FETUS, PLACENTA, AND NEWBORN
Relationship between cortisol levels in umbilical cord plasma and development of the respiratory distress syndrome in premature newborn infants S. SYBULSKI,
M.Sc.,
G. B. MAUGHAN, Montreal,
PH.D.
M.Sc.,
M.D
Quebec, Canada
The aim of this study was to determine whther there is a decrease in fetal cortirol levels msoriclted with the respiratory distress syndrome (RDS). Eighteen newborn infants of less than 37 weeks’ gestation who developed moderate to severe forms of RDS did have a signzjicantly lower (P < 0.02) mean cord plasma co&sol concentration at birth thon that observed in 67 unaffected infants of similar gestationul age; mean values + standard error,s were 3.36 of: 0.42 and 5.58 + 0.43 Hper 100 ml, respectively. However, whether or not RDS developed in neonates appeared to depend more upon the degree of prematurity (with a 71.5 per cent incidence in gestations of less than 32 weeks compared to 17.1 per cent in those of 32 to less than 37 weeks) than upon cortisol levels at delivery. Blood cortisol levels in the $rst days of life of four infants with RDS were considerably increased in comparison to those at birth. Mean cord plasma cortisol concwtrations increased with duration of pregnancy, with the previously observed value for term infants (of 37 or mare weeks) being apfwoximately twice that for infants of less than 32 week’s gestation. These findings appear to justqy carefully controlled studies with antepartum glucocorticoid administration with the aim of reducing the incidence of RDS in premature newborn infants.
THE RESPIRATORY DISTRESS syndrome(RDS)is disease of prematurity, rarely occurring in neonates 37 or more weeks’ gestation.’ In comparison to lungs infants at or close to term, the lungs of premature infants are less likely to be sufficiently mature
From
the Hellenic
Research
Laboratory,
Department
a of of
support extrauterine life due to inadequate levels of surface-active lecithin (surfactant) production.‘, 3 EXperiments in the sheep and rabbit indicate that certain glucocorticoids accelerate fetal lung maturation, presumably by influencing surfactant biosynthesis or release.47 ’ Naeye and associates8 suggested that there is a relationship between adrenal cortical function in the fetus and RDS development; this possibility was based on autopsy findings showing that adrenal glands of infants who died from RDS weighed 19 per cent less than those of neonates who died from other causes. The aim of this study was to determine whether there is a significant decrease in fetal cortisol levels associated with RD.% Cord cortisol levels were investi-
to
of
Obstetrics and Gymecology, Royal Victoria Hospital. Received for publication May 30, 1975. Revised
October
Accepted October
2, 1975. 13, 1975.
Reprint requests: Dr. S. Sybuiski, Hellenic &search Luboratoly, Department of Obstetrics and Gynecology, Royal Victoria Hospital, Montreal, Quebec, H3A IAI, Canada
239
240
Sybulski
20
and Maughan
. F
2 if,,-
.
o No RDS . RDS
l
22 -
s d 0
.J 3
.
12-
4
0
.
0
:
.. 3
O-
No RDS
,L*-1I 1I I I / I I I 29
RDS o mild
WEEKS
31
33
35
37
OF GESTATION
2. The relationship between cortisol levels in cord plasma and gestational age (according to the clinical evaluation by neonatologists) in infants with and without RDS. The curved lines join values in multiple pregnancies.
Fig.
Fig. 1. Individual cord plasma cortisol concentrations in pregnancies ranging from 26 to less than 37 weeks’ gestation. The solid horizontal lines indicate the mean values for infants without RDS and for those with mild to severe RDS. The dashed horizontal line indicates the mean value for infants with moderate to severe forms of RDS. gated in relation to degree development of RDS. Blood days of life of neonates with well. Cortisol levels in these compared to those previously or more weeks’ gestation.7
of prematurity and the cortisol levels in the first RDS were determined as premature infants were observed in infants of 37
Subjects and methods The reported gestational age of newborn infants was in all cases according to the clinical evaluation by neonatologists. The criteria for diagnosis of presence and severity of RDS were the clinical manifestations, radiologic evidence (diffuse reticulogranular pattern in the lungs), and biochemical findings as described by Usher.R Cortisol levels in plasma obtained from mixed umbilical cord blood were determined by a competitive protein-binding method with human late pregnancy plasma used as the source of transcortin, as described in detail elsewhere.’ Cortisol levels in neonatal blood obtained by heel prick were measured by the same method. The Student t test was used for statistical evaluations.
Results Individual cord plasma cortisol concentrations for all pregnancies from 26 to less than 37 weeks’ gestation are shown in Fig. 1; there was considerable overlap in cortisol levels in infants with and without RDS. The mean value +- standard error for 67 infants without RDS was 5.58 t 0.43 pg per 100 ml. The difference between the latter value and that for al1 23 infants with RDS ranging from mild to severe (3.98 +- 0.79 pg per 100 ml.) was only of borderline significance (P > 0.05 < 0. I). The mean cortisol concentration associated with moderate to severe forms of RDS (3.36 ? 0.42 pg per 100 ml.) was significantly less than that for the non-RDS group (P < 0.02). Some interesting facets become evident when the incidence of RDS development is related to both cord cortisol levels and weeks of gestation (Fig. 2). First, ten of the 14 infants (71.5 per cent) born before 32 weeks developed RDS; cortisol levels in the cord plasma of four of these affected neonates were not low but were close to the mean value for infants who did not have RDS. Second, in this very premature group, the firstborn infants of a twin and a triplet pregnancy did not develop RDS although their cortisol levels were as low as those of their siblings who did develop RDS. Third, in the pregnancies of 32 to less than 37 weeks’
Volume
125
Number
2
Table
Umbilical cord cortisol and RDS
I. Comparison
of cord plasma cortisol
levels in premature
241
and term infants Cortiso1/100 ml. plasma (pg)
Premature Nature
of labor and delivery
Spontaneous labor, vaginal delivery No RDS RDS All cases Induced labor, vaginal delivery No RDS RDS All cases Cesarean section after labor No RDS RDS All cases Cesarean section, no labor No RDS All cases Values shown are the means -+ standard errors; *Term values are being published in the article tsignificantly different from the corresponding fsignificantly different from the corresponding
(less than 37 weeks’ gestation)
(37 or more weekr’ gestation)
6.10 +- 0.57 (45)t 4.18 k 0.90 (20)$ 5.37 2 0.52 (65)$
7.43
5 0.29 (162)
4.89 2.43 4.75
+ 0.41 (17) (1) k 0.41 (18)
6.53
f 0.50 (51)
7.63 2.68 5.13
(2) (2) 2 1.55 (4)
3.34 3.34
(3) (3)
figures in parentheses are the numbers mentioned in Reference 7. term value (P < 0.05). term value (P < 0.001).
gestation, the incidence of RDS decreased from 71.5 to 17.1 per cent. All but one value for infants of this gestational age who developed RDS (this one being associated with gestational diabetes) were below the mean value for the infants without RDS, but low cortisol concentrations were observed as well in some of the infants without RDS. Cortisol levels were determined in the first days of life in four infants with RDS (Fig. 3). Since steroids are contained in the plasma, cortisol values per unit volume of whole blood are obviously underestimations compared to those per unit volume of plasma. Nevertheless, in Case A, the cortisol level in heel blood was considerably greater at Day 1 of life than in cord plasma and increased further thereafter. In Case B, cortisol levels were high at Days 2 and 3 compared to the concentration in cord plasma and subsequently declined. No cord specimen was available for Case C (this infant developed severe RDS and died), but cortisol levels were relatively high, increasing from 11.80 at Day 1 to 34.60 pg per 100 ml. of blood at Day 3 of life. The infant in Case D developed severe RDS and died within 24 hours; the cortisol level in cord plasma was normal, and a very high concentration (70 pg per 100 ml. of plasma) was observed at 12 hours of age. Cord plasma cortisol concentrations in premature infants were compared to those previously observed in infants of 37 or more weeks’ gestation (Table I). The nature of labor and delivery is specified because it has
Term*
6.21 f 0.66 (47)
4.67
f 0.60 (23)
of samples.
been observed that these factors may affect cortisol concentrations.T Mean cortisol values were less in the premature group regardless of whether labor was spontaneous, induced, or absent and regardless of whether delivery was vaginal or by cesarean section. Nevertheless, it was only in the category of spontaneous labor with vaginal delivery that the difference between cortisol values in premature and term groups reached statistical significance, whether or not infants with RDS were included in the premature series. In Table II, cord plasma cortisol levels are classified simply by gestational age. Mean concentrations increased with duration of pregnancy, with the value at term being almost twice that for gestations of less than 32 weeks; the differences between the value at term and those for gestations of less than 37 weeks are significant (P < 0.01).
Comment The purpose of this investigation was to determine whether there is a significant decrease in fetal cortisol levels in association with RDS. Based on the present findings on cortisol levels in cord plasma at birth, such a decrease apparently exists; newborn infants of less than 37 weeks’ gestation who developed moderate to severe forms of RDS had a significantly lower mean cortisol concentration than that observed in unaffected infants of similar gestational age. This result confirms our preliminary finding of low cord cortisol values in two cases of severe RDS in a previous study.”
242
Sybulski
o
80r
8 d
-
and Maughan
Y 0
? 603 8 -
Plasma
0 Whole
blood
r” j40P T 8 c s; zoP 8 g
0
&I
’
Plasma
2
3
4
AGE OF NEWBORN
5
6
7
(daya)
Fig. 3. Comparison of cortisol levels in heel blood the first days of life of four neonates (designated RDS with levels in cord plasma at birth. Since contained in plasma, whole-blood cortisol values estimations compared to plasma values.
or plasma in A to D) with steroids are at-e under-
Table II. Relationship between cortisol levels in cord plasma and duration of pregnanq
26 to (all 32 to (all 3i or (all
less than 32 weeks cases) less than 37 weeks cases) more weeks (term) cases)
3.54
2 0.51 (14)*
5.47
2 0.43 (7@+
6.84
+ 0.22 (283)
Values shown are the means r?rstandard errors; figures in parentheses are the numbers of samples. *Significantly different from the term value (P < 0.01). However, whether or not RDS developed in the neonate appeared to depend less upon the cord cortisol level than upon the degree of prematurity. In gestations of less than 32 weeks, the incidence of RDS was 71.5 per cent with four of 10 affected infants having essentially normal cord cortisol concentrations for their gestational age. In gestations of 32 to less than 37 weeks, the incidence of RDS was decreased to 17.1 per cent: while cord cortisol values in association with RDS were relatively low in all but one case, low cortisol concentrations were also observed in some unaffected infants. The fact that the highest cortisol value in the RDS group was in the infant of a pregnancy complicated by gestational diabetes is of interest in view of reports “. I2 that newborn infants of diabetic mothers may be predisposed to develop RDS even when
lecithin/sphingotnyelin ratios in amniotic fluid are normal. It is of interest that the first born infants in two multiple pregnancies of less than 32 weeks’ gestation did not develop RDS although their cortisol concentrations at birth were as low as those of the later-born ones who did develop RDS. The fact that the latter infants differed from the first born ones in that they had lower one-minute Apgar scores and were moderately to severely asphvxiated at birth mav have been a contributing factor to RDS. Perhaps some aspect of labot. and/or delivery in a multiple pregnancy is in some wa\ detrimental to the later-horn infants with respect to pulmonary function. Although we had the opportunity to measure cortisol levels in only four newborn infants with RDS, we observed that blood levels in their first days of life were considerably increased in comparison to those in cord plasma at birth. Other investigators also have observed relatively high cortisol levels in neonates with RD.%‘“, I4 ‘l’his suggesrs that low cord plasma concentratiotts i!~ thcsc cases are probablv not due 10 incapacit\ of’ the fttal adrenals to biosynthesize c.ortisol: tertainlv the abililv to respond to stress in extr:iuterine life as reflected by an elevated blood cortisol 1~~1 is apparently not lacking in infants with RDS, Not only the levels of cortisol but also those CJf cortisone,‘” estriol.16 and estradiol” are reduced in cord blood in association with RD.5 This could be a reflection of a decrease in the transfer of maternal steroids to the fetus and/or a result of reduced fetal adrenal function. There is evidence that the placenta converts cortisol to cortisone” and that fetal cortisone thus arises mailllv from maternal cortisol.‘” Estriol anti estradiol are biosvnthesized in the placenta predonlinanth from androgen precursors produced bv the fetal &enalslg; however, a reduction in estrogen levels in cord blood has been observed IIOI onlv in association with hvaline membrane disease but also in other forms of neonatal rt5piratory distress.‘O. ” As the preceding comments indicate, we did observe lower cortisol concentrations in premature gestations, particularly in those of less than 32 weeks, than in those at term; we also found decreased cortisol levels in association with RDS, although the relationship hetweet1 fetal cot-tisol levels and de\elopntent of RDS in newborn infants was less than strict. These findings appear to ,justif> carefully conducted studies with antepartum glucocorticoid administration in premature pregnancies as pioneered by Liggins and HowiezO with the aim of reducing the incidence of RDS. Essentially similar results with respect to cord cortisol
Volume
125
Number
2
Umbilical cord cortisol and RDS 243
term whose cord cortisol levels were determined previous study) developed RDS.
levels have recently been reported by Murphy.‘j However, an important difference between the present study and Murphy’s is that a third of the infants in the latter investigation were at term with 18 per cent of these developing RDS. This study includes only infants of less than 37 weeks’ gestation since, in the experience of our maternity hospital, RDS is virtually nonexistent after this period; in fact, only one of the 283 infants at
The authors are grateful to the Department of Neonatology of the Royal Victoria Hospital, headed by Dr. R. H. Usher, for information on newborn infants and blood specimens. We also wish to thank all physicians and nurses who assisted in the collection of cord blood.
REFERENCES 1. Usher,
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
R. H.: Clinical implications of perinatal mortality statistics, Clin. Obstet. Gynecol. 14: 885, 1971. Gluck, L.., and Kulovich, M. V.: Fetal lung development: Current concepts, Pediatr. Clin. North Am. 20: 367, 1973. Brown, B. J., Gabert, H. A., and Stenchever, M. A.: Respiratory distress syndrome, surfactant biochemistry, and acceleration of fetal lung maturity: A review, Obstet. Gynecol. Survey 30: 71, 1975. Kotas, R. V., Fletcher, B. D., Torday, J., and Avery, M. E.: Evidence for independent regulators of organ maturation in fetal rabbits, Pediatrics 47: 57, 1971. DeLemos, R. A., Shermetta, D. W., Knelson, j. G., Kotas, R., and Avery, M. E.: Acceleration of appearance of pulmonary surfactant in the fetal lamb by administration of corticosteroids, Am. Rev. Resp. Dis. 102: 459, 1970. Naeye, R. L., Harcke, H. T., and Blanc, W. A.: Adrenal gland structure and the development of hyaline membrane disease, Pediatrics 47: 650, 1971. G. B.: Cortisol levels in Sybulski, S., and Maughan, umbilical cord plasma in relation to labor and delivery, AM. J. OBSTET. GYNECOL. 125: 236, 1976. Usher. R. H.: The respiratory distress syndrome of prematurity: clinical and therapeutic aspects, Pediatr. Clin. North Am. 8: 525, 1961. Sybulskl, S., and Maughan, G. B.: A rapid method for the measurement of estradiol and hydrocortisone levels in maternal and fetal blood and amniotic fluid, AM. J. OBSTET. GYNECOL. 121: 32,1975. Sybulski, S., and Maughan, G. B.: Umbilical cord plasma estradiol levels in relation to complications of pregnancy and newborn and to cortisol levels, Biol. Neonate 27: 302, 1975. Boughton. K., Gandy, G., and Gairdner, D.: Hyaline
12.
13.
14.
15.
16.
17.
18
19. 20.
membrane disease: Il. Lung lecithin, Arch. Dis. Child 45: 311, 1970. Gabert, H. A., Bryson, M. J., and Stenchever, M. A.: The effect of cesarean section on respiratory distress in the presence of a mature lecithin-sphingomyelin ratio, AM. J. OBSTET. GYNECOL. 116: 366, 1973. Reynolds, J. W.: Serum total corticoid and cortisol levels in premature infants with respiratory distress syndrome. Pediatrics 51: 884, 1973. Klein, G. P., Baden, M., and Giroud, C. J. P.: Quantitative measurement and significance of five plasma corticosteroids during the perinatal period, J, &in. Endocrinol. Metab. 36: 944, 1973. Murphy, B. E. P.: Cortisol and cortisone levels in the cord blood at delivery of infants with and without the respiratory distress syndrome, AM. J. OBSTET. GYNECOL. 119: 1112, 1974. Conly, P. W., LeMaire, W. J., Monkus, E. F., and Cleveland, W. W.: Plasma estriol concentration in infants with the respiratory distress syndrome, J. Pediatr. 83: 851, 1973. E. H.: The possibility of Sybulski, S., and Venning, corticosteroid production by human and rat placental tissue under in vitro conditions, Can. J. B&hem. 39: 203, 1961. Murphy, B. E. P., Clark, S. J., Donald, I. R., Pinsky, M., and Vedady, D.: Conversion of maternal cortisol to cortisone during placental transfer in the human fetus, AM. J. OBSTET. GYNECOL. 11% 538, 1974. Diczfalusy, E.: Endocrine functions of the human fetus and placenta, AM. J. OBSTET. GYNECOL. 119: 419, 1974. Liggins, G. C., and Howie, R. N.: A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants, Pediatrics 50: 515, 1972.
Course in Gynecologic Laparoscopy The
New
Jersey
Fertility
Foundation
is
sponsoring
a
course
in
“Gynecologic
Laparoscopy,
” to be held June 3 and 4, 1976, at Roselle Park, New Jersey. For further
information,
contact:
07204.
Dr.
S. A. Wilchins,
(in a
14 E. Westfield
Ave.,
Roselle
Park,
New
Jersey
Relationship between cortisol levels in umbilical cord plasma and development of the respiratory distress syndrome in premature newborn infants S. SYBULSKI,
M.Sc.,
G. B. MAUGHAN, Montreal,
PH.D.
M.Sc.,
M.D
Quebec, Canada
The aim of this study was to determine whther there is a decrease in fetal cortirol levels msoriclted with the respiratory distress syndrome (RDS). Eighteen newborn infants of less than 37 weeks’ gestation who developed moderate to severe forms of RDS did have a signzjicantly lower (P < 0.02) mean cord plasma co&sol concentration at birth thon that observed in 67 unaffected infants of similar gestationul age; mean values + standard error,s were 3.36 of: 0.42 and 5.58 + 0.43 Hper 100 ml, respectively. However, whether or not RDS developed in neonates appeared to depend more upon the degree of prematurity (with a 71.5 per cent incidence in gestations of less than 32 weeks compared to 17.1 per cent in those of 32 to less than 37 weeks) than upon cortisol levels at delivery. Blood cortisol levels in the $rst days of life of four infants with RDS were considerably increased in comparison to those at birth. Mean cord plasma cortisol concwtrations increased with duration of pregnancy, with the previously observed value for term infants (of 37 or mare weeks) being apfwoximately twice that for infants of less than 32 week’s gestation. These findings appear to justqy carefully controlled studies with antepartum glucocorticoid administration with the aim of reducing the incidence of RDS in premature newborn infants.
THE RESPIRATORY DISTRESS syndrome(RDS)is disease of prematurity, rarely occurring in neonates 37 or more weeks’ gestation.’ In comparison to lungs infants at or close to term, the lungs of premature infants are less likely to be sufficiently mature
From
the Hellenic
Research
Laboratory,
Department
a of of
support extrauterine life due to inadequate levels of surface-active lecithin (surfactant) production.‘, 3 EXperiments in the sheep and rabbit indicate that certain glucocorticoids accelerate fetal lung maturation, presumably by influencing surfactant biosynthesis or release.47 ’ Naeye and associates8 suggested that there is a relationship between adrenal cortical function in the fetus and RDS development; this possibility was based on autopsy findings showing that adrenal glands of infants who died from RDS weighed 19 per cent less than those of neonates who died from other causes. The aim of this study was to determine whether there is a significant decrease in fetal cortisol levels associated with RD.% Cord cortisol levels were investi-
to
of
Obstetrics and Gymecology, Royal Victoria Hospital. Received for publication May 30, 1975. Revised
October
Accepted October
2, 1975. 13, 1975.
Reprint requests: Dr. S. Sybuiski, Hellenic &search Luboratoly, Department of Obstetrics and Gynecology, Royal Victoria Hospital, Montreal, Quebec, H3A IAI, Canada
239
240
Sybulski
20
and Maughan
. F
2 if,,-
.
o No RDS . RDS
l
22 -
s d 0
.J 3
.
12-
4
0
.
0
:
.. 3
O-
No RDS
,L*-1I 1I I I / I I I 29
RDS o mild
WEEKS
31
33
35
37
OF GESTATION
2. The relationship between cortisol levels in cord plasma and gestational age (according to the clinical evaluation by neonatologists) in infants with and without RDS. The curved lines join values in multiple pregnancies.
Fig.
Fig. 1. Individual cord plasma cortisol concentrations in pregnancies ranging from 26 to less than 37 weeks’ gestation. The solid horizontal lines indicate the mean values for infants without RDS and for those with mild to severe RDS. The dashed horizontal line indicates the mean value for infants with moderate to severe forms of RDS. gated in relation to degree development of RDS. Blood days of life of neonates with well. Cortisol levels in these compared to those previously or more weeks’ gestation.7
of prematurity and the cortisol levels in the first RDS were determined as premature infants were observed in infants of 37
Subjects and methods The reported gestational age of newborn infants was in all cases according to the clinical evaluation by neonatologists. The criteria for diagnosis of presence and severity of RDS were the clinical manifestations, radiologic evidence (diffuse reticulogranular pattern in the lungs), and biochemical findings as described by Usher.R Cortisol levels in plasma obtained from mixed umbilical cord blood were determined by a competitive protein-binding method with human late pregnancy plasma used as the source of transcortin, as described in detail elsewhere.’ Cortisol levels in neonatal blood obtained by heel prick were measured by the same method. The Student t test was used for statistical evaluations.
Results Individual cord plasma cortisol concentrations for all pregnancies from 26 to less than 37 weeks’ gestation are shown in Fig. 1; there was considerable overlap in cortisol levels in infants with and without RDS. The mean value +- standard error for 67 infants without RDS was 5.58 t 0.43 pg per 100 ml. The difference between the latter value and that for al1 23 infants with RDS ranging from mild to severe (3.98 +- 0.79 pg per 100 ml.) was only of borderline significance (P > 0.05 < 0. I). The mean cortisol concentration associated with moderate to severe forms of RDS (3.36 ? 0.42 pg per 100 ml.) was significantly less than that for the non-RDS group (P < 0.02). Some interesting facets become evident when the incidence of RDS development is related to both cord cortisol levels and weeks of gestation (Fig. 2). First, ten of the 14 infants (71.5 per cent) born before 32 weeks developed RDS; cortisol levels in the cord plasma of four of these affected neonates were not low but were close to the mean value for infants who did not have RDS. Second, in this very premature group, the firstborn infants of a twin and a triplet pregnancy did not develop RDS although their cortisol levels were as low as those of their siblings who did develop RDS. Third, in the pregnancies of 32 to less than 37 weeks’
Volume
125
Number
2
Table
Umbilical cord cortisol and RDS
I. Comparison
of cord plasma cortisol
levels in premature
241
and term infants Cortiso1/100 ml. plasma (pg)
Premature Nature
of labor and delivery
Spontaneous labor, vaginal delivery No RDS RDS All cases Induced labor, vaginal delivery No RDS RDS All cases Cesarean section after labor No RDS RDS All cases Cesarean section, no labor No RDS All cases Values shown are the means -+ standard errors; *Term values are being published in the article tsignificantly different from the corresponding fsignificantly different from the corresponding
(less than 37 weeks’ gestation)
(37 or more weekr’ gestation)
6.10 +- 0.57 (45)t 4.18 k 0.90 (20)$ 5.37 2 0.52 (65)$
7.43
5 0.29 (162)
4.89 2.43 4.75
+ 0.41 (17) (1) k 0.41 (18)
6.53
f 0.50 (51)
7.63 2.68 5.13
(2) (2) 2 1.55 (4)
3.34 3.34
(3) (3)
figures in parentheses are the numbers mentioned in Reference 7. term value (P < 0.05). term value (P < 0.001).
gestation, the incidence of RDS decreased from 71.5 to 17.1 per cent. All but one value for infants of this gestational age who developed RDS (this one being associated with gestational diabetes) were below the mean value for the infants without RDS, but low cortisol concentrations were observed as well in some of the infants without RDS. Cortisol levels were determined in the first days of life in four infants with RDS (Fig. 3). Since steroids are contained in the plasma, cortisol values per unit volume of whole blood are obviously underestimations compared to those per unit volume of plasma. Nevertheless, in Case A, the cortisol level in heel blood was considerably greater at Day 1 of life than in cord plasma and increased further thereafter. In Case B, cortisol levels were high at Days 2 and 3 compared to the concentration in cord plasma and subsequently declined. No cord specimen was available for Case C (this infant developed severe RDS and died), but cortisol levels were relatively high, increasing from 11.80 at Day 1 to 34.60 pg per 100 ml. of blood at Day 3 of life. The infant in Case D developed severe RDS and died within 24 hours; the cortisol level in cord plasma was normal, and a very high concentration (70 pg per 100 ml. of plasma) was observed at 12 hours of age. Cord plasma cortisol concentrations in premature infants were compared to those previously observed in infants of 37 or more weeks’ gestation (Table I). The nature of labor and delivery is specified because it has
Term*
6.21 f 0.66 (47)
4.67
f 0.60 (23)
of samples.
been observed that these factors may affect cortisol concentrations.T Mean cortisol values were less in the premature group regardless of whether labor was spontaneous, induced, or absent and regardless of whether delivery was vaginal or by cesarean section. Nevertheless, it was only in the category of spontaneous labor with vaginal delivery that the difference between cortisol values in premature and term groups reached statistical significance, whether or not infants with RDS were included in the premature series. In Table II, cord plasma cortisol levels are classified simply by gestational age. Mean concentrations increased with duration of pregnancy, with the value at term being almost twice that for gestations of less than 32 weeks; the differences between the value at term and those for gestations of less than 37 weeks are significant (P < 0.01).
Comment The purpose of this investigation was to determine whether there is a significant decrease in fetal cortisol levels in association with RDS. Based on the present findings on cortisol levels in cord plasma at birth, such a decrease apparently exists; newborn infants of less than 37 weeks’ gestation who developed moderate to severe forms of RDS had a significantly lower mean cortisol concentration than that observed in unaffected infants of similar gestational age. This result confirms our preliminary finding of low cord cortisol values in two cases of severe RDS in a previous study.”
242
Sybulski
o
80r
8 d
-
and Maughan
Y 0
? 603 8 -
Plasma
0 Whole
blood
r” j40P T 8 c s; zoP 8 g
0
&I
’
Plasma
2
3
4
AGE OF NEWBORN
5
6
7
(daya)
Fig. 3. Comparison of cortisol levels in heel blood the first days of life of four neonates (designated RDS with levels in cord plasma at birth. Since contained in plasma, whole-blood cortisol values estimations compared to plasma values.
or plasma in A to D) with steroids are at-e under-
Table II. Relationship between cortisol levels in cord plasma and duration of pregnanq
26 to (all 32 to (all 3i or (all
less than 32 weeks cases) less than 37 weeks cases) more weeks (term) cases)
3.54
2 0.51 (14)*
5.47
2 0.43 (7@+
6.84
+ 0.22 (283)
Values shown are the means r?rstandard errors; figures in parentheses are the numbers of samples. *Significantly different from the term value (P < 0.01). However, whether or not RDS developed in the neonate appeared to depend less upon the cord cortisol level than upon the degree of prematurity. In gestations of less than 32 weeks, the incidence of RDS was 71.5 per cent with four of 10 affected infants having essentially normal cord cortisol concentrations for their gestational age. In gestations of 32 to less than 37 weeks, the incidence of RDS was decreased to 17.1 per cent: while cord cortisol values in association with RDS were relatively low in all but one case, low cortisol concentrations were also observed in some unaffected infants. The fact that the highest cortisol value in the RDS group was in the infant of a pregnancy complicated by gestational diabetes is of interest in view of reports “. I2 that newborn infants of diabetic mothers may be predisposed to develop RDS even when
lecithin/sphingotnyelin ratios in amniotic fluid are normal. It is of interest that the first born infants in two multiple pregnancies of less than 32 weeks’ gestation did not develop RDS although their cortisol concentrations at birth were as low as those of the later-born ones who did develop RDS. The fact that the latter infants differed from the first born ones in that they had lower one-minute Apgar scores and were moderately to severely asphvxiated at birth mav have been a contributing factor to RDS. Perhaps some aspect of labot. and/or delivery in a multiple pregnancy is in some wa\ detrimental to the later-horn infants with respect to pulmonary function. Although we had the opportunity to measure cortisol levels in only four newborn infants with RDS, we observed that blood levels in their first days of life were considerably increased in comparison to those in cord plasma at birth. Other investigators also have observed relatively high cortisol levels in neonates with RD.%‘“, I4 ‘l’his suggesrs that low cord plasma concentratiotts i!~ thcsc cases are probablv not due 10 incapacit\ of’ the fttal adrenals to biosynthesize c.ortisol: tertainlv the abililv to respond to stress in extr:iuterine life as reflected by an elevated blood cortisol 1~~1 is apparently not lacking in infants with RDS, Not only the levels of cortisol but also those CJf cortisone,‘” estriol.16 and estradiol” are reduced in cord blood in association with RD.5 This could be a reflection of a decrease in the transfer of maternal steroids to the fetus and/or a result of reduced fetal adrenal function. There is evidence that the placenta converts cortisol to cortisone” and that fetal cortisone thus arises mailllv from maternal cortisol.‘” Estriol anti estradiol are biosvnthesized in the placenta predonlinanth from androgen precursors produced bv the fetal &enalslg; however, a reduction in estrogen levels in cord blood has been observed IIOI onlv in association with hvaline membrane disease but also in other forms of neonatal rt5piratory distress.‘O. ” As the preceding comments indicate, we did observe lower cortisol concentrations in premature gestations, particularly in those of less than 32 weeks, than in those at term; we also found decreased cortisol levels in association with RDS, although the relationship hetweet1 fetal cot-tisol levels and de\elopntent of RDS in newborn infants was less than strict. These findings appear to ,justif> carefully conducted studies with antepartum glucocorticoid administration in premature pregnancies as pioneered by Liggins and HowiezO with the aim of reducing the incidence of RDS. Essentially similar results with respect to cord cortisol
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Umbilical cord cortisol and RDS 243
term whose cord cortisol levels were determined previous study) developed RDS.
levels have recently been reported by Murphy.‘j However, an important difference between the present study and Murphy’s is that a third of the infants in the latter investigation were at term with 18 per cent of these developing RDS. This study includes only infants of less than 37 weeks’ gestation since, in the experience of our maternity hospital, RDS is virtually nonexistent after this period; in fact, only one of the 283 infants at
The authors are grateful to the Department of Neonatology of the Royal Victoria Hospital, headed by Dr. R. H. Usher, for information on newborn infants and blood specimens. We also wish to thank all physicians and nurses who assisted in the collection of cord blood.
REFERENCES 1. Usher,
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R. H.: Clinical implications of perinatal mortality statistics, Clin. Obstet. Gynecol. 14: 885, 1971. Gluck, L.., and Kulovich, M. V.: Fetal lung development: Current concepts, Pediatr. Clin. North Am. 20: 367, 1973. Brown, B. J., Gabert, H. A., and Stenchever, M. A.: Respiratory distress syndrome, surfactant biochemistry, and acceleration of fetal lung maturity: A review, Obstet. Gynecol. Survey 30: 71, 1975. Kotas, R. V., Fletcher, B. D., Torday, J., and Avery, M. E.: Evidence for independent regulators of organ maturation in fetal rabbits, Pediatrics 47: 57, 1971. DeLemos, R. A., Shermetta, D. W., Knelson, j. G., Kotas, R., and Avery, M. E.: Acceleration of appearance of pulmonary surfactant in the fetal lamb by administration of corticosteroids, Am. Rev. Resp. Dis. 102: 459, 1970. Naeye, R. L., Harcke, H. T., and Blanc, W. A.: Adrenal gland structure and the development of hyaline membrane disease, Pediatrics 47: 650, 1971. G. B.: Cortisol levels in Sybulski, S., and Maughan, umbilical cord plasma in relation to labor and delivery, AM. J. OBSTET. GYNECOL. 125: 236, 1976. Usher. R. H.: The respiratory distress syndrome of prematurity: clinical and therapeutic aspects, Pediatr. Clin. North Am. 8: 525, 1961. Sybulskl, S., and Maughan, G. B.: A rapid method for the measurement of estradiol and hydrocortisone levels in maternal and fetal blood and amniotic fluid, AM. J. OBSTET. GYNECOL. 121: 32,1975. Sybulski, S., and Maughan, G. B.: Umbilical cord plasma estradiol levels in relation to complications of pregnancy and newborn and to cortisol levels, Biol. Neonate 27: 302, 1975. Boughton. K., Gandy, G., and Gairdner, D.: Hyaline
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membrane disease: Il. Lung lecithin, Arch. Dis. Child 45: 311, 1970. Gabert, H. A., Bryson, M. J., and Stenchever, M. A.: The effect of cesarean section on respiratory distress in the presence of a mature lecithin-sphingomyelin ratio, AM. J. OBSTET. GYNECOL. 116: 366, 1973. Reynolds, J. W.: Serum total corticoid and cortisol levels in premature infants with respiratory distress syndrome. Pediatrics 51: 884, 1973. Klein, G. P., Baden, M., and Giroud, C. J. P.: Quantitative measurement and significance of five plasma corticosteroids during the perinatal period, J, &in. Endocrinol. Metab. 36: 944, 1973. Murphy, B. E. P.: Cortisol and cortisone levels in the cord blood at delivery of infants with and without the respiratory distress syndrome, AM. J. OBSTET. GYNECOL. 119: 1112, 1974. Conly, P. W., LeMaire, W. J., Monkus, E. F., and Cleveland, W. W.: Plasma estriol concentration in infants with the respiratory distress syndrome, J. Pediatr. 83: 851, 1973. E. H.: The possibility of Sybulski, S., and Venning, corticosteroid production by human and rat placental tissue under in vitro conditions, Can. J. B&hem. 39: 203, 1961. Murphy, B. E. P., Clark, S. J., Donald, I. R., Pinsky, M., and Vedady, D.: Conversion of maternal cortisol to cortisone during placental transfer in the human fetus, AM. J. OBSTET. GYNECOL. 11% 538, 1974. Diczfalusy, E.: Endocrine functions of the human fetus and placenta, AM. J. OBSTET. GYNECOL. 119: 419, 1974. Liggins, G. C., and Howie, R. N.: A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants, Pediatrics 50: 515, 1972.
Course in Gynecologic Laparoscopy The
New
Jersey
Fertility
Foundation
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sponsoring
a
course
in
“Gynecologic
Laparoscopy,
” to be held June 3 and 4, 1976, at Roselle Park, New Jersey. For further
information,
contact:
07204.
Dr.
S. A. Wilchins,
(in a
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Ave.,
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