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Postnatal maturation of peripheral nervesin preterm and full-term infants
December, 1971 T h e Journal of P E D I A T R I C S
915
Postnatal maturation of peripheral nerves in preterm and full-term infants The conduction velocity of the ulnar and posterior tibial nerves was measured serially during the first year of life in normal preterm and full-term infants. At birth the preterm infants had significantly slower velocities than did the full-term infants. The conduction velocities of the ulnar and posterior tibial nerves remained significantly slower until 9 months and 3 months of age, respectively. When related to postconceptional age, however, the conduction velocities in preterm infants were slower than those of full-term infants only at 40 weeks; from 44 weeks onward there was no significant difference in the mean velocities. The rate of maturation of the peripheral nerves of preterm infants is thus retarded for only a few weeks after birth; subsequently it is the same as that of full-term infants of similar postconceptional age.
Allie Moosa, M.B., Ch.B., and Victor Dubowitz, B.Sc., M.D., Ph.D., M.R.C.P., D.C.H.* SHEFFIELD,
ENGLAND
T I-I 1~ M A T U R A T I O N of the n e r v o u s system in the fetus has been studied by a number of parameters; anatomic, 1 behavioral, 2 and electroencephalographic 3 methods have all shown a fairly consistent pattern of change. Several factors may influence this process of maturation. Our particular interest has been to determine whether the prematurely born infant continues to mature at the same rate as he would in utero, or
From the Department of Child Health, University of She~eld. Supported by the Muscular Dystrophy Group of Great Britain. This work forms part of a thesis accepted for the Doctorate in Medicine at the University of Shet~eId (A.M.). *Address: Department o] Child Health, University oI She~eld, She~ield 10, England.
whether environmental factors influence the rate of maturation of the nervous system. Earlier studies have suggested that there may be a postnatal acceleration in some aspects of development in the premature infant, such as myelination, *, 5 "vitality and general visual behavior, ''" and social smiling. ~ However, Dittrichova s found that preterm and full-term infants started smiling at the same postconceptional age. Some studies of the neurologic behavior of preterm infants have also suggested that the process of maturation is unaltered in the outside environment. 2 This has been supported by electroencephalographic studies, 8 although differences in electroencephalograms between infants of the same age born after different periods in utero have been noted." BenVoI. 79, No. 6, pp. 915-922
9 16
Moosa and Dubowitz
jamin 10 found well-defined sleep spindles present 8 to 15 days earlier in preterm infants, suggesting some acceleration of the bioelectric process, whereas EngeI ~1 found the latency of visually evoked responses to be longer in preterm infants reaching full-term age after birth than in utero, suggesting some retardation of the process of impulse conduction in the central nervous system. There have been only two studies: of peripheral nerve maturation in preterm infants after birth, 12, la although a few workers have suggested, on the basis of isolated examples, that peripheral nerve myelination is unaltered after birth in preterm infants? 4, 1~ Dubowitz and associates 12 found the mean velocities of the ulnar and posterior tibial nerves in preterm infants of 39 to 41 weeks' postconceptional age to be significantly slower than those of full-term infants immediately after birth. In contrast, the rate of increase as assessed by three or more sequential measurements of conduction velocity on each infant, appeared to be faster than that occurring in utero over the same period of time. In order to explain these seemingly contradictory findings, Dubowitz and associates 12 postulated that the factors which caused the premature birth could possibly have affected the peripheral nerve function, with resultant slowing of the conduction velocity; after birth, these factors would no longer be operative and the conduction velocity might therefore increase more rapidly. Ruppert and Johnson ~3 did serial nerve conduction studies on 11 premature and 8 small-for-date infants until one year of age and concluded that neither premature birth nor intrauterine growth retardation had any appreciable effect on the maturation of the peripheral nerves. There was clearly a need for further study to try and establish if the peripheral nerve maturation was unchanged after birth or if it was accelerated. MATERIAL
AND METHODS
Part I. Rate of maturation of peripheral nerves of preterm infants after birth and in utero. Serial ulnar and posterior tibial nerve
The ]ournal of Pediatrics December 1971
conduction velocities were measured in 9 normal preterm infants under 36 weeks' gestational age, at weekly or biweekly intervals until they reached 40 weeks' postconeeptional age. The method used was similar to that described by Hodes and associates? 6 Surface electrodes were used for both stimulating the nerve and recording the motor response. The ulnar nerve was stimulated at the elbow and wrist, and the motor response was recorded from the hypothenar muscles. The posterior tibial nerve was stimulated in the popliteal fossa and behind the medial malleolus, and the motor response was recorded from the flexor hallucis brevis muscle. The same ulnar and posterior tibial nerves were examined on each occasion. The stimulus consisted of square wave impulses of variable intensity and 0.1 msec. duration. Supramaximal stimulation was ensured by increasing the intensity of stimulus until no further increase in amplitude of motor response occurred. The response was photographed (Polaroid) and the latency calculated from the stimulus artefact to the first well-defined negative peak of the motor response. T h e difference in latency between the proximal and distal responses was divided into the intercathodal distance to give the conduction velocity in meters per second. The intercathodaI distance was measured with a steel tape, the limb being held in the same position as during stimulation. The gestational age of all the infants was calculated from the last menstrual period of the mother. We included infants for analysis only when the mothers, whom we personally interviewed, were certain of their last menstrual period, had regular 28 (-+2) day cycles, and had no bleeding subsequent to the last menstrual period. Infants of mothers who had been receiving oral contraceptives during the 12 months prior to conception were excluded. Analysis of data. The mean conduction velocity for the preterm infants at the time they reached their anticipated full-term age was compared with the mean conduction velocity of a group of normal full-term newborn infants between 39 and 41 weeks' gesta-
Volume 79 Number 6
Postnatal maturation o[ peripheral nerves
9 17
Table I. Ulnar and posterior tibial nerve conduction velocities of preterm infants reaching 39 to 41 weeks' postconeeptional age, and full-term infants (39 to 41 weeks' gestation) at birth
Nerve Ulnar (M./sec.) Posterior tiblal (M./sec.)
Preterm at 39-4l weeks (n=9) Range I Mean I2 S.E.M. 21.4-28.6 24.0 2.38 20.0-23.5 21.8 0.94
tion. A regression line of nerve conduction against postconceptional age was calculated for each preterm infant on the basis of three or more sequential measurements of conduction velocity. A mean regression line was then calculated for these 9 preterm infants. A regression line was also obtained from the first measurement of conduction velocity done immediately after birth in 43 normal newborn infants of varying gestation. This was assumed to reflect the rate of increase in nerve conduction in utero with gestational age. The two regression lines thus provided a comparison between the relative rate of increase in nerve conduction of preterm infants in utero and in the extrauterine environment. Part II. Sequential studies on normal fullterm and preterm infants until one year of age. Serial nerve conduction measurements were made at 3 monthly intervals on 6 apparently normal full-term infants and at 6 weekly intervals on 10 apparently normal preterm infants. The postconceptional age of these infants was obtained from the last menstrual period, or from the maturity score 17 in some of the preterm infants. In the preterm infants the nerve conductions were also measured as near to one year from the expected date of delivery as possible. The mean velocities of the full-term and the preterm infants were compared at birth and at 3, 6, 9, and 12 months after birth. RESULTS Part I. Rate of maturation of preterm infants until term. The results of the mean conduction velocities for the preterm and full-term infants at 39 to 41 weeks' postconceptional age are given in Table I. T h e mean conduction velocities of the ulnar nerve
Full-term (n • 15) Range I Mean 12 S.E.M. 24.4-33.3 27.7 1.24 18.1-27.3 22.2 1.18
p value <0.0t ~0.3
(24.0 + 2.38 M. per second [2 S.E.M.]) and posterior tibial nerve (21.8 _+ 0.94 M. per second [2 S.E.M.]) in the preterm infants were less than those of the full-term infants (27.7 + 1.24 and 22.2 + 1.18 M. per second, respectively). T h e mean regression line for the increase in conduction velocity in the 9 preterm infants reaching term after birth is compared with that of the 43 newborn infants of varying gestational ages in Figs. 1 and 2. The slope for the preterm infants is slightly steeper than the "in utero" line, indicating a slower rate of maturation in the external environment. This fits in with the slower mean conduction velocity for the ulnar and posterior tibial nerves at 39 to 41 weeks' postconceptional age in preterm infants as compared to full-term infants. Part II. Rate of maturation of peripheral nerves until one year. The mean ulnar and posterior tibial nerve velocities at birth and at 3, 6, 9, and 12 months postnatal age for the full-term and preterm infants are shown in Tables I I and I I I and in Figs. 3 and 4. At birth both the ulnar and posterior tibial nerve conduction velocities were significantly slower for the preterm infants than for the full-term infants. The ulnar nerve conduction remained significantly slower until 9 months of age, but at one year the difference was not statistically significant. T h e posterior tibial conduction velocity remained significantly slower in the preterm infants until 3 months of age, whereas at 6 months, 9 months, and 1 year, the difference was not statistically significant. At one year from the expected date of delivery (i.e., postconceptional age of 92 weeks), there was no difference in the mean
9 1 8 Moosa and Dubowitz
42-
The Journal of Pediatrics December 1971
//~ j
Ulnar nerve
y = 18'4250+ 0"8350X
4o38-
~ 36-
//
:
?o 34-
Y
/
/
y=21.s283+o~,431x
2~2
I 24
/S/ / ~ "
32302 28/
26
10
l 12
i 14
~ 16
i 18
Conduction
~ 20
I 26
I 28
I 30
velocity (m/sec.)
Fig. 1. Graph of intrauterine (solid line) versus extrauterlne (broken llne) increase in ulnar nerve conduction velocity with age in preterm infants. 42-
f
Posterior tibial nerve
40" 38&
/~/ y=22-,,~,+o-,22,•
36-
<
-~ 34-
.o
L~
32-
3028-
26 10
l
12
I
14
I
16
I
18
Conduction
I
20
I
22
I
24
I
26
I
28
'l
30
velocity ( m / s e e . )
Fig. 2. Graph of intrauterine (solid line) versus extrauterine (broken line) increase in posterior tibial conduction velocity with age in preterm infants. conduction velocity of the ulnar (48.8 M. per second) and posterior tibial nerves (40.7 M. per second) of the preterm infants, compared to that of the full-term infants (50.9 and 40.2 M. per second, respectively).
T h e rate of change in mean ulnar and posterior tibial conduction velocities after birth is shown in. Table IV. During the first three months of extrauterine life, the peripheral nerves of the preterm infants matured
Volume 79 Number 6
Postnatal maturation of peripheral nerves
9 19
T a b l e I I . Serial u l n a r nerve c o n d u c t i o n velocities ( m e a n + 2 S.E.M.) from b i r t h to one y e a r in n o r m a l full-term a n d p r e t e r m infants
Infants Full-term Preterm p Value
Mean gestation (wk.) 40.2 31.7
N 6 10
0 28.3+2.70 15.5+1.80 < 0.001
3 35.5 -2 2.04 29.8+2.72 < 0.01
Postnatal age in months 6 9 41.7-+ 2.08 47.6-+ 1.20 37.0+-3.04 42.7-+2.16 < 0.02 < 0~01
12 I 14 50.2-+ 1.88 47.1-+2.46 48.8+2.26 > 0.05
T a b l e I I I . Serial posterior tibial nerve c o n d u c t i o n velocities ( m e a n _+ 2 S.E.M.) f r o m b i r t h to one y e a r in n o r m a l full-term a n d p r e t e r m infants
Infants
Mean gestation (wk.)
N
0
3
40.2 31.7
6 10
20.9+2.20 12.4-+ 1.36 < 0.001
26.3+1.80 23.5 + 1.20 ~ 0.02
Full-term Preterm p Value
Postnatal age in months 6 32.0+1.64 31.1+ 1.96 > 0.2
9 38.4-+1.34 35.5-+ 2.16 > 0.05
12 ] 14 40.2+1.60 38.1 + 1.52 40.7 + 3.76 > 0.05
T a b l e I V . R a t e of increase in c o n d u c t i o n velocity of p r e t e r m a n d full-term infants after b i r t h Ulnar Preterm
Posterior tibial Full-term
% Increase
Age (moo
0-3 3-6 6-9 9-12 12-14 32-40 weeks in utero
Preterm
% Increase
Over Per Over M./sec. Over Per period month M./sec. period month M./sec. period 25.4 8.5 11.1 89.5 14.3 92.2 30.7 7.2 17.5 5.8 7.6 32.3 7.2 24.2 8.1 6.2 14.1 4.7 4.4 14.1 5.7 15.4 5.1 5.9 5.5 1.8 2.6 7.3 4.4 10.3 3.4 2.6 2.6 6.8 1.7 3.6 1.8
78.0
39.0
at a p p r o x i m a t e l y the same rate as those of the p r e t e r m infants in utero from 32 to 40 weeks. F r o m 3 to 6 months, the conduction velocity increased at a rate equivalent to t h a t of the full-term infants d u r i n g the first three months. I n other words, the rate of increase in c o n d u c t i o n velocity of p r e t e r m infants lagged b e h i n d t h a t of full-term infants by a b o u t 2 to 3 months. A l t h o u g h continuing to lag behind, the m e a n velocity a p p r o a c h e s t h a t of full-term infants by 9 m o n t h s for the u l n a r a n d 3 m o n t h s for the posterior tibial nerve. This is not due to a " c a t c h - u p " in c o n d u c t i o n velocity for the p r e t e r m infants, b u t to the falloff in rate of increase of cond u c t i o n velocity in full-term infants with
Full-term
% Increase
85.0
% Increase
Over Per Per month M./sec. period month
29.8 10.8 4.7 2.4 3.3
5.4 5.7 6.4 1.8
25.8 21.7 20.0 4.7
8.6 7.2 6.7 1.6
42.5
time (Figs. 3 a n d 4). T h e two curves (of m e a n velocity) are thus convergent. This i n t e r p r e t a t i o n is well illustrated by r e d r a w i n g the curves based on the postconceptional age r a t h e r t h a n the postnatal age. This effectively shifts the curve of the preterm infants by 2 months to the left. I t will be seen t h a t the two curves then become superimposed (Fig. 5). DISCUSSION
T h e slower c o n d u c t i o n velocity of the preterm infants r e a c h i n g 40 weeks' postconceptional age after birth is in a g r e e m e n t with the results o b t a i n e d by Dubowitz a n d associates. 12 W h e r e a s they found an accelerated
920
The Journal of Pediatrics December 1971
Moosa and Dubowitz
56
Umnar nerve
48,
J $ / t
d
0 >
32-
.o_
•
3 0
24-
16"
Full t e r m i n f a n t s
o
Premature infants
*
Postnatal Age in m o n t h s
Fig. 3. Sequential ulnar nerve conduction velocities in normal preterm and full-term infants after birth. The bars on either side of the mean represent 2 S.E.M. Posterior tibial nerve
48
d f 5
_o 32
_g "D tO O
24
16 ~ r
0
~
:
Furl-term infants Premature infants
3
6 9 Postnatal Age in m o n t h s
o 9
12
15
Fig. 4. Sequential posterior tibiaI nerve conduction velocities in normat preterm and full-term infants after birth. rate of increase in the conduction velocity of p r e t e r m infants after birth, the present study revealed a slower rate of increase, which fits in with the slower m e a n velocities at 40 weeks' postconceptional age. F o r the first few weeks after birth the pc-
ripheral nerves of the p r e t e r m infant thus seem to m a t u r e at a slightly slower rate t h a n over the same period in utero. This parallels the longer latency found by EngeP 1 for visually evoked cortical responses in p r e t e r m infants after birth c o m p a r e d to those in new-
Volume 79 Number 6
Postnatal maturation of peripheral nerves
92 1
56 ~ Ulnar nerve o 48-
d 40-
E
~>
32-
o// 0
24-
/ 16-
e/
Full-term infants
o
Premature infants
9
8
3o
4'0
5o Postconceptional
6;
7o
8'0
9;
A g e in w e e k s
Fig. 5. Ulnar nerve conduction velocity in preterm and full-term infants after birth plotted against postconceptional age instead of postnatal age. Note almost identical course of the 2 curves.
born full-term infants at similar postconceptional ages. Whereas both the central and peripheral impulse conducting pathways of preterm infants are slightly delayed in maturation after birth, the electroencephalographie maturation ~ is not influenced by premature birth. This suggests that myelination is slightly retarded in these infants while dendritic arborization and the development of axodendritic synapses is unaltered. The degree of retardation of peripheral nerve conduction, however, is small and probably of no clinical significance. This is borne out by the fact that the maturation of the neurologic behavior of preterm infants is unaltered by premature birth. 2, 18 Moreover, the difference in conduction velocity between preterm and full-term infants of 40 weeks' postconceptional age is not maintained during the first year of life. By 44 weeks' postconceptional age the conduction velocities are similar and remain so throughout the rest of the first year of life (Fig. 5). This correlates well with the neurologic
maturation of preterm infants during the first year of life. Gesell and Amatruda 19 and Illingworth 2~ maintain that the developmental assessment of the preterm infant should be related to the postconceptional age and not age from birth. Parmelee and Schulte ~1 did developmental tests on preterm, normal full-term, and small-for-date fullterm infants 40 weeks after birth and found that preterm infants scored less than the normal full-term and small-for-date infants. They concluded that preterm infants should have their age determined from their expected date of delivery for the purposes of developmental assessment. The maturation of the peripheral nerves in preterm infants during the first year of life also correlates with that of the electroencephalogram. Parmelee and associateP 2 found the electroencephalogram at term and at 3 months and 8 months after term to be the same in preterm and full-term infantsl in spite of the fact that the preterm infants were chronologically advanced by 2 to 3 months. These results suggest that the peripheral
922
Moosa and Dubowitz
nervous system of p r e t e r m infants continues to m a t u r e as a function of postconceptional age a n d not of postnatal age. We wish to thank Dr. J. A. Black for access to patients under his care, Miss M. Flavin, Miss W. Wallace, and the Nursing Staff for help with the measurements, Mrs. C. Goldberg for helpful advice with the statistics, and Mr. A. Tunstill for the photography. REFERENCES
1. Larroche, J. C.: The development of the central nervous system during intrauterine lif% in Faulkner, F., editor: Human development, Philadelphia, 1966, W. B. Saunders Company, p. 257. 2. Salnt-Anne Dargassies, S.: Neurological maturation of the premature infant of 28 to 41 weeks' gestational age, in Faulkner, F., editor: Human development, Philadelphi% 1966, W. B. Saunders Company, p. 306. 3. Dreyfus-Brisac, C.: The bioelectric development of the central nervous system during early 1lie, in Faulkner, F., editor: Human development, Philadelphia, 1966~ W. B. Saunders Company, p. 286. 4. Westphal, A.: Die electrlsche Erregbarkeitsverh~iltnisse des peripherischen Nervensystems des Mensehen in jugendlichem Zustand und ihre Beziehungen zu dem anatomisehen Bau desselben, Arch. Psychiat. 26: 1, 1894. 5. Langworthy, O. R.: Development of behavior patterns and myelinization of the nervous system in the human fetus and infant. Contrib. Embryol. Carnegie Inst. Wash. 24: 1, 1933. 6. Esente, I.: Physiologle de la vision chez le premature et le nourrisson normal, Quoted by Peiper, A. (1963), in Cerebral function in infancy and childhood, New York, 1958, Consultants Bureau, p. 66. 7. Michaelis, R.: Quoted by Schuhe in Robinson, R. J., editor: Brain and early behavior, London, 1969, Academic Press, Inc., p. 112. 8. Dittrichova, J.: Social smiling, in Robinson, R. J., editor: Brain and early behavior, London, 1969, Academic Press, Inc., p. 112. 9. Dreyfus-Brisac, C.: The electroencephalogram of the premature infant, World Neurol. 3: 5, 1962.
The Journal o[ Pediatrics December 1971
10. Benjamin, J. D.: In Brosin, A. W., editor: The innate and the expericntial in developmen L Pittsburg, 1961, University of Pittsburg Press, p. 19. 11. Engel, R.: Maturational changes and abnormalities in the newborn electroencephalogram, Develop, Med. Child. Neurol. 7: 498, 1965. 12. Dubowitz, V.~ Whittaker, G. F, Brown, B. H., and Robinson, A.: Nerve conduction velocity - - a n index of neurological maturity of the newborn infant, Develop. Med. Child Neurol. 10: 741, 1968. 13. Ruppert, E. S., and Johnson, E. W.: Motor nerve conduction velocities in low birth weight infants, Pediatrics 43: 255, 1968. 14. Thomas, J. E., and Lambert, E. H.: Ulnar nerve conduction velocity and H-reflex in infants and children~ J. Appl. Physiol. 15: 1, 1960. 15. Blom, S., and Finnstr6m, O.: Motor conduction velocities in newborn infants of various gestational ages, Acta Paediatr. Scand. 57: 377, 1968. 16. Hodes, R., Larrabee, M. G., and German, W.: The human electromyogram in response to nerve stimulation and conduction velocity of motor axons, Arch. Neurot. Psychiat. 60: 340, 1948. 17. Dubowitz, L., Dubowitz, V., and Goldberg, C.: Clinical assessment of gestational age in the newborn infant, J. P~DIATm 77: 1, 1970. i8. Robinson, R. J.: Assessment of gestational age by neurological examination, Arch. Dis. Child. 41: 437, 1966. 19. Gesell, A., and Amatruda, C. S.: Developmental diagnosis, New York, 1947, Hoeber Medical Division, Harper & Row, Publishers, Inc., p. 290. 20. Illingworth, R. S.: Development of the infant and young child, ed. 4, Edinburgh, 1970, E. & S. Livingstone, Ltd., p. 359. 21. Parmelee, A. H., and S~chulte, F. J.: Developmental testing of preterm and small-for-dates infants, Pediatrics, 45: 2I, I970. 22. Parmelee, A. H., Wenner, W. H., Akiyama, Y., Stern, E., and Flescher, J.: Electroencephalography and brain maturation, in Minkowski, A., editor: Regional development of the brain in early life, Oxford, 1967, Blaekwell Scientific Publications, Inc., p. 459.
915
Postnatal maturation of peripheral nerves in preterm and full-term infants The conduction velocity of the ulnar and posterior tibial nerves was measured serially during the first year of life in normal preterm and full-term infants. At birth the preterm infants had significantly slower velocities than did the full-term infants. The conduction velocities of the ulnar and posterior tibial nerves remained significantly slower until 9 months and 3 months of age, respectively. When related to postconceptional age, however, the conduction velocities in preterm infants were slower than those of full-term infants only at 40 weeks; from 44 weeks onward there was no significant difference in the mean velocities. The rate of maturation of the peripheral nerves of preterm infants is thus retarded for only a few weeks after birth; subsequently it is the same as that of full-term infants of similar postconceptional age.
Allie Moosa, M.B., Ch.B., and Victor Dubowitz, B.Sc., M.D., Ph.D., M.R.C.P., D.C.H.* SHEFFIELD,
ENGLAND
T I-I 1~ M A T U R A T I O N of the n e r v o u s system in the fetus has been studied by a number of parameters; anatomic, 1 behavioral, 2 and electroencephalographic 3 methods have all shown a fairly consistent pattern of change. Several factors may influence this process of maturation. Our particular interest has been to determine whether the prematurely born infant continues to mature at the same rate as he would in utero, or
From the Department of Child Health, University of She~eld. Supported by the Muscular Dystrophy Group of Great Britain. This work forms part of a thesis accepted for the Doctorate in Medicine at the University of Shet~eId (A.M.). *Address: Department o] Child Health, University oI She~eld, She~ield 10, England.
whether environmental factors influence the rate of maturation of the nervous system. Earlier studies have suggested that there may be a postnatal acceleration in some aspects of development in the premature infant, such as myelination, *, 5 "vitality and general visual behavior, ''" and social smiling. ~ However, Dittrichova s found that preterm and full-term infants started smiling at the same postconceptional age. Some studies of the neurologic behavior of preterm infants have also suggested that the process of maturation is unaltered in the outside environment. 2 This has been supported by electroencephalographic studies, 8 although differences in electroencephalograms between infants of the same age born after different periods in utero have been noted." BenVoI. 79, No. 6, pp. 915-922
9 16
Moosa and Dubowitz
jamin 10 found well-defined sleep spindles present 8 to 15 days earlier in preterm infants, suggesting some acceleration of the bioelectric process, whereas EngeI ~1 found the latency of visually evoked responses to be longer in preterm infants reaching full-term age after birth than in utero, suggesting some retardation of the process of impulse conduction in the central nervous system. There have been only two studies: of peripheral nerve maturation in preterm infants after birth, 12, la although a few workers have suggested, on the basis of isolated examples, that peripheral nerve myelination is unaltered after birth in preterm infants? 4, 1~ Dubowitz and associates 12 found the mean velocities of the ulnar and posterior tibial nerves in preterm infants of 39 to 41 weeks' postconceptional age to be significantly slower than those of full-term infants immediately after birth. In contrast, the rate of increase as assessed by three or more sequential measurements of conduction velocity on each infant, appeared to be faster than that occurring in utero over the same period of time. In order to explain these seemingly contradictory findings, Dubowitz and associates 12 postulated that the factors which caused the premature birth could possibly have affected the peripheral nerve function, with resultant slowing of the conduction velocity; after birth, these factors would no longer be operative and the conduction velocity might therefore increase more rapidly. Ruppert and Johnson ~3 did serial nerve conduction studies on 11 premature and 8 small-for-date infants until one year of age and concluded that neither premature birth nor intrauterine growth retardation had any appreciable effect on the maturation of the peripheral nerves. There was clearly a need for further study to try and establish if the peripheral nerve maturation was unchanged after birth or if it was accelerated. MATERIAL
AND METHODS
Part I. Rate of maturation of peripheral nerves of preterm infants after birth and in utero. Serial ulnar and posterior tibial nerve
The ]ournal of Pediatrics December 1971
conduction velocities were measured in 9 normal preterm infants under 36 weeks' gestational age, at weekly or biweekly intervals until they reached 40 weeks' postconeeptional age. The method used was similar to that described by Hodes and associates? 6 Surface electrodes were used for both stimulating the nerve and recording the motor response. The ulnar nerve was stimulated at the elbow and wrist, and the motor response was recorded from the hypothenar muscles. The posterior tibial nerve was stimulated in the popliteal fossa and behind the medial malleolus, and the motor response was recorded from the flexor hallucis brevis muscle. The same ulnar and posterior tibial nerves were examined on each occasion. The stimulus consisted of square wave impulses of variable intensity and 0.1 msec. duration. Supramaximal stimulation was ensured by increasing the intensity of stimulus until no further increase in amplitude of motor response occurred. The response was photographed (Polaroid) and the latency calculated from the stimulus artefact to the first well-defined negative peak of the motor response. T h e difference in latency between the proximal and distal responses was divided into the intercathodal distance to give the conduction velocity in meters per second. The intercathodaI distance was measured with a steel tape, the limb being held in the same position as during stimulation. The gestational age of all the infants was calculated from the last menstrual period of the mother. We included infants for analysis only when the mothers, whom we personally interviewed, were certain of their last menstrual period, had regular 28 (-+2) day cycles, and had no bleeding subsequent to the last menstrual period. Infants of mothers who had been receiving oral contraceptives during the 12 months prior to conception were excluded. Analysis of data. The mean conduction velocity for the preterm infants at the time they reached their anticipated full-term age was compared with the mean conduction velocity of a group of normal full-term newborn infants between 39 and 41 weeks' gesta-
Volume 79 Number 6
Postnatal maturation o[ peripheral nerves
9 17
Table I. Ulnar and posterior tibial nerve conduction velocities of preterm infants reaching 39 to 41 weeks' postconeeptional age, and full-term infants (39 to 41 weeks' gestation) at birth
Nerve Ulnar (M./sec.) Posterior tiblal (M./sec.)
Preterm at 39-4l weeks (n=9) Range I Mean I2 S.E.M. 21.4-28.6 24.0 2.38 20.0-23.5 21.8 0.94
tion. A regression line of nerve conduction against postconceptional age was calculated for each preterm infant on the basis of three or more sequential measurements of conduction velocity. A mean regression line was then calculated for these 9 preterm infants. A regression line was also obtained from the first measurement of conduction velocity done immediately after birth in 43 normal newborn infants of varying gestation. This was assumed to reflect the rate of increase in nerve conduction in utero with gestational age. The two regression lines thus provided a comparison between the relative rate of increase in nerve conduction of preterm infants in utero and in the extrauterine environment. Part II. Sequential studies on normal fullterm and preterm infants until one year of age. Serial nerve conduction measurements were made at 3 monthly intervals on 6 apparently normal full-term infants and at 6 weekly intervals on 10 apparently normal preterm infants. The postconceptional age of these infants was obtained from the last menstrual period, or from the maturity score 17 in some of the preterm infants. In the preterm infants the nerve conductions were also measured as near to one year from the expected date of delivery as possible. The mean velocities of the full-term and the preterm infants were compared at birth and at 3, 6, 9, and 12 months after birth. RESULTS Part I. Rate of maturation of preterm infants until term. The results of the mean conduction velocities for the preterm and full-term infants at 39 to 41 weeks' postconceptional age are given in Table I. T h e mean conduction velocities of the ulnar nerve
Full-term (n • 15) Range I Mean 12 S.E.M. 24.4-33.3 27.7 1.24 18.1-27.3 22.2 1.18
p value <0.0t ~0.3
(24.0 + 2.38 M. per second [2 S.E.M.]) and posterior tibial nerve (21.8 _+ 0.94 M. per second [2 S.E.M.]) in the preterm infants were less than those of the full-term infants (27.7 + 1.24 and 22.2 + 1.18 M. per second, respectively). T h e mean regression line for the increase in conduction velocity in the 9 preterm infants reaching term after birth is compared with that of the 43 newborn infants of varying gestational ages in Figs. 1 and 2. The slope for the preterm infants is slightly steeper than the "in utero" line, indicating a slower rate of maturation in the external environment. This fits in with the slower mean conduction velocity for the ulnar and posterior tibial nerves at 39 to 41 weeks' postconceptional age in preterm infants as compared to full-term infants. Part II. Rate of maturation of peripheral nerves until one year. The mean ulnar and posterior tibial nerve velocities at birth and at 3, 6, 9, and 12 months postnatal age for the full-term and preterm infants are shown in Tables I I and I I I and in Figs. 3 and 4. At birth both the ulnar and posterior tibial nerve conduction velocities were significantly slower for the preterm infants than for the full-term infants. The ulnar nerve conduction remained significantly slower until 9 months of age, but at one year the difference was not statistically significant. T h e posterior tibial conduction velocity remained significantly slower in the preterm infants until 3 months of age, whereas at 6 months, 9 months, and 1 year, the difference was not statistically significant. At one year from the expected date of delivery (i.e., postconceptional age of 92 weeks), there was no difference in the mean
9 1 8 Moosa and Dubowitz
42-
The Journal of Pediatrics December 1971
//~ j
Ulnar nerve
y = 18'4250+ 0"8350X
4o38-
~ 36-
//
:
?o 34-
Y
/
/
y=21.s283+o~,431x
2~2
I 24
/S/ / ~ "
32302 28/
26
10
l 12
i 14
~ 16
i 18
Conduction
~ 20
I 26
I 28
I 30
velocity (m/sec.)
Fig. 1. Graph of intrauterine (solid line) versus extrauterlne (broken llne) increase in ulnar nerve conduction velocity with age in preterm infants. 42-
f
Posterior tibial nerve
40" 38&
/~/ y=22-,,~,+o-,22,•
36-
<
-~ 34-
.o
L~
32-
3028-
26 10
l
12
I
14
I
16
I
18
Conduction
I
20
I
22
I
24
I
26
I
28
'l
30
velocity ( m / s e e . )
Fig. 2. Graph of intrauterine (solid line) versus extrauterine (broken line) increase in posterior tibial conduction velocity with age in preterm infants. conduction velocity of the ulnar (48.8 M. per second) and posterior tibial nerves (40.7 M. per second) of the preterm infants, compared to that of the full-term infants (50.9 and 40.2 M. per second, respectively).
T h e rate of change in mean ulnar and posterior tibial conduction velocities after birth is shown in. Table IV. During the first three months of extrauterine life, the peripheral nerves of the preterm infants matured
Volume 79 Number 6
Postnatal maturation of peripheral nerves
9 19
T a b l e I I . Serial u l n a r nerve c o n d u c t i o n velocities ( m e a n + 2 S.E.M.) from b i r t h to one y e a r in n o r m a l full-term a n d p r e t e r m infants
Infants Full-term Preterm p Value
Mean gestation (wk.) 40.2 31.7
N 6 10
0 28.3+2.70 15.5+1.80 < 0.001
3 35.5 -2 2.04 29.8+2.72 < 0.01
Postnatal age in months 6 9 41.7-+ 2.08 47.6-+ 1.20 37.0+-3.04 42.7-+2.16 < 0.02 < 0~01
12 I 14 50.2-+ 1.88 47.1-+2.46 48.8+2.26 > 0.05
T a b l e I I I . Serial posterior tibial nerve c o n d u c t i o n velocities ( m e a n _+ 2 S.E.M.) f r o m b i r t h to one y e a r in n o r m a l full-term a n d p r e t e r m infants
Infants
Mean gestation (wk.)
N
0
3
40.2 31.7
6 10
20.9+2.20 12.4-+ 1.36 < 0.001
26.3+1.80 23.5 + 1.20 ~ 0.02
Full-term Preterm p Value
Postnatal age in months 6 32.0+1.64 31.1+ 1.96 > 0.2
9 38.4-+1.34 35.5-+ 2.16 > 0.05
12 ] 14 40.2+1.60 38.1 + 1.52 40.7 + 3.76 > 0.05
T a b l e I V . R a t e of increase in c o n d u c t i o n velocity of p r e t e r m a n d full-term infants after b i r t h Ulnar Preterm
Posterior tibial Full-term
% Increase
Age (moo
0-3 3-6 6-9 9-12 12-14 32-40 weeks in utero
Preterm
% Increase
Over Per Over M./sec. Over Per period month M./sec. period month M./sec. period 25.4 8.5 11.1 89.5 14.3 92.2 30.7 7.2 17.5 5.8 7.6 32.3 7.2 24.2 8.1 6.2 14.1 4.7 4.4 14.1 5.7 15.4 5.1 5.9 5.5 1.8 2.6 7.3 4.4 10.3 3.4 2.6 2.6 6.8 1.7 3.6 1.8
78.0
39.0
at a p p r o x i m a t e l y the same rate as those of the p r e t e r m infants in utero from 32 to 40 weeks. F r o m 3 to 6 months, the conduction velocity increased at a rate equivalent to t h a t of the full-term infants d u r i n g the first three months. I n other words, the rate of increase in c o n d u c t i o n velocity of p r e t e r m infants lagged b e h i n d t h a t of full-term infants by a b o u t 2 to 3 months. A l t h o u g h continuing to lag behind, the m e a n velocity a p p r o a c h e s t h a t of full-term infants by 9 m o n t h s for the u l n a r a n d 3 m o n t h s for the posterior tibial nerve. This is not due to a " c a t c h - u p " in c o n d u c t i o n velocity for the p r e t e r m infants, b u t to the falloff in rate of increase of cond u c t i o n velocity in full-term infants with
Full-term
% Increase
85.0
% Increase
Over Per Per month M./sec. period month
29.8 10.8 4.7 2.4 3.3
5.4 5.7 6.4 1.8
25.8 21.7 20.0 4.7
8.6 7.2 6.7 1.6
42.5
time (Figs. 3 a n d 4). T h e two curves (of m e a n velocity) are thus convergent. This i n t e r p r e t a t i o n is well illustrated by r e d r a w i n g the curves based on the postconceptional age r a t h e r t h a n the postnatal age. This effectively shifts the curve of the preterm infants by 2 months to the left. I t will be seen t h a t the two curves then become superimposed (Fig. 5). DISCUSSION
T h e slower c o n d u c t i o n velocity of the preterm infants r e a c h i n g 40 weeks' postconceptional age after birth is in a g r e e m e n t with the results o b t a i n e d by Dubowitz a n d associates. 12 W h e r e a s they found an accelerated
920
The Journal of Pediatrics December 1971
Moosa and Dubowitz
56
Umnar nerve
48,
J $ / t
d
0 >
32-
.o_
•
3 0
24-
16"
Full t e r m i n f a n t s
o
Premature infants
*
Postnatal Age in m o n t h s
Fig. 3. Sequential ulnar nerve conduction velocities in normal preterm and full-term infants after birth. The bars on either side of the mean represent 2 S.E.M. Posterior tibial nerve
48
d f 5
_o 32
_g "D tO O
24
16 ~ r
0
~
:
Furl-term infants Premature infants
3
6 9 Postnatal Age in m o n t h s
o 9
12
15
Fig. 4. Sequential posterior tibiaI nerve conduction velocities in normat preterm and full-term infants after birth. rate of increase in the conduction velocity of p r e t e r m infants after birth, the present study revealed a slower rate of increase, which fits in with the slower m e a n velocities at 40 weeks' postconceptional age. F o r the first few weeks after birth the pc-
ripheral nerves of the p r e t e r m infant thus seem to m a t u r e at a slightly slower rate t h a n over the same period in utero. This parallels the longer latency found by EngeP 1 for visually evoked cortical responses in p r e t e r m infants after birth c o m p a r e d to those in new-
Volume 79 Number 6
Postnatal maturation of peripheral nerves
92 1
56 ~ Ulnar nerve o 48-
d 40-
E
~>
32-
o// 0
24-
/ 16-
e/
Full-term infants
o
Premature infants
9
8
3o
4'0
5o Postconceptional
6;
7o
8'0
9;
A g e in w e e k s
Fig. 5. Ulnar nerve conduction velocity in preterm and full-term infants after birth plotted against postconceptional age instead of postnatal age. Note almost identical course of the 2 curves.
born full-term infants at similar postconceptional ages. Whereas both the central and peripheral impulse conducting pathways of preterm infants are slightly delayed in maturation after birth, the electroencephalographie maturation ~ is not influenced by premature birth. This suggests that myelination is slightly retarded in these infants while dendritic arborization and the development of axodendritic synapses is unaltered. The degree of retardation of peripheral nerve conduction, however, is small and probably of no clinical significance. This is borne out by the fact that the maturation of the neurologic behavior of preterm infants is unaltered by premature birth. 2, 18 Moreover, the difference in conduction velocity between preterm and full-term infants of 40 weeks' postconceptional age is not maintained during the first year of life. By 44 weeks' postconceptional age the conduction velocities are similar and remain so throughout the rest of the first year of life (Fig. 5). This correlates well with the neurologic
maturation of preterm infants during the first year of life. Gesell and Amatruda 19 and Illingworth 2~ maintain that the developmental assessment of the preterm infant should be related to the postconceptional age and not age from birth. Parmelee and Schulte ~1 did developmental tests on preterm, normal full-term, and small-for-date fullterm infants 40 weeks after birth and found that preterm infants scored less than the normal full-term and small-for-date infants. They concluded that preterm infants should have their age determined from their expected date of delivery for the purposes of developmental assessment. The maturation of the peripheral nerves in preterm infants during the first year of life also correlates with that of the electroencephalogram. Parmelee and associateP 2 found the electroencephalogram at term and at 3 months and 8 months after term to be the same in preterm and full-term infantsl in spite of the fact that the preterm infants were chronologically advanced by 2 to 3 months. These results suggest that the peripheral
922
Moosa and Dubowitz
nervous system of p r e t e r m infants continues to m a t u r e as a function of postconceptional age a n d not of postnatal age. We wish to thank Dr. J. A. Black for access to patients under his care, Miss M. Flavin, Miss W. Wallace, and the Nursing Staff for help with the measurements, Mrs. C. Goldberg for helpful advice with the statistics, and Mr. A. Tunstill for the photography. REFERENCES
1. Larroche, J. C.: The development of the central nervous system during intrauterine lif% in Faulkner, F., editor: Human development, Philadelphia, 1966, W. B. Saunders Company, p. 257. 2. Salnt-Anne Dargassies, S.: Neurological maturation of the premature infant of 28 to 41 weeks' gestational age, in Faulkner, F., editor: Human development, Philadelphi% 1966, W. B. Saunders Company, p. 306. 3. Dreyfus-Brisac, C.: The bioelectric development of the central nervous system during early 1lie, in Faulkner, F., editor: Human development, Philadelphia, 1966~ W. B. Saunders Company, p. 286. 4. Westphal, A.: Die electrlsche Erregbarkeitsverh~iltnisse des peripherischen Nervensystems des Mensehen in jugendlichem Zustand und ihre Beziehungen zu dem anatomisehen Bau desselben, Arch. Psychiat. 26: 1, 1894. 5. Langworthy, O. R.: Development of behavior patterns and myelinization of the nervous system in the human fetus and infant. Contrib. Embryol. Carnegie Inst. Wash. 24: 1, 1933. 6. Esente, I.: Physiologle de la vision chez le premature et le nourrisson normal, Quoted by Peiper, A. (1963), in Cerebral function in infancy and childhood, New York, 1958, Consultants Bureau, p. 66. 7. Michaelis, R.: Quoted by Schuhe in Robinson, R. J., editor: Brain and early behavior, London, 1969, Academic Press, Inc., p. 112. 8. Dittrichova, J.: Social smiling, in Robinson, R. J., editor: Brain and early behavior, London, 1969, Academic Press, Inc., p. 112. 9. Dreyfus-Brisac, C.: The electroencephalogram of the premature infant, World Neurol. 3: 5, 1962.
The Journal o[ Pediatrics December 1971
10. Benjamin, J. D.: In Brosin, A. W., editor: The innate and the expericntial in developmen L Pittsburg, 1961, University of Pittsburg Press, p. 19. 11. Engel, R.: Maturational changes and abnormalities in the newborn electroencephalogram, Develop, Med. Child. Neurol. 7: 498, 1965. 12. Dubowitz, V.~ Whittaker, G. F, Brown, B. H., and Robinson, A.: Nerve conduction velocity - - a n index of neurological maturity of the newborn infant, Develop. Med. Child Neurol. 10: 741, 1968. 13. Ruppert, E. S., and Johnson, E. W.: Motor nerve conduction velocities in low birth weight infants, Pediatrics 43: 255, 1968. 14. Thomas, J. E., and Lambert, E. H.: Ulnar nerve conduction velocity and H-reflex in infants and children~ J. Appl. Physiol. 15: 1, 1960. 15. Blom, S., and Finnstr6m, O.: Motor conduction velocities in newborn infants of various gestational ages, Acta Paediatr. Scand. 57: 377, 1968. 16. Hodes, R., Larrabee, M. G., and German, W.: The human electromyogram in response to nerve stimulation and conduction velocity of motor axons, Arch. Neurot. Psychiat. 60: 340, 1948. 17. Dubowitz, L., Dubowitz, V., and Goldberg, C.: Clinical assessment of gestational age in the newborn infant, J. P~DIATm 77: 1, 1970. i8. Robinson, R. J.: Assessment of gestational age by neurological examination, Arch. Dis. Child. 41: 437, 1966. 19. Gesell, A., and Amatruda, C. S.: Developmental diagnosis, New York, 1947, Hoeber Medical Division, Harper & Row, Publishers, Inc., p. 290. 20. Illingworth, R. S.: Development of the infant and young child, ed. 4, Edinburgh, 1970, E. & S. Livingstone, Ltd., p. 359. 21. Parmelee, A. H., and S~chulte, F. J.: Developmental testing of preterm and small-for-dates infants, Pediatrics, 45: 2I, I970. 22. Parmelee, A. H., Wenner, W. H., Akiyama, Y., Stern, E., and Flescher, J.: Electroencephalography and brain maturation, in Minkowski, A., editor: Regional development of the brain in early life, Oxford, 1967, Blaekwell Scientific Publications, Inc., p. 459.