The relationship between accelerated pulmonary maturity and accelerated neurological maturity in certain chronically stressed pregnancies

FETUS, PLACENTA, AND NEWBORN

The relationship between accelerated pulmonary maturity and accelerated neurological maturity in certain chronically stressed pregnancies JEHREY B. GOULD, M.D. Boston, Massachusetts

LOUIS GLUCK, M.D. MARIE V. KULOVICH La Jolla, California

Two studies were done. In the jit'St, 51 infants from high~risk pregnancies were evaluatrd for accelerated clinical neurological maturation. Eight infants had accelerated neurological maturation 3 or more weeks in excess of gestational age. In the second study, a sample of 25 infants with documentl'd acceleration of pulmonary surfactant (lefithinlsphingomyelin ratio 52 at gestational age <32 weeks) all infants showed accelerated neurological maturation (range 3 to 8 weeks) with the conditions studied assoriatr'd with accelerated pulmonary maturation (for instance, retroplacental bleeding, prolonged rupture of membranes, placental infarction, severe toxemia, hypertensive disrase, rircumvallation, and amnionitis). Chronic retroplacental bleeding was associated with tht• most dramatic pulmonary and rn•urologiral accelerations. (AM. J. 0BSTET. GYNECOL.

127: 181, 1977J

PREMATURE BIRTHS exact a heavy toll in deaths and especially in morbidity, leaving residual neurological deficits among a number of infants born early. Preventing or modifying prematurity before birth is among the highest priority needs in perinatal medicine. Currently there is much interest in studies to accelerate the maturation of those fetal organs essential to successful

extrauterine adaptation, especially the lung. One of these studies is on the effects of pharmacologic agents, notably corticosteroids, on the maturation of the fetal lung and the prevention of the respiratory distress syndrome (RDS) in those premature infants whose births are not preventable .1 RDS is a progressive atelectasis affecting inmature lungs due to an inability to synthesize adequate surfactant, a detergent lining which keeps alveoli stable at low lung volumes. In normal pregnancy, the biochemical maturation necessary for the biosynthesis of surfactant lecithin, the principal component phospholipid, occurs at about 35 weeks (range 33 to 37 weeks). 2 As shown recently, by 37 weeks, phosphatidylglycerol, an acidic phospholipid, appears which acts to stabilize surfactant.3· 4 Surfactant maturity may be measured by the lecithin/sphingomyelin (LIS) ratio in amniotic fluid. where maturity is represented by a ratio of2.0 or great-

From thi Departments of Pediatrics and Obstetrics, Boston University, and the Departments of Pediatrics, Obstetrics, and Biochemistry, School of Medicine, University of California, San Diego. Supported principally by funds from National Institutes Health Grant HD-04380.

rif

Rereivedfor publication March 29, 1976. Acceptt•d August 12, 1976. Reprint requests: Dr. Jeffrey B. Gould, Department rif Pediatncs, Mat. II, Boston City Hospital, 818 Harrison A;•e., Boston. Massachusetts 92118

181

182 Gould, Gluck, and Kulovich

January 15, 1977 Am.]. Obstet. G\'ll<"r"l

Table I. Incidence of maternal high-risk factors in 49 49 mothers of Study I No.

Fador

Hypertrnsion Chronic Toxemia and seizures Toxemia Total Rnwl disease Pylonephritis Glomerulonephritis Renal failure Total Placental abnormality Leak or rupture- >24 hours Amnionitis Third-trimester bleeding Total Diabetes Class A-C Class D ·rota I Rh disease

2 2

4 I

4 3

t)

I

7 3

Cesarean section

Repeat complicated Repeat uncomplicated Complicated pregnancy Complicated labor Total Prnnaturity Premature induction Premature twins Premature labor Total

6

7 8 3

24 3 3 !8

24

er, by the absence of clinical RDS in the neonate, and by the appearance of phosphatidylglycerol (PG) in either amniotic fluid or tracheal secretions after birth. Recently we described the effects of certain abnormal pregnancies (e-g., maternal hypertensive disease, chronic retroplacental bleeding) on acceleration of the maturation of pulmonary surfactant. 5 In these pregnancies. the LIS ratios are over 2.0 prior to 33 weeks' gestation and thtlse infants born at that time do not have RDS. In a preliminary report 6 we stated that some infants with accelerated lung development also have significantly accelerated clinical neurological maturation. The purpose of this study was to document and extend these findings. Material and methods

Two studies were done. The initial study (Study I) was designed to screen preliminarily a variety of unselected high-risk pregnancies (Table I) to determine conditions with chronic intrauterine stress in which there is an association between accelerated pulmonary maturity and accelerated neurological development, to establish the suitability of the technique of Dubowitz

and associates 7 for evaluation of infants from high-risk pregnancies, and to standardize techniques. In the snond study (Study 2), evaluation was limited to infants from high-risk pregnancies with demonstrated aut:!eration of LIS ratios prior to 33 weeks' gestation. Criteria for selection. In Study 1. 51 infants, ~HI male and 21 female. from 25 Caucasian, four black. and 20 Mexican-American mothers. delivered · the investigator at the time of assessment. Birth weight was taken from the patient's chart. Gestational age was assessed by the technique of Dubowitz and associates/ hereafter called the '·Dubowitz technique," with the use of IO clinical neurologiral criteria and I l external physiml criteria. The maximum score for each subtest was 35. In developing their scoring system, Dubowitz and associates applierl these

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Accelerated pulmonary and neurological maturity

criteria to 167 infants from unselected pregnancies. Their best regression line was linear, with a correlation coefficient of 0.93. The error of prediction of gestational age with the total score (neurological and physical) was 1.02 weeks, and the 95 per cent confidence limits were ±2 weeks. The total swre of each infant in the first study was obtained to establish the applicability of the Dubowitz technique to abnormal pregnancies. The neurological score and the physical score also were analyzed independendy to test the predictive reliahility of each component in abnormal pregnancy.

183

Y • ,2298 X + 25.11717

Results

Clinical estimation of gestational and neurological age. Stud.v 1. Fig. I shows the total score (neurological and physical) in the 51 infants in Study I in relation to known gestational age. The best regression line for total score (x) against gestation (y) is linear and is described by the formula y = 0.229 x ± 25.4717. The correlation coefficient is 0.88. The error of prediction of gestational age from the total score was 1.74 weeks with 95 per cent confidence limits of ±3.5 weeks. This compares favorably with the data of Dubowitz and associates7 from their 167 unselected pregnancies and is better than the estimation of gestational age based on birth weight whirh has 95 per cent confidence limits of ±4.5 weeks. The total neurological subscore was doubled and compared similarly against the known gestational age (y). The best regression line was linear, described by the formula y 0.2497 X +24.5320. The correlation coefficient was 0.83 with 95 per cent confidence limits of ±4 weeks. By keeping the physical age constant (i.e., weight appropriate for gestational age), one can compare neurological ages, and the neurological subscore thus was considered synonymous with the neurological age. Accelerated neurological maturation was defined arbitrarily as an observed neurological age 3 weeks in advance of the reported gestational age. Three weeks was chosen since this fell well outside Dubowitz's 95 per cent confidence limits for his group of unselected infants. Eight infants in the first study had neurological ages accelerated more than 3 weeks beyond their gestational age. Pertinent data on these eight are summarized in Table II. Study 2. In the second study, 25 patients were selected whose infants had marked acceleration of pulmonary function. The LIS ratios were 2.0 or more before 32 weeks of gestation, and they were in the tenth to ninetieth percentiles for weight/ gestational

10

20

30

40

50

60

70

TOTAL StoRE

Fig. I. Relationship between gestational age and total Dubowitz score in 51 high-risk infants.

age. The gestational ages of nine of these infants were between 26 and 30 weeks; 16 were between 30 and 32 weeks. With the use of criteria, of Dubowitz and associates, all 25 had neurological scores in excess of both their gestational ages and their physical scores. Tht' average acceleration was 4.5 weeks, ranging between 3 and 8 weeks, all well beyond Dubowitz's 95 per cent confidence limits of 2.6 weeks. These data are summarized in Table III where the conditions complicating the various pregnancies also are listed. The association between marked acceleration of fetal lung development and significant acceleration of neurological development were most dramatically shown in those pregnancies with chronic retroplacental bleeding (chronic abruptio placentae). Comment

The purpose of Study 2 was to document further preliminary observations 6 that in some infants of certain high-risk pregnancies significantly accelerated neurological maturation seems to accompany accelerated pulmonary maturation. The initial observations (Study 1) provided clear evidence that some abnormalities of pregnancy contribute to this phenomenon. while in the second study infants were evaluated according to the criteria for accelerated pulmonary maturation which were defined strictly as an LIS ratio grea-

184 Gould, Gluck, and Kulovich Am

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January 15, 197i Obstet. GynecoL

Table II. Infants with accelerated neurological maturation-Study I Birth weight

Gestatiorzal age

Phy11cal age

Neurologiml age

Sex

Race

(grams)

(wk.)

(wk.)

(wk.)

M M

Black Caucasian Caucasian Mexican Mexican White White l\.fexican

1,077 1.247 1,400 1,540 1,940 2,183 2,218 4,479

28 28 30 30 33 34 36 38.3

27.8 29.8 29.5 33 34 32.5 38.8 41.5

33.2 31.8 33.8 34.4 37.8 37.2 39.6 41.7

F F

M M F M

Maternal history Third-trimester bleeding Third-trimester bleeding Toxemia and seizures Premature labor, slow abruptio placenta Premature labor Mild toxemia Pylonephritis 3 times Gestational diabetes, rupture of membranes for >24 hours

Table III. Infants with accelerated neurological maturation-Study 2 Case No. I

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Birth weight (grams)

Gestational age (wk.)

Physical age

Neurological age

(wk.)

(wk.)

675 810 1,000 1,020 1,200 1.325 1,210 1,215 1,375 1,180 1,225 1,225 1,245 1,350 1,620 1,510 1,290 1,360 1,400 1,420 1,450 1,550 1,390 1,480 1,550

26 26 26-27 28 28 28-29 29 29-30 29-30 30 30 30 30-31 30-31 30-31 30-31 31 31-32 31-32 31-32 31-32 31-32 32 32 32

26 26 26 28 29 29-30 29-30 30 30 30 30 30 30 30 30 30-31 30-31 30-31 31 31 32 32 32 32 32-33

34 33 34 33 33 35 33 34 35 33 34 35 36 34 35 34 35 36 35 35 36 35 36 36 36

Pregnancy condition RPB, PROM, PI RPB, A, PROM. PI RPB, PI. MI RPB, PROM, PI RPB, A, PI, Ml RPB, PROM, PI A, PI PROM, PI RPB. PI

c A, PI RPB,A,C,Ml RPB. PT PI PI MI, T PROM. PI RPB. PI R, Ml A, PI. T A,R, MI RPB, Pl. T A,R PI, T PROM. Pi

RPB Retroplacental bleeding (partial abruptio placental); PROM = prolonged rupture of membranes (72 hours); PI = "piacental insufficiency"'-small, infarcted placenta; T = severe toxemia; C cardiovascular hypertensive disease; R renal hypertensive disease; C circumvallate placenta; Ml maternal genitourinary infection; A amnionitis.

ter than 2.0 prior to week 33 of gestation and/or lack of RDS in an infant of less than 33 weeks' gestation. With these criteria, Study 2 confirms the finding of accelerated neurological maturation associated with accelerated pulmonary maturation (Table Ill). The procedure of Dubowitz and associates 7 was chosen to evaluate neurological maturation for several reasons. It is simple; the developmental components, neurological and physical ages, can be evaluated independently, and there is a high degree of correlation in unselected populations between gestational age and neurological score, physical score, and total score. The

usefulness of this technique was tested in Study I on a diverse population of so-called "high-risk infants," described in Table L The 95 per cent confidence limits for the estimation of gestational age from weight, total score. neurological score, and physical score for the high-risk infants of Study I are listed in Table IV. Although the high-risk confidence limits were wider than those reported by Dubowitz and associates, the relative predictive efficacy of these measures is quite similar. In both studies, weight was the least accurate and total score was the most accurate predictor of gestational age.

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Accelerated pulmonary and neurological maturity

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!';umber 2

These results support the value of the Dubowitz technique which incorporates total score for the clinical estimation of gestational age in high-risk as well as unsclened pregnancies. The ability to assess independently physical and neurological maturity allows one to compare the stated gestational age with either or both of these. This type of analysis (i.e. comparing physical score. neurological score, and head circumference, length, and birth weight) may provide important insights on the effects of high-risk pregnancy on Intrauterine development. The list of known abnormalities of pregnancy associated with accelerated development of pulmonary .\!lrfwtant" includes hypertensive disease (renal and cardio\'ascular. longstanding severe hypertensive toxemia), diabetes mellitus (Classes D, F, and R), some narcotic addiction (especially morphine and heroin), and severe placental disease (retroplacental bleeding or chronic abruptio placentae, placental infarction, circumvallate placenta, "placental insufficiency"). Of these, chronic (partial) abruptio placentae (retroplacemal bleeding) seemed the most potent and most consistent stimulus to acceleration of maturation of the central nervous system. Recentlv Amiel-Tison 8 • 9 verified these findings of accelerated neurological maturation in certain infants of high-risk pregnancies. She predicted that this is not a common syndrome. However, she did not especially look for infants born after chronic retroplacental bleeding. Although there are some highly provocative suggestions possible from the findings presented, more importantly there are some very basic warnings, the significance of which will await further study and long-term follow-up. Since many very young fetuses in highly unfavorable intrauterine environments (e.g., partial abruptio placentae) show accelerated maturation of pulmonary surfactant and do not have RDS after birth and since these tend to have acceleration of maturation of the central nervous system-"accelerated functional maturity"-it is tempting to suggest that these pregnancies threatened by uteroplacental insufficiency be terminated when the LIS ratio is mature. Theoretically, factors are considered balanced where the benefits of the accelerated pulmonary-central nervous system maturations offset and prevent the hazards of continuing intrauterine life with potential chronic hypoxia and damage, lack of growth, and postnatal hypoglycemia, also dangerous since these infants tend not to have normal glycogen stores. The sobering findings seem to be that, despite the maturity as stated, these tiny infants continue to have

Table IV. The 95 per cent confidence limits for the estimation of gestational age from weight, total score, neurological score, and physical score for Study I infants Gestational age predicted by Weight Total score Neurological score Physical score

High· risk (No. =51) (wk.)

4.5 3.5 4 4

Dubow1/z 7 (No. = 167) (wk.) 3 2 2.4 2.6

apneic episodes essentially to the same extent as "normal" premature infants of like gestational age. Frequent apnea is a symptom in this time of life which may be a harbinger of serious problems as the infant grows. This report considered only clinical neurological maturity during the first few days of life. Further studies are required to correlate the clinical neurological maturity with maturation defined by nene conduction velocity and the sleep electroencephlogram and in order to define the developmental consequences of these phenomena. Further studies also are needed to define the true incidence of the phenomena described in this study. All of the conditions which lead to a stress capable of producing accelerated (or delayed) maturation must be identified. Furthermore, identification of the biochemical mechanisms involved in altering fetal de\'elopment is essential. Pharmacologic induction of the pulmonary surfactant system with steroids has been carried out in animal modelsw and human subjects. 1 Although studies on animals given steroids have shown that "induction" of pulmonary phospholipids follows, they also suggest that other organ systems may be affected, especially the brain. Decreased brain weight, decreased brain cholesterol, and decreased brain deoxyribonucleic acid, are seen in rats treated with corticoids. 11 ' 12 Of primary concern is that acceleration of clinical neurological maturation secondary to high-stress pregnancy may result from endogenously elevated levels of corticosteroids and that the human central nervous system may also be subject to similar phenomena. Since the developing central nervous system would be exposed at an early stage of development, both pharmacologic and endogenous induction must be carefully examined for possible long-term consequences on neurological function. We would like to thank Ms. Nancy Willsey, Nancy M. Coyne, and Susan Coons for their assistance in the preparation of the manuscript.

186 Gould, Gluck. and Kulovich Am.

REFERENCES I. Liggins, G. C., and Howie, R. N.: A nmtrolled tria! of antepartum glucocorticoid treatment for the prevention of the respiratory distress syndrome in premature infants. Pediatrics 50: 115. 1972. 2. Gluck, L., Kulovich. M. V., Borer, R. C., Jr., and Keidel, W. N .: Interpretation and significance of the lecithinsphingomyelin ratio in amniotic fluid. A;;,r. J. 0BSTET. GYNECOL. 120: 142, 1974. 3. Hallman, M., and Gluck, L.: Phosphatidyl glycerol in lung surfactant: III. Possible modifier of surfactant function, J. Lipid Res. In press. 4. Hallman. M., Kulovich, M.. Kirkpatrick, E., Sugarman, R. G., and Gluck, L.: Phosphatidylinositol and phosphatidylglycerol in amniotic fluid: Indices of lung maturity, AM. J. OBSTET. GYNECOL 125: 613. 1976. 5. Gluck, L., Kulovich, M. V.: Lecithin-sphingomyelin ratios in amniotic fluid in normal and abnormal pregnancy, AM. j. 0BSTET. GYNECOL. 115: 539, 1973. 6. Gould,J. B., Gluck, L., and Kulovich, M. V.: The acceleration of neurologic maturation in high stress pregnancy and its relation to fetal lung maturity, Pediatr. Res. 6:335. 1972.

January 15, 1971 Obster. Gvnecol

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7. Dubowitz, L .\L S., Dubowitz, V., and Goldberg, C.: Clin· ical assessment of gestational age in the newborn infant . .J. Pediatr. 77: I, I 970. 8. Amiel-Tison, C.: Neurologic problems in perinatology, Clin. Perinatol. I: 33, 1974. 9. Amiel-Tison. C.: Neurologic evaluation of the ~mall neonate: The importance of head straightening reactions. in Gluck, I.., editor: Modern Perinatal Medicine, Chicago, 1974, Year Book Medical Publishers, Inc., pp. 347-357. 10. DeLemos, R. A., and McLaughlin, G. \N.: Induction ol pulmonary surfactant in the fetal primate by intrauterine administration of corticosrernids, Pediatr. Res. 7: 4~'). 197:1. II. Cotterrell. :VL, Balazs, R., and Johnson. A. L.: Effects ot corticosteroids on the biochemical maturation of rat brain: Postnatal cell formation, J. 1\'eurochem. 19: 2 I 51. 1972. 12. Balazs. R.. and CotterrelL M.: Effects of hormonal stalc on cell numbers and functional maturation of the brain. Nature 236: 348. 1972.