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Effects of hydrocortisone on lecithin-sphingomyelin ratio
CURRENT INVESTIGATION
I---
This section offers prompt first announcement of new observations or discoveries. Articles should be limited to 1,500 words and six references. Illustrations or additional references require a proportionate reduction in total words.
I
Effects of hydrocortisone on lecithin-sphingomyelin FREmDERICK
P. ZUSPAN,
LEANDRO STEFAN Columbus,
CORDERO, SEMCHYSHYN,
ratio
M.D. M.D. M.D.
Ohio
An intravenous infusion of hydrocortisone succinate was given in four divided doses during a 24 hour period to 17 high-risk pregnant women to accelerate fetal pulmonary maturity. Amniocentesis was performed before and 48 to 72 hours after treatment in all 17 patients. Comparisoni were made of lecithinlsphingomyelin (L/S) ratios before and after treatment. The L/S ratio rose in 12 of the 17 cases and was not influenced by the type or severity of maternal disease. Neither length of rupture of the membranes nor gestational age at the time of treatment affected the change in L/S ratio. Pretreatment L/S ratios (1.21 2 0.435 S.D.) ‘were found to have a statistically significant difference from posttreatment values (2.31 2 1.52 SD.) at the p < 0.01 level. (AM. J. OBSTET. GYNECOL. 128: 571, 1977.)
LECITHIN-!SPHINGOMYELIN (L/S) ratios in amniotic fluid are widely accepted biochemical markers of pulmonary maturity with a predictive value as to the incidence and severity of hyaline membrane disease. Corticosteroids have been shown to enhance lung maturation. .4dministration of corticosteroids to pregnant women is believed to increase the L/S ratio, although there is no agreement among investigators as to the magnitude, timing, and consistency of such changes.* Liggins and Howie’ reported that L/S ratios were unaffected by intramuscular administration of
From t/ze Departments of Obstetrics and Gynecology Pediatrics, The Ohio State University, College of Medicine.
betamethasone acetate and phosphate. A comparison of two glucocorticoid regimens (intravenous hydrocortisone and intramuscular betamethasone) for acceleration of pulmonary maturity has shown that intravenous cortisol has a more rapid and profound effect on the fetal hypothalamic-adrenal axis.3 This study evaluates the L/S ratio changes following the administration of intravenous hydrocortisone sodium succinate* to highrisk pregnant women.
Material and methods This study took place between January, 19’75, and December, 1976. Fifty-nine high-risk obstetric patients qualified for antepartum corticosteroid treatment. Selection criteria included: (1) premature labor, (2)
and
Reprin.t requests: Dr. Frederick P. Zuspan, The Ohio State University, Department of Obstetrics and Gynecology, 410 W. 10th Ave., Columbus, Ohio 43210.
*Solu-Cortef, 49001. 571
The
Upjohn
Co.,
Kalamazoo,
Michigan
572
Zuspan, Cordero, and Semchyshyn
Table
I. Clinical
information
and
biochemical
data I, i.7 MliO
CUSP 1v 0.
Obstetric
1 2 3 4 5 6 7
Gcstcrlionnl ngr* (?~r~ek\J
complication
Pyelonephritis-PROM PROM Premature labor Pre-eclampsia Vaginal bleeding Pre-eclampsia Hypertension-diabetes (Class B), positive oxytocin challenge test Erythroblastosis Hypertension Renal failure and hypertension Pre-eclampsia IUGR PROM PROM Chronic hypertension Hypertension, obesity PROM and uncertain dates
8 9 10 11 12 13 14 15 16 17
Pretrrntment
31 31 32 32 32 32 33
n..r I 1 1 1 1 1
1 1 I 2 2 I I
33 34 34 34 35 35 36 37 37 37
2 2 2 1 1 1.5 1 I 1 I.5
7 3 3 2 1 2.5 3 2 4 2.7
IUGR = Intrauterine growth retardation; PROM = premature rupture *At the time of initial L/S ratio. tlnterval: Time elapsed between pre- and posttreatment samples. SROM: Time elapsed between ROM and posttreatment sample. $Died from severe RDS on Day 3.
Table
II. Corticosteroid
Posttrrntmenl
of membranes.
effects on L/S ratios No. of
Year
Author
Glucocorticoid
1973 1974
Spellacy et al Liggins and
Dexamethasone Betamethasone
1975
Schwenzel and associates’ Caspi and
1976 1977
Howie’ Betamethasone Dexamethasone
associates’ Present
*Interval
report between
Hydrocortisone L/S ratio
Route Oral Intramuscular Intramuscular Intramuscular Intravenous
Intewal*
Dosage
0.5 mg./day 6.0 mg.lday
x x
10.5 mg every 4.0 mg. 3 times 1 Gm.
4 times
1% 2 12 hours a day
x 2 x 1-7
a day x 1
patients
Cases with LIS t-nrreases
2 weeks Up to 6 days
10 ?
2-7 days
I1
3 to lOdays
10
lO/lO
2 to 3 days
17
12117
10110
Unchanged 617 I
determinations.
premature rupture of membranes, (3) estimated fetal weight less than 2,500 grams, (4) maternal disease necessitating premature termination of pregnancy, and (5) delivery that could be deferred for at least 48 hours. An additional selection criterion included a pretreatment L/S ratio less than 2 to 1 (50 of 59 patients). A mature L/S ratio in our laboratories is considered 3 to 1. If the patient fulfilled the above criteria, 1 Gm. of hydrocortisone succinate was given every six hours for four doses (4 Gm. in 24 hours). Premature labor, if present, as determined by clinical and electronic monitoring, was treated with intravenous alcohol which was often supplemented with intramuscular isoxsuprine hydrochloride* to stop uterine activity. Analysis of amniotic fluid samples was done with
standard techniques, and LB ratio determinations were made by thin-layer chromatography and transmission densitometry. Seventeen of 59 patients studied qualified for the rigid selection criteria in this report which includedprrand post-treatment LIS ratios of no more than 72 hours apart. Gestational age at the time of treatment was determined retrospectively by neonataf developmental assessment (Dubowitz).
Rssults Clinical and biochemical information Table I which shows that hypertension *Vasodilan, diana 4772 1.
Mead
Johnson
Laboratories,
is presented in in pregnancy Evansville,
In-
Hydrocortisone effects on L/S ratio
Volume 128 Number 5
was the most common high-risk factor (seven patients). Treatment did not worsen any maternal condition, and no fetal deaths were recorded. One infant (Case 7) died at three days of age of severe hyaline membrane disease, This infant showed no change in L/S ratio after therapy. Another infant (Case 1) presented mild transient respiratory distress. ,411 other infants were free of any neonatal illness. Most of our patients were delivered two or more weeks after treatment. The major issue in this report is to evaluate the effect of maternal intravenous hydrocortisone on L/S ratios rather than clinical implications of its use. Gestational ages ranged from 3 1 to 37 weeks for the entire group and between 31 and 35 weeks for 13 of the 17 patients. The Dubowitz score for gestational age agreed with that obtained from the obstetric history in 13 of these 17 cases. The L/S ratios increased in 12 and did not change in five of 17 patients (Fig. 1). Over-all values when pretreatment L/S ratios (1.21 & 0.435 S.D.), were compared with posttreatment ratios (2.31 ? 1.52 S.D.) were found to be statistically significant by a metametric t test (p < 0.01).
Comment Severe pre-eclampsia, cardiovascular and renal disease, severe diabetes, placental insufficiency, infection, and prolonged rupture of the membranes are some of the conditions believed to accelerate maturation of the fetal lungs (2). The patients in this study who presented these complications did not have elevated L/S ratios prior to therapy. It has been shown that ruptured membranes (ROM) accelerated L/S ratios”; however, in this study, four of five patients with ROM and eight of 12 patients with intact membranes had increased L/S ratios after therapy. There may be a best time for treatment in which better clinical results can be achieved, and this may also be the ideal time for changes in the L/S ratio. We were able to observe changes in L/S ratio in three of the six cases at 31 to 32 weeks of gestation and nine of the 11 with1 gestations varying from 33 to 37 weeks. It is important that all investigators agree on a uniform way of documenting gestational age. There was agreement between pediatric and obstetric calculation of gestational age in only 13 of 17 cases in this study.
573
76s0
4-
h v)
3-
ii-
2I -
0’ BER31K AFTER IRDIVIDUAL VAUfES
BEFWE
AFTER
Fig. 1. Individual L/S ratios are on the left of the graph. On the right are mean values. The pretreatment mean value of 1.21 (S.D. + 0.435) rose to a mean value after treatment of 2.31 (SD. f 1.52). These values found by a t test were significant at the p < 0.01 level. The time factor between treatment and L/S ratio changes seemed critical to us. We arbitrarily chose an interval of 48 to 72 hours between the first and the repeated amniocentesis. This time was chosen for better interpretation of our results by limiting variables such as time, urgency of delivery, and effect of other factors. It is unlikely that any change in the L/S ratio would occur by chance with this short period of time. As it can be seen in Table II, other studies did not control those variables. Pharmacologic responses to different glucocorticosteroids has been clearly documented by Whitt and associates3 in their studies of the fetal hypothalamicadrenal axis challenged transplacentally and evaluated as the percentage of supression of unconjugated estriol at different posttreatment intervals. We chose to utilize hydrocortisone in this study since it was most rapid and profound in its effects upon the supression of maternal estriol. The assumption was made that a similar effect on fetal pulmonary maturity would occur. We have proved our original hypothesis that hydrocortisone given to the mother will alter the L/S ratio. The one question which remains unanswered is the long-term effect of corticosteroid therapy on growth and development.
REFERENC:ES
1. Liggins, G. C., and Howie, R. N.: The Prevention of R.D.S. by Maternal Steroid Therapy, in Gluck, L., editor: Modern Perinatal Medicine, Chicago, 1974, Year Book Medical Publishers, Inc.
2. Gluck, L.: Administration of corticosteroids to induce maturation of Fetal Lung, Am. J. Dis. Child. 130: 976, 1976. 3. Whitt, G. G., Buster, J. E., Killam, A. P., and Scragg, W.
574
Zuspan, Cordero, and Semchyshyn
I-1.: A comparison of two glucocorticoid regimens releration of fetal lung maturation in premature AM.J.
OBSTET.
CYNECOL.
124:479,
for aclabor,
1976.
4. Richardson, C. J., Pomeranee, J. J., Cunningham, M. P., and Gluck, L.: Acceleration of fetal lung maturation following prolonged rupture of membranes, AM. J. OBSTET. GYNECOL.
5. Caspi,
118:1115,1974.
F.., Schreyer.
P.. Weinraub.
Z., Reif,
R.. Levi,
1.. and
Mundel. G.: Prevention of the respirator! distress s);ndrome in premature infants by antepartum glut-oc ortic~~id therapy, Br. J. Obstet. Gynaecol. 83: 187, 1976. 6. Schwenzrl. U’., Jung, H., Lahmann. tl.. ~,UIIXII. A.. Sticherling, C., Korz, K.. Liedtke. B., and ChantI-sine, H.: Erste Erfahrungen mit der praenatalen Beeinflussung der kindlichen Lungenreife durch Betamethason. Z. Geburtshilfe Perinator 179: 45, 1975
I---
This section offers prompt first announcement of new observations or discoveries. Articles should be limited to 1,500 words and six references. Illustrations or additional references require a proportionate reduction in total words.
I
Effects of hydrocortisone on lecithin-sphingomyelin FREmDERICK
P. ZUSPAN,
LEANDRO STEFAN Columbus,
CORDERO, SEMCHYSHYN,
ratio
M.D. M.D. M.D.
Ohio
An intravenous infusion of hydrocortisone succinate was given in four divided doses during a 24 hour period to 17 high-risk pregnant women to accelerate fetal pulmonary maturity. Amniocentesis was performed before and 48 to 72 hours after treatment in all 17 patients. Comparisoni were made of lecithinlsphingomyelin (L/S) ratios before and after treatment. The L/S ratio rose in 12 of the 17 cases and was not influenced by the type or severity of maternal disease. Neither length of rupture of the membranes nor gestational age at the time of treatment affected the change in L/S ratio. Pretreatment L/S ratios (1.21 2 0.435 S.D.) ‘were found to have a statistically significant difference from posttreatment values (2.31 2 1.52 SD.) at the p < 0.01 level. (AM. J. OBSTET. GYNECOL. 128: 571, 1977.)
LECITHIN-!SPHINGOMYELIN (L/S) ratios in amniotic fluid are widely accepted biochemical markers of pulmonary maturity with a predictive value as to the incidence and severity of hyaline membrane disease. Corticosteroids have been shown to enhance lung maturation. .4dministration of corticosteroids to pregnant women is believed to increase the L/S ratio, although there is no agreement among investigators as to the magnitude, timing, and consistency of such changes.* Liggins and Howie’ reported that L/S ratios were unaffected by intramuscular administration of
From t/ze Departments of Obstetrics and Gynecology Pediatrics, The Ohio State University, College of Medicine.
betamethasone acetate and phosphate. A comparison of two glucocorticoid regimens (intravenous hydrocortisone and intramuscular betamethasone) for acceleration of pulmonary maturity has shown that intravenous cortisol has a more rapid and profound effect on the fetal hypothalamic-adrenal axis.3 This study evaluates the L/S ratio changes following the administration of intravenous hydrocortisone sodium succinate* to highrisk pregnant women.
Material and methods This study took place between January, 19’75, and December, 1976. Fifty-nine high-risk obstetric patients qualified for antepartum corticosteroid treatment. Selection criteria included: (1) premature labor, (2)
and
Reprin.t requests: Dr. Frederick P. Zuspan, The Ohio State University, Department of Obstetrics and Gynecology, 410 W. 10th Ave., Columbus, Ohio 43210.
*Solu-Cortef, 49001. 571
The
Upjohn
Co.,
Kalamazoo,
Michigan
572
Zuspan, Cordero, and Semchyshyn
Table
I. Clinical
information
and
biochemical
data I, i.7 MliO
CUSP 1v 0.
Obstetric
1 2 3 4 5 6 7
Gcstcrlionnl ngr* (?~r~ek\J
complication
Pyelonephritis-PROM PROM Premature labor Pre-eclampsia Vaginal bleeding Pre-eclampsia Hypertension-diabetes (Class B), positive oxytocin challenge test Erythroblastosis Hypertension Renal failure and hypertension Pre-eclampsia IUGR PROM PROM Chronic hypertension Hypertension, obesity PROM and uncertain dates
8 9 10 11 12 13 14 15 16 17
Pretrrntment
31 31 32 32 32 32 33
n..r I 1 1 1 1 1
1 1 I 2 2 I I
33 34 34 34 35 35 36 37 37 37
2 2 2 1 1 1.5 1 I 1 I.5
7 3 3 2 1 2.5 3 2 4 2.7
IUGR = Intrauterine growth retardation; PROM = premature rupture *At the time of initial L/S ratio. tlnterval: Time elapsed between pre- and posttreatment samples. SROM: Time elapsed between ROM and posttreatment sample. $Died from severe RDS on Day 3.
Table
II. Corticosteroid
Posttrrntmenl
of membranes.
effects on L/S ratios No. of
Year
Author
Glucocorticoid
1973 1974
Spellacy et al Liggins and
Dexamethasone Betamethasone
1975
Schwenzel and associates’ Caspi and
1976 1977
Howie’ Betamethasone Dexamethasone
associates’ Present
*Interval
report between
Hydrocortisone L/S ratio
Route Oral Intramuscular Intramuscular Intramuscular Intravenous
Intewal*
Dosage
0.5 mg./day 6.0 mg.lday
x x
10.5 mg every 4.0 mg. 3 times 1 Gm.
4 times
1% 2 12 hours a day
x 2 x 1-7
a day x 1
patients
Cases with LIS t-nrreases
2 weeks Up to 6 days
10 ?
2-7 days
I1
3 to lOdays
10
lO/lO
2 to 3 days
17
12117
10110
Unchanged 617 I
determinations.
premature rupture of membranes, (3) estimated fetal weight less than 2,500 grams, (4) maternal disease necessitating premature termination of pregnancy, and (5) delivery that could be deferred for at least 48 hours. An additional selection criterion included a pretreatment L/S ratio less than 2 to 1 (50 of 59 patients). A mature L/S ratio in our laboratories is considered 3 to 1. If the patient fulfilled the above criteria, 1 Gm. of hydrocortisone succinate was given every six hours for four doses (4 Gm. in 24 hours). Premature labor, if present, as determined by clinical and electronic monitoring, was treated with intravenous alcohol which was often supplemented with intramuscular isoxsuprine hydrochloride* to stop uterine activity. Analysis of amniotic fluid samples was done with
standard techniques, and LB ratio determinations were made by thin-layer chromatography and transmission densitometry. Seventeen of 59 patients studied qualified for the rigid selection criteria in this report which includedprrand post-treatment LIS ratios of no more than 72 hours apart. Gestational age at the time of treatment was determined retrospectively by neonataf developmental assessment (Dubowitz).
Rssults Clinical and biochemical information Table I which shows that hypertension *Vasodilan, diana 4772 1.
Mead
Johnson
Laboratories,
is presented in in pregnancy Evansville,
In-
Hydrocortisone effects on L/S ratio
Volume 128 Number 5
was the most common high-risk factor (seven patients). Treatment did not worsen any maternal condition, and no fetal deaths were recorded. One infant (Case 7) died at three days of age of severe hyaline membrane disease, This infant showed no change in L/S ratio after therapy. Another infant (Case 1) presented mild transient respiratory distress. ,411 other infants were free of any neonatal illness. Most of our patients were delivered two or more weeks after treatment. The major issue in this report is to evaluate the effect of maternal intravenous hydrocortisone on L/S ratios rather than clinical implications of its use. Gestational ages ranged from 3 1 to 37 weeks for the entire group and between 31 and 35 weeks for 13 of the 17 patients. The Dubowitz score for gestational age agreed with that obtained from the obstetric history in 13 of these 17 cases. The L/S ratios increased in 12 and did not change in five of 17 patients (Fig. 1). Over-all values when pretreatment L/S ratios (1.21 & 0.435 S.D.), were compared with posttreatment ratios (2.31 ? 1.52 S.D.) were found to be statistically significant by a metametric t test (p < 0.01).
Comment Severe pre-eclampsia, cardiovascular and renal disease, severe diabetes, placental insufficiency, infection, and prolonged rupture of the membranes are some of the conditions believed to accelerate maturation of the fetal lungs (2). The patients in this study who presented these complications did not have elevated L/S ratios prior to therapy. It has been shown that ruptured membranes (ROM) accelerated L/S ratios”; however, in this study, four of five patients with ROM and eight of 12 patients with intact membranes had increased L/S ratios after therapy. There may be a best time for treatment in which better clinical results can be achieved, and this may also be the ideal time for changes in the L/S ratio. We were able to observe changes in L/S ratio in three of the six cases at 31 to 32 weeks of gestation and nine of the 11 with1 gestations varying from 33 to 37 weeks. It is important that all investigators agree on a uniform way of documenting gestational age. There was agreement between pediatric and obstetric calculation of gestational age in only 13 of 17 cases in this study.
573
76s0
4-
h v)
3-
ii-
2I -
0’ BER31K AFTER IRDIVIDUAL VAUfES
BEFWE
AFTER
Fig. 1. Individual L/S ratios are on the left of the graph. On the right are mean values. The pretreatment mean value of 1.21 (S.D. + 0.435) rose to a mean value after treatment of 2.31 (SD. f 1.52). These values found by a t test were significant at the p < 0.01 level. The time factor between treatment and L/S ratio changes seemed critical to us. We arbitrarily chose an interval of 48 to 72 hours between the first and the repeated amniocentesis. This time was chosen for better interpretation of our results by limiting variables such as time, urgency of delivery, and effect of other factors. It is unlikely that any change in the L/S ratio would occur by chance with this short period of time. As it can be seen in Table II, other studies did not control those variables. Pharmacologic responses to different glucocorticosteroids has been clearly documented by Whitt and associates3 in their studies of the fetal hypothalamicadrenal axis challenged transplacentally and evaluated as the percentage of supression of unconjugated estriol at different posttreatment intervals. We chose to utilize hydrocortisone in this study since it was most rapid and profound in its effects upon the supression of maternal estriol. The assumption was made that a similar effect on fetal pulmonary maturity would occur. We have proved our original hypothesis that hydrocortisone given to the mother will alter the L/S ratio. The one question which remains unanswered is the long-term effect of corticosteroid therapy on growth and development.
REFERENC:ES
1. Liggins, G. C., and Howie, R. N.: The Prevention of R.D.S. by Maternal Steroid Therapy, in Gluck, L., editor: Modern Perinatal Medicine, Chicago, 1974, Year Book Medical Publishers, Inc.
2. Gluck, L.: Administration of corticosteroids to induce maturation of Fetal Lung, Am. J. Dis. Child. 130: 976, 1976. 3. Whitt, G. G., Buster, J. E., Killam, A. P., and Scragg, W.
574
Zuspan, Cordero, and Semchyshyn
I-1.: A comparison of two glucocorticoid regimens releration of fetal lung maturation in premature AM.J.
OBSTET.
CYNECOL.
124:479,
for aclabor,
1976.
4. Richardson, C. J., Pomeranee, J. J., Cunningham, M. P., and Gluck, L.: Acceleration of fetal lung maturation following prolonged rupture of membranes, AM. J. OBSTET. GYNECOL.
5. Caspi,
118:1115,1974.
F.., Schreyer.
P.. Weinraub.
Z., Reif,
R.. Levi,
1.. and
Mundel. G.: Prevention of the respirator! distress s);ndrome in premature infants by antepartum glut-oc ortic~~id therapy, Br. J. Obstet. Gynaecol. 83: 187, 1976. 6. Schwenzrl. U’., Jung, H., Lahmann. tl.. ~,UIIXII. A.. Sticherling, C., Korz, K.. Liedtke. B., and ChantI-sine, H.: Erste Erfahrungen mit der praenatalen Beeinflussung der kindlichen Lungenreife durch Betamethason. Z. Geburtshilfe Perinator 179: 45, 1975