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sphingomyelin ratio in pregnancies complicated by diabetes mellitus
Lecithin/ sphingomyelin ratio in pregnancies complicated by diabetes mellitus STEVEN G. GABBE, M.D. RICHARD I. LOWENSOHN, M.D. JORGE H. MESTMAN, M.D. ROGER K. FREEMAN, M.D. UWE GOEBELSMANN, M.D. Los Angeles, California The amniotic fluid lecithin/sphingomyelin (LIS) ratio was determined in 182 pregnancies complicated by Classes B and C diabetes and in 28 patients with Classes D, F. and R diabetes. These data were retrospectively correlated with the occurrence of the respiratory distress syndrome (RDS) or hyaline membrane disease (HMO). Only four cases of RDS and two cases of HMO were observed in 200 patients with an LIS ratio of 2.0 or greater prior to delivery. This 3 per cent incidence of complications is no higher than that of the nondiabetic population in our institution. Seven of 10 neonates with an antenatal LIS ratio of 1.5 to 1.9 developed RDS. An L/S ratio of 2.0 or more appears to be a reliable predictor of fetal pulmonary maturity even in pregnancies complicated by diabetes meHitus. (AM. J. 0BSTET. GYNECOL. 128: 757, 1977.}
St:DDEN, AND OFTEN unexplained, intrauterine deaths are a major component of the perinatal mortality rate in the pregnancy complicated by diabetes mellitus. Attempting to decrease these losses, obstetricians have electively terminated such pregnancies between 33 and 37 weeks' gestation. 1 This approach has been associated with significant neonatal morbidity and death due to hyaline membrane disease (HMD). 2 The lecithin/sphingomyelin (LIS) ratio in amniotic fluid has been accepted as a useful indicator of fetal pulmonary maturity,3 but its prognostic value in pregnancies complicated by diabetes mellitus has been questioned. 4 The present study examines the usefulness of the L/ S ratio in the management of 210 overtly diabetic women at Los Angeles County-University of
Southern California Medical Center Women's Hospital during the period January, 1971, to June, 1976. Material and methods
The LIS ratio was measured in duplicate in 210 amniotic fluid samples with the Borer modification of the original method of Gluck and associates. 3 The final LIS ratio was determined by planimetry. Samples were obtained by transabdominal amniocentesis from diabetic women on the antenatal high-risk ward. Twenty-six specimens contaminated by blood or meconium have been excluded from this study. Gestational age was assessed with the use of the patient's menstrual history, ultrasound studies, and the pediatrician's assessment of neonatal maturity. Retrospective analysis of all newborn charts was initially performed to evaluate neonatal respiratory status. The diagnosis of respiratory distress syndrome (RDS) was based on physical examinations, clinical course, blood gas studies, and x-ray findings.' Infants requiring artificial ventilation were diagnosed as having severe RDS. Autopsy findings were used to establish the presence of HMD. Infants suffering from transient tachypnea, sepsis, meconium aspiration, congenital heart disease, or trauma were excluded from the RDS group. The L/S ratio was not known by the pediatrician or radiologist reviewing the charts and x-ray films to de-
From the Department of Obstetrics and Gynecology, University of Southern California. Computing assistance was obtained from the Health Sciences Computing Facility, University of California Los Angeles, supported by National Institutes of Health Special Research Resources Grant RR-3.
Received for publication September 3, 1976. Revised February 17, 1977. Accepted February 28, 1977. Reprint requests: Dr. Steven G. Gabbe, Women's Hospital, 5K9 1240 N. Mission Rd., Los Angeks, California 90033.
757
758
Gabbe et al. Am.
J
August 1, !977 Obstet. Gvneml.
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::J 30
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2.0
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• 10
30 31 32 33 34 35 36 37 38 39 40
WEEKS
WEEKS
Fig. I. Plot of mean LIS ratio versus gestational age in 182 Class B and C diabetic patients. Two standard errors of the mean are represented by the bars. The numbers in parentheses represent the number of amniotic fluid specimens analyzed at each week of gestation.
Fig. 2. Plot of mean LIS ratio versus gestational age in 28 Class D, F, and R diabetic patients. Two standard error~ of ihe mean are represented by the bars. The numbers in parentheses represent the number of amniotic fluid specimen~ analyzed at each week of gestation.
teet the presence of RDS or HMD or the absence of these complications. Unless otherwise noted, statistical significance was determined with chi-square analysis.
sacral agenesis. Five of the six neonates who developed RDS or HMD with an LIS ratio over 2 had good fiveminute Apgar scores. In one patient with Class C diabetes, however, daily 24 hour urine estriol levels suddenly fell over 50 per cent. An emergency ce~arean section was performed with delivery of an infant with Apgar scores of 3 and 3 and an umbilical arterial pH of 6.9. The infant died of HMD despite an LIS ratio of 2.6. An infant of a mother with Class B diabetes had HMD and died, but death was attributed to bowel perforation secondary to necrotizing enterocolitis. Of the neonates with an L/S ratio greater than 2 who developed RDS or HMD, four were delivered by cesar:ean section and two were delivered vaginally. The 3 per cent incidence of RDS and HMD in 200 infants of diabetic women with LIS ratios of 2.0 or greater is not significandy different from the 2:6 per cent incidence observed in 270 nondiabetic patients previously studied in our institution.6 Of the 200 patients with LIS ratios of2.0 or greater, 122 were delivered of their infants within one week of amniocentesis (Table II). AU six cases of RDS and HMD with a mature LIS ratio occurred in this group.
ResuHs The LIS ratio was determined in 182 patients with Classes B and C diabetes and in 28 patients with Classes D, F, and R diabetes. 5 LIS ratios increased with advancing gestational age (Figs. l and 2). Two hundred infants with an LIS ratio of 2.0 or greater were delivered, while l 0 had values between 1.5 and 1. 9. Only three of the 133 LIS ratios determined after 36 weeks' gestation were less than 2.0. The mean LIS ratio preceding delivery at each gestational age was not significantly different for Classes Band C versus Classes D, F, and R, with the use of the nonparametric Mann-Whitney U test. Of the 210 infants studied, II had RDS, while two neonates were found to have HMD at autopsy. Four cases of RDS and both cases of HMD occurred in the 200 patients with an LIS ratio of 2 or greater prior to delivery (Table 1). The only case of severe RDS was observed in an infant with congenital heart disease and
LIS ratio in pregnancies complicated by diabetes
Volume 128 ~umber
Table I. Cases of RDS and deaths from HMD among newborn infants with LIS ratios ~2.0 Dia-
Weeks'
betes
gestation
Infant birth weight (Gm.)
35 36 35 33 38 38
2,050 3,410 3,020 1,280 2,880 4,564
Class B B
D .F B
c
759
7
LIS ratio
Apgar scores
2.3
8/9
2.4
2/7 718 9/9 8/9 3/3
2.4 2.4
2.1 2.6
Table II. Incidence of RDS and death from HMD among newborn infants with LIS ratios :2:2.0 Interval*
HMD
43 22 13 44 78
l 1 l l 0
0 I 0 1
2
0
0
9 8 5 0
200
4
2
6
3
Outcome
RDS RDS RDS Severe RDS HMD-died HMD-died
o524 hr. 24-48 hr. 48-72 hr. 72 hr.-1 wk. >1 wk.
Total
Total LVO.
RDS
No.
1 2 l
%
2
*Indicates time from amniocentesis to delivery.
Only one infant of the 43 delivered within 24 hours after determination of a mature LIS ratio developed RDS. Ten infants had LIS ratios of 1.5 to 1.9. Seven of these infants were delivered within one day of the amniocentesis. RDS occurred in seven neonates, but no deaths resulted. This high incidence of RDS with an immature LIS ratio is similar to the 63 per cent figure reported in nondiabetic patients studied at our institution.6 Pre-eclampsia occurred in a total of 21 patients, 17 in patients with Classes B and C diabetes and four in patients with Classes D, F, and R diabetes. None of these neonates developed RDS or HMD. Nineteen infants had LIS ratios greater than 2.0, and two had values of 1.5 and 1.9. A significant difference in the LIS ratio at each gestational age could not be demonstrated between the pre-eclamptic and normotensive patients. Comment
During the past five years, we have found the LIS ratio to be a valuable tool i~ the management of the pregnant diabetic woman. An LIS ratio of 2.0 or greater has been associated with a 3 per cent incidence of RDS and HMD. Infants of diabetic mothers delivered soon after the determination of a mature L/S ratio are not at greater risk for RDS than infants of the nondiabetic population in our hospital. Several other authors have also recently reported a low incidence of RDS with an LIS ratio of 2.0 or greater in pregnancies complicated by diabetes. 7 • 8 Intrauterine asphyxia and neonatal acidosis may lead to RDS despite a mature LIS ratio. Only one death due to HMD occurred in 200 infants of diabetic women with an LIS ratio of 2.0 or greater. As described previously, the neonate was asphyxiated at delivery. The 0.5 per cent incidence of death resulting from HMD despite a mature LIS ratio is not significantly different from that of our nondiabetic patients.6 Many investigators continue to question the reliabil-
ity of an LIS ratio of 2.0 or greater as an indicator of pulmonary maturity in infants of diabetic patients. This impression may have arisen because few patients were studied,9 because other causes of respiratory distress have not been excluded,9 or because the original technique of Gluck and associates has been modified. 10 Occasionally, the acetone-precipitation step which isolates the most surface-active lecithin fraction has been eliminated.3 Kulovich and Gluck11 also stressed that a densitometer be used to determine the L/S ratio in diabetes. They noted that an abnormal sphingomyelin value may appear in a very small number of cases of diabetes. The extreme denseness of the sphingomyelin on chromatography yields a small spot which could give a false high LIS ratio by planimetry. In our experience, the planimetric method has. been very satisfactory. A terminal decline in the LIS ratio or a failure of the ratio to rise has been demonstrated in diabetic patientsP Serial ratios were not investigated in our series. However, those infants delivered more than 72 hours after determination of a mature L/S ratio did not demonstrate an increased incidence of RDS. A mature LIS ratio can be observed earlier in gestation in Classes D, F, and R pregnancies or later in Classes B and C, according to some investigators. 13 • 14 Pre-eclampsia may also accelerate pulmonary maturity. Our data do not support these observations. Additional markers of antenatal lung maturity, phosphatidylinositol and phosphatidylglycerol, may prove to be valuable in pregnancies complicated by diabetes. 15 One of our patients, a Class C diabetic at 33 weeks' gestation, required elective induction of labor for severe pre-eclampsia. An LIS ratio obtained the day of delivery was 1.5, but further analysis revealed the presence of phosphatidylglycerol; RDS did not occur. The authors wish to thank Dr. Feizal Waffarn, Department of Pediatrics, and Dr. John Richmond, Department of Radiology; for their assistance in reviewing the neonatal records.
760 Gabbe et al. Am.
REFERENCES l. Gugliucci, C. L., O'Sullivan, M. J., Opperman, W., Gordon, M., and Stone, M. L.: Intensive care of the pregnant
diabetic, AM. J. OssTET. GYNECOL. 125: 435, 1976. 2. Driscoll, S. G., Benirschke, K, and Curtis, G. W.: Neonatal deaths among infants of diabetic mothers, Am. J. Dis. Child. 100: 818, 1961. 3. Gluck, L., Kulovich, 1vL V .. Borer, R. C., Jr., and Keidel, W. N.: The interpretation and significance of the lecithin/sphingomyelin ratio in amniotic fluid, AM. J. OsSTET. GYNECOL. 120: 142, 1974. 4. Farrell, P. M.: Indices of maturation in diabetic pregnancy, Lancet 1: 596, 1976. 5. White, P.: Pregnancy and diabetes, medical aspects. Med. Clin. North Am. 49: 1015, 1965. 6. Donald. J. R., Freeman, R. K., Goebelsmann, U., Chan, W. H., and Nakamura, R. M.: Clinical experience with the amniotic fluid lecithin/sphingomyelin ratio. I. Antenatal prediction of pulmonary maturity, A. M. J. 0BSTET. GYNECOL. 115: 54 7, 1973. 7. Tchobroutsky, C., Cedard, L., Rouvillois, J. L., and Amiel-Tison, C.: The lecithin/sphingomyelin ratio in amniotic fluid in diabetic pregnancies treated with insulin, J. Gynecol. Obstet. Bioi. Reprod. 4: 93, 197 5. 8. Aubry, R. H., Rourke, j. E., Almanza, R., Cantor, R. M., and Van Doren, J. E.: The lecithin/sphingomyelin ratio in a high-risk obstetric population, Obstet. Gynecol. 47: 21, - 197~.
J
August I, 1977 Obstet. GyiH•col.
9. Cruz, A. C., Buhi, W. C., Birk, S. A .. and Spellacy. W. N.: Respiratory distress syndrome with mature lecithin/ sphingomyelin ratios: Diabetes mellitus and low Apgar scores, AM. J. OssTET. GYNECOL 126: 78, 1976. ! 0. Dunn. L j.. Bush, C., Davis, S. E., Til. and Bhatnagar. A. S.: Use of laboratory and clinical factors in the management of pregnancies complicated by maternal disease. AM. j. 0BSTET. CYNECOL. 120: 522, 1971. 11. Kulovich, M. V., and Gluck, L.: Maturation of the fetal lung in offspring of diabetic mothers. in CameriniDavalos, R. A., and Cole, H. S., editors: Early Diabetes in Early Life, New York, 1975, Academic Press, Inc, p. 531. 12. Whitfield, C. R .. Sproule, W. B., and Brudenell, M.: The amniotic fluid lecithin/sphingomyelin area ratio in pregnancies complicated by diabetes, Br. J. Obstet. Gvnaecol. 80: 918, 1973. 13. Gluck, L., and Kulovich, M. V.: Lecithin/spjlingomyelin ratios in amniotic fluid in normal and abnormal pregnancy, .A.M. J. 0BSTET. GYNECOL. 1!5: 539, 1973. 14. Singh, E. ] .. Mejia, A., and Zuspan, F. J.: Studies of human amniotic fluid phospholipids in normal, diabetic, and drug-abuse pregnancy, AM . .J. 0BSTET. GYNECOL. 119: 623, I 974. 15. Hallman, M., Kulovich, M.. Kirkpatrick, E., Sugarman, R. G., and Gluck, L.: Phosphatidylinositol and phosphatidylglycerol in amniotic fluid: Indices of lung maturity, AM. J. 0BSTET. GYNECOL. 125: 617. 1976.
St:DDEN, AND OFTEN unexplained, intrauterine deaths are a major component of the perinatal mortality rate in the pregnancy complicated by diabetes mellitus. Attempting to decrease these losses, obstetricians have electively terminated such pregnancies between 33 and 37 weeks' gestation. 1 This approach has been associated with significant neonatal morbidity and death due to hyaline membrane disease (HMD). 2 The lecithin/sphingomyelin (LIS) ratio in amniotic fluid has been accepted as a useful indicator of fetal pulmonary maturity,3 but its prognostic value in pregnancies complicated by diabetes mellitus has been questioned. 4 The present study examines the usefulness of the L/ S ratio in the management of 210 overtly diabetic women at Los Angeles County-University of
Southern California Medical Center Women's Hospital during the period January, 1971, to June, 1976. Material and methods
The LIS ratio was measured in duplicate in 210 amniotic fluid samples with the Borer modification of the original method of Gluck and associates. 3 The final LIS ratio was determined by planimetry. Samples were obtained by transabdominal amniocentesis from diabetic women on the antenatal high-risk ward. Twenty-six specimens contaminated by blood or meconium have been excluded from this study. Gestational age was assessed with the use of the patient's menstrual history, ultrasound studies, and the pediatrician's assessment of neonatal maturity. Retrospective analysis of all newborn charts was initially performed to evaluate neonatal respiratory status. The diagnosis of respiratory distress syndrome (RDS) was based on physical examinations, clinical course, blood gas studies, and x-ray findings.' Infants requiring artificial ventilation were diagnosed as having severe RDS. Autopsy findings were used to establish the presence of HMD. Infants suffering from transient tachypnea, sepsis, meconium aspiration, congenital heart disease, or trauma were excluded from the RDS group. The L/S ratio was not known by the pediatrician or radiologist reviewing the charts and x-ray films to de-
From the Department of Obstetrics and Gynecology, University of Southern California. Computing assistance was obtained from the Health Sciences Computing Facility, University of California Los Angeles, supported by National Institutes of Health Special Research Resources Grant RR-3.
Received for publication September 3, 1976. Revised February 17, 1977. Accepted February 28, 1977. Reprint requests: Dr. Steven G. Gabbe, Women's Hospital, 5K9 1240 N. Mission Rd., Los Angeks, California 90033.
757
758
Gabbe et al. Am.
J
August 1, !977 Obstet. Gvneml.
,,tl
u
I
T
,,,
40
I
Q ,_
0
~
j
_:,
a:
(f)
::J 30
~
0 I
1
2.0
0
I
0 I
"'
• 10
30 31 32 33 34 35 36 37 38 39 40
WEEKS
WEEKS
Fig. I. Plot of mean LIS ratio versus gestational age in 182 Class B and C diabetic patients. Two standard errors of the mean are represented by the bars. The numbers in parentheses represent the number of amniotic fluid specimens analyzed at each week of gestation.
Fig. 2. Plot of mean LIS ratio versus gestational age in 28 Class D, F, and R diabetic patients. Two standard error~ of ihe mean are represented by the bars. The numbers in parentheses represent the number of amniotic fluid specimen~ analyzed at each week of gestation.
teet the presence of RDS or HMD or the absence of these complications. Unless otherwise noted, statistical significance was determined with chi-square analysis.
sacral agenesis. Five of the six neonates who developed RDS or HMD with an LIS ratio over 2 had good fiveminute Apgar scores. In one patient with Class C diabetes, however, daily 24 hour urine estriol levels suddenly fell over 50 per cent. An emergency ce~arean section was performed with delivery of an infant with Apgar scores of 3 and 3 and an umbilical arterial pH of 6.9. The infant died of HMD despite an LIS ratio of 2.6. An infant of a mother with Class B diabetes had HMD and died, but death was attributed to bowel perforation secondary to necrotizing enterocolitis. Of the neonates with an L/S ratio greater than 2 who developed RDS or HMD, four were delivered by cesar:ean section and two were delivered vaginally. The 3 per cent incidence of RDS and HMD in 200 infants of diabetic women with LIS ratios of 2.0 or greater is not significandy different from the 2:6 per cent incidence observed in 270 nondiabetic patients previously studied in our institution.6 Of the 200 patients with LIS ratios of2.0 or greater, 122 were delivered of their infants within one week of amniocentesis (Table II). AU six cases of RDS and HMD with a mature LIS ratio occurred in this group.
ResuHs The LIS ratio was determined in 182 patients with Classes B and C diabetes and in 28 patients with Classes D, F, and R diabetes. 5 LIS ratios increased with advancing gestational age (Figs. l and 2). Two hundred infants with an LIS ratio of 2.0 or greater were delivered, while l 0 had values between 1.5 and 1. 9. Only three of the 133 LIS ratios determined after 36 weeks' gestation were less than 2.0. The mean LIS ratio preceding delivery at each gestational age was not significantly different for Classes Band C versus Classes D, F, and R, with the use of the nonparametric Mann-Whitney U test. Of the 210 infants studied, II had RDS, while two neonates were found to have HMD at autopsy. Four cases of RDS and both cases of HMD occurred in the 200 patients with an LIS ratio of 2 or greater prior to delivery (Table 1). The only case of severe RDS was observed in an infant with congenital heart disease and
LIS ratio in pregnancies complicated by diabetes
Volume 128 ~umber
Table I. Cases of RDS and deaths from HMD among newborn infants with LIS ratios ~2.0 Dia-
Weeks'
betes
gestation
Infant birth weight (Gm.)
35 36 35 33 38 38
2,050 3,410 3,020 1,280 2,880 4,564
Class B B
D .F B
c
759
7
LIS ratio
Apgar scores
2.3
8/9
2.4
2/7 718 9/9 8/9 3/3
2.4 2.4
2.1 2.6
Table II. Incidence of RDS and death from HMD among newborn infants with LIS ratios :2:2.0 Interval*
HMD
43 22 13 44 78
l 1 l l 0
0 I 0 1
2
0
0
9 8 5 0
200
4
2
6
3
Outcome
RDS RDS RDS Severe RDS HMD-died HMD-died
o524 hr. 24-48 hr. 48-72 hr. 72 hr.-1 wk. >1 wk.
Total
Total LVO.
RDS
No.
1 2 l
%
2
*Indicates time from amniocentesis to delivery.
Only one infant of the 43 delivered within 24 hours after determination of a mature LIS ratio developed RDS. Ten infants had LIS ratios of 1.5 to 1.9. Seven of these infants were delivered within one day of the amniocentesis. RDS occurred in seven neonates, but no deaths resulted. This high incidence of RDS with an immature LIS ratio is similar to the 63 per cent figure reported in nondiabetic patients studied at our institution.6 Pre-eclampsia occurred in a total of 21 patients, 17 in patients with Classes B and C diabetes and four in patients with Classes D, F, and R diabetes. None of these neonates developed RDS or HMD. Nineteen infants had LIS ratios greater than 2.0, and two had values of 1.5 and 1.9. A significant difference in the LIS ratio at each gestational age could not be demonstrated between the pre-eclamptic and normotensive patients. Comment
During the past five years, we have found the LIS ratio to be a valuable tool i~ the management of the pregnant diabetic woman. An LIS ratio of 2.0 or greater has been associated with a 3 per cent incidence of RDS and HMD. Infants of diabetic mothers delivered soon after the determination of a mature L/S ratio are not at greater risk for RDS than infants of the nondiabetic population in our hospital. Several other authors have also recently reported a low incidence of RDS with an LIS ratio of 2.0 or greater in pregnancies complicated by diabetes. 7 • 8 Intrauterine asphyxia and neonatal acidosis may lead to RDS despite a mature LIS ratio. Only one death due to HMD occurred in 200 infants of diabetic women with an LIS ratio of 2.0 or greater. As described previously, the neonate was asphyxiated at delivery. The 0.5 per cent incidence of death resulting from HMD despite a mature LIS ratio is not significantly different from that of our nondiabetic patients.6 Many investigators continue to question the reliabil-
ity of an LIS ratio of 2.0 or greater as an indicator of pulmonary maturity in infants of diabetic patients. This impression may have arisen because few patients were studied,9 because other causes of respiratory distress have not been excluded,9 or because the original technique of Gluck and associates has been modified. 10 Occasionally, the acetone-precipitation step which isolates the most surface-active lecithin fraction has been eliminated.3 Kulovich and Gluck11 also stressed that a densitometer be used to determine the L/S ratio in diabetes. They noted that an abnormal sphingomyelin value may appear in a very small number of cases of diabetes. The extreme denseness of the sphingomyelin on chromatography yields a small spot which could give a false high LIS ratio by planimetry. In our experience, the planimetric method has. been very satisfactory. A terminal decline in the LIS ratio or a failure of the ratio to rise has been demonstrated in diabetic patientsP Serial ratios were not investigated in our series. However, those infants delivered more than 72 hours after determination of a mature L/S ratio did not demonstrate an increased incidence of RDS. A mature LIS ratio can be observed earlier in gestation in Classes D, F, and R pregnancies or later in Classes B and C, according to some investigators. 13 • 14 Pre-eclampsia may also accelerate pulmonary maturity. Our data do not support these observations. Additional markers of antenatal lung maturity, phosphatidylinositol and phosphatidylglycerol, may prove to be valuable in pregnancies complicated by diabetes. 15 One of our patients, a Class C diabetic at 33 weeks' gestation, required elective induction of labor for severe pre-eclampsia. An LIS ratio obtained the day of delivery was 1.5, but further analysis revealed the presence of phosphatidylglycerol; RDS did not occur. The authors wish to thank Dr. Feizal Waffarn, Department of Pediatrics, and Dr. John Richmond, Department of Radiology; for their assistance in reviewing the neonatal records.
760 Gabbe et al. Am.
REFERENCES l. Gugliucci, C. L., O'Sullivan, M. J., Opperman, W., Gordon, M., and Stone, M. L.: Intensive care of the pregnant
diabetic, AM. J. OssTET. GYNECOL. 125: 435, 1976. 2. Driscoll, S. G., Benirschke, K, and Curtis, G. W.: Neonatal deaths among infants of diabetic mothers, Am. J. Dis. Child. 100: 818, 1961. 3. Gluck, L., Kulovich, 1vL V .. Borer, R. C., Jr., and Keidel, W. N.: The interpretation and significance of the lecithin/sphingomyelin ratio in amniotic fluid, AM. J. OsSTET. GYNECOL. 120: 142, 1974. 4. Farrell, P. M.: Indices of maturation in diabetic pregnancy, Lancet 1: 596, 1976. 5. White, P.: Pregnancy and diabetes, medical aspects. Med. Clin. North Am. 49: 1015, 1965. 6. Donald. J. R., Freeman, R. K., Goebelsmann, U., Chan, W. H., and Nakamura, R. M.: Clinical experience with the amniotic fluid lecithin/sphingomyelin ratio. I. Antenatal prediction of pulmonary maturity, A. M. J. 0BSTET. GYNECOL. 115: 54 7, 1973. 7. Tchobroutsky, C., Cedard, L., Rouvillois, J. L., and Amiel-Tison, C.: The lecithin/sphingomyelin ratio in amniotic fluid in diabetic pregnancies treated with insulin, J. Gynecol. Obstet. Bioi. Reprod. 4: 93, 197 5. 8. Aubry, R. H., Rourke, j. E., Almanza, R., Cantor, R. M., and Van Doren, J. E.: The lecithin/sphingomyelin ratio in a high-risk obstetric population, Obstet. Gynecol. 47: 21, - 197~.
J
August I, 1977 Obstet. GyiH•col.
9. Cruz, A. C., Buhi, W. C., Birk, S. A .. and Spellacy. W. N.: Respiratory distress syndrome with mature lecithin/ sphingomyelin ratios: Diabetes mellitus and low Apgar scores, AM. J. OssTET. GYNECOL 126: 78, 1976. ! 0. Dunn. L j.. Bush, C., Davis, S. E., Til. and Bhatnagar. A. S.: Use of laboratory and clinical factors in the management of pregnancies complicated by maternal disease. AM. j. 0BSTET. CYNECOL. 120: 522, 1971. 11. Kulovich, M. V., and Gluck, L.: Maturation of the fetal lung in offspring of diabetic mothers. in CameriniDavalos, R. A., and Cole, H. S., editors: Early Diabetes in Early Life, New York, 1975, Academic Press, Inc, p. 531. 12. Whitfield, C. R .. Sproule, W. B., and Brudenell, M.: The amniotic fluid lecithin/sphingomyelin area ratio in pregnancies complicated by diabetes, Br. J. Obstet. Gvnaecol. 80: 918, 1973. 13. Gluck, L., and Kulovich, M. V.: Lecithin/spjlingomyelin ratios in amniotic fluid in normal and abnormal pregnancy, .A.M. J. 0BSTET. GYNECOL. 1!5: 539, 1973. 14. Singh, E. ] .. Mejia, A., and Zuspan, F. J.: Studies of human amniotic fluid phospholipids in normal, diabetic, and drug-abuse pregnancy, AM . .J. 0BSTET. GYNECOL. 119: 623, I 974. 15. Hallman, M., Kulovich, M.. Kirkpatrick, E., Sugarman, R. G., and Gluck, L.: Phosphatidylinositol and phosphatidylglycerol in amniotic fluid: Indices of lung maturity, AM. J. 0BSTET. GYNECOL. 125: 617. 1976.