malformations, 20 had meconium staining in this study. These 20 cases included 8 ventricular septal defects, 5 atria1 septal defects, 4 transpositions of the great vessels, 3 preductal coarctations, and one tetralogy of Fallot. Meconium staining may produce a warning sign of fetal anoxia, hypoxia, and distress in the malformed infants. Erythroblastosis. The relationship between erythroblastosis and meconium staining was significantly high among neonatal deaths (22.4 per cent). Out of 391 live-born infants with definite erythroblastosis, 72 (18.4 per cent) were associated with meconium staining. According to Potter,ll fetuses with severe erythroblastosis excrete large amounts of bili-
REFERENCES
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Fuchs, GYNECOL.
K.,
and 118:
1974.
2. Bourne, G.: The Human Amnion and Chorion, Chicago, 1962, Year Book Medical Publishers, Inc., pp. 3.
143-154.
Clifford,
S. H.: J. Pediatr. 44: 1, 1954.
of
meconium
staining
49
rubin in the urine, and it discolors the placental surface, umbilical cord, and vernix caseosa, giving a false impression of meconium discoloration of the skin. However, the hemolysis and anemia could produce fetal hypoxia and the passage of meconium with erythroblastosis. Since meconium or bilirubin staining of the fetus and placenta are respectively indicators of fetal hypoxia and hyperbilirubinemia, their presence should alert the clinician to the possibility of subsequent bilirubin encephalopathy which is associated with both the level of bilirubin and the extent of hyp0xia.l” The role of time. Time is an important factor in the development of meconium staining. Evidence available from in vivo and in vitro observations’, 4 suggests that a minimum of 4 to 6 hours is required between passage of meconium into the amniotic fluid and staining of the placenta or fetus. There appears to be a critical difference between the presence of meconium in the amniotic fluid and meconium staining. This difference involves time and the probability of exacerbation of the pathologic physiology which leads to passage of meconium. Meconium is infrequently found in normal amniotic fluid and the initial passage of meconium most often occurs as a warning sign late in gestation and very shortly before delivery, presumably from mild or transient degrees of hypoxia that are not harmful to the fetus.’ Many investigators agree that the presence of meconium-stained amniotic fluid is not necessarily a sign of severe hypoxia, acidosis, or acute fetal distress; rather, it may be considered as an indicator of either a previous bout of intrauterine anoxia or a state of compensated fetal distress.’ If, following the initial bout of hypoxia and passage of meconium, delivery is delayed for the substantial length of time required to produce meconium staining, there exists a greater probability that the stresses of cumulative or repeated bouts of chronic hypoxia can produce intrauterine death or the increased neonatal mortality rate observed in this study or in others.4, 5, I3
4. Desmond, M. M., Lindley, J. E., Moore, J., and Brown, C. A.: J. Pediatr. 49: 540, 1956. 5. Desmond, M. M., Moore, J., Lindley, J. E., and Brown, C. A.: Obstet. Gynecol. 9: 91, 1957. 6. Gluck, L., and Kulovich, M. V.: Zn Syndrome, Villee, C. A., Villee, D. B., and Zuckerman, J., editors: Respiratory Diseases Syndrome, New York, 1973, Academic Press, Inc., pp. 183-196.
50
7.
8.
9.
10. 11.
Fujikura
and Klionsky
Hellman, L. H., and Pritchard, J. A.: Williams’ Obstetrics, New York, 1971, Appleton-Century-Crofts, pp. 685-689. Froehlich, L. A., and Fujikura, T.: In Nishimura, H., and Miller, J. R., editors: Methods for Teratological Studies in Experimental Animals and Man, Tokyo, 1969, Igaku Shoin Ltd., pp. 167-194. Naeye, R.: In Villee, C. A., Villee, D. B., and Zuckerman, J., editors: Respiratory Distress Syndrome, New York. 1973. Academic Press. Inc.. DD. 147-156. O’Sullivan,‘J. B., and Mahan, d.‘M.: Diabetes 13: 278, 1964. Potter, E. L.: Pathology of the fetus and the infant, Chicago, 1961, Year Book Medical Publishers, Inc., pp. 613-614.
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13. 14.
15. 16. 17.
Richardson, C. J., Pomerance, J. H., Cunningham, M. D., and Gluck, L.: AM. J. OBSTET. GYNECOI.. 118: 1115, 1974. Rooth, G.: J. Perinat. Med. 1: 7, 1973. Smith, C. A.: The physiology of the newborn infant, Springfield, Ill., 1959, Charles C Thomas, Publisher, pp. 244-250. Smith, J. F.: Pediatric neuropathology, New York. 1974, McGraw-Hill Book Company, Inc., page 90. Walker, J.: J. Obstet. Gynecol. Br. Commonw. 61: 162, 1954. West, E. S., Todd, M. R., Mason, H. S., and Van Bruggen, J. T.: Textbook of biochemistry, New York, 1966, MacMillan Co., p. 97.