N E O N A T A L S E R U M B I L I R U B I N LEVELS F O L L O W I N G T H E U S E O F P R O S T A G L A N D I N E2 IN LABOUR

A.RoL. Weekes, S e n i o r R e g i s t r a r and JoM. Beazley, P r o f e s s o r D e p a r t m e n t o f O b s t e t r i c s and O y n a e c o l o g y , U n i v e r s i t y o f Liverpool, N e w M e d i c a l School, Liverpool, L69 3BX, England°

ABSTRACT A p r o s p e c t i v e study of 447 labours a n d the r e s u l t i n g n e o n a t e s f a i l e d to reveal a s i g n i f i c a n t difference between the mean serum bilirubin concentrations on the t h i r d a n d sixth day f o l l o w i n g spontaneous, a c c e l e r a t e d or i n d u c e d labour. A similar incidence of neonatal jaundice (bilirubin c o n c e n t r a t i o n s of I0 m g / l O 0 or more) was f o u n d in the s t u d i e d groups. However, there was a t e n d e n c y for neonates b o r n after a c c e l e r a t e d or i n d u c e d labour to have s l i g h t l y higher b i l i r u b i n levels than those born after s p o n t a n e o u s labour. N o strong dose dependent effect on the level of b i l i r u b i n concentration following Prostaglandin E 2 induced labour was d e m o n s t r a t e d .

ACKNOWLEDGEMENTS We are g r a t e f u l to Mr. R. D. A t l a y a n d Mr. D. P r y s o r - J o n e s for a l l o w i n g us to study their p a t i e n t s , and to the n u r s i n g staff whose a s s i s t a n c e was invaluable° We w o u l d like to thank Mr. ~ D o d d for m e a s u r i n g the s e r u m b i l i r u b i n levels a n d Mr. M.C.K. T w e e d i e and Mr. C. R. West for s t a t i s t i c a l advice°

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INTRODUCTION Recent studies have c o n f i r m e d an a s s o c i a t i o n b e t w e e n o x y t o c i n i n d u c e d labour and neonatal jaundice (i~2). The tendency for neonates to develop high b i l i r u b i n levels after o x y t o c i n i n d u c e d labour appears to be dose related. There have been two small studies to date relating to neonatal b i l i r u b i n levels after P r o s t a g l a n d i n E 2 induced labour. Calder et al (3) r e p o r t e d a s i g n i f i c a n t l y greater m e a n b i l i r u b i n level following P r o s t a g l a n d i n E 2 i n d u c e d labour w h e n c o m p a r e d with patients who h a d spontaneous labour. In contrast, de H e m p t i n n e et al (4) f a i l e d to d e m o n s t r a t e a difference. The object of this study was to e s t a b l i s h if there was a r e l a t i o n s h i p b e t w e e n P r o s t a g l a n d i n E 2 induced or a c c e l e r a t e d labour and a tendency for the r e s u l t i n g neonates to develop higher levels o f serum b i l i r u b i n when c o m p a r e d with neonates resulting from s p o n t a n e o u s labour. PATIENTS AND METHODS A p r o s p e c t i v e study was m a d e of 476 c o n s e c u t i v e patients who d e l i v e r e d v a g i n a l l y at M i l l R o a d M a t e r n i t y Hospital. All patients were m o r e than 37 weeks g e s t a t i o n at delivery. They were g r o u p e d according to the type of labour: i. 2o 3o

S p o n t a n e o u s - 188 patients A c c e l e r a t e d with P r o s t a g l a n d i n E 2 - 5 5 patients I n d u c e d by low amniotomy and s i m u l t n e o u s iov. P r o s t a g l a n d i n E 2 infusion - 204 patients.

The c r i t e r i a u s e d for group d i s t r i b u t i o n were as follows:

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io S p o n t a n e o u s : - p a t i e n t s in this c a t e g o r y all h a d s p o n t a n e o u s onset o f labour w h i c h p r o c e e d e d u n a i d e d by exogenous u t e r i n e s t i m u l a t i o n (oxytocin or P r o s t a g l a n d i n E2) e v e n t u a l l y c u l m i n a t i n g in v a g i n a l delivery. 2. A c c e l e r a t e d : - labour was o f s p o n t a n e o u s onset b u t if progress, as j u d g e d by p a r t o g r a p h i c m o n i t o r i n g of c e r v i c a l dilation (5), was d e l a y e d for 2 hours or more labour was a c c e l e r a t e d w i t h Prostaglandin E 2 . 3. Induced: - this group c o n s i s t e d o f p a t i e n t s in w h o m p r e g n a n c y was a r t i f i c a l l y i n t e r r u p t e d by simultaneous low amniotomy and Prostaglandin E 2 infusion. The d e c i s i o n to induce labour was m a d e by the a t t e n d i n g physician~

T h e rate of i n f u s i o n of P r o s t a g l a n d i n E 2 was c o n t r o l l e d by IVAC pumps. The i n f u s i o n rate was t i t r a t e d against u t e r i n e response. R e c o r d s were kept of i n f u s i o n rates, the i n d u c t i o n d e l i v e r y interval and d u r a t i o n o f labour. The dose of P r o s t a g l a n d i n E 2 r e c e i v e d by each patient was calculated. All neonates were given an i n t r a - m u s c u l a r i n j e c t i o n o f 1 mg of p h y t o m e n a d i o n e w i t h i n twentyfour hours of birth. N e o n a t a l serum b i l i r u b i n c o n c e n t r a t i o n s were e s t i m a t e d f r o m heel p r i c k c a p i l l a r y b l o o d o b t a i n e d on the t h i r d and sixth day o f life. T h e m e a s u r e m e n t s were done u s i n g a direct r e a d i n g b i l i r u b i n o m e t e r (American O p t i c a l Corporation). A h u n d r e d and four neonates (23 per cent) who were d i s c h a r g e d early from h o s p i t a l did not have sixth day b i l i r u b i n e s t i m a t i o n s performed° N e o n a t e s w h o s e serum b i l i r u b i n c o n c e n t r a t i o n s r e a c h e d or e x c e e d e d i0 m g / l O 0 ml were c o n s i d e r e d to have s i g n i f i c a n t levels o f jaundice and were further investigated° No n e o n a t e was a l l o w e d home i f the b i l i r u b i n level on the third day r e a c h e d or e x c e e d e d 9 m g / 1 0 0 ml.

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E x c l u d e d f r o m the study were neonates weighing less than 2.5 kg, dysmature neonates, and mothers who p o s s e s s e d erythrocyte antibodies. Twenty-nine patients were thus excluded from the final analysis. Amongst these exclusions were neonates with other recognized causes of jaundice°

RESULTS Cumulative Frequency Concentrations

Distribution

of Bilirubin

Figure 1 shows the cumulative frequency distribution of neonatal bilirubin concentrations on the third day° Following spontaneous labour 50 per cent of neonates had a bilirubin concentration of at least 5.7 m g / 1 0 0 ml. After accelerated or induced labour the 50th percentile value was 6.2 mg/lOO ml. The 90th percentile value of bilirubin concentration was 9.6 mg/100 ml following spontaneous labour and 10.2 mg/lO0 ml following accelerated or induced labour. Figure II shows the cumulative frequency distribution of neonatal bilirubin concentrations on the 6th day. The 50th percentile value of bilirubin c o n c e n t r a t i o n was 3.7 mg/lO0 ml following spontaneous labour and 4°2 mg/lO0 ml f o l l o ~ n g accelerated or induced labour. At the 90th percentile the corresponding values were spontaneous, 8°7 mg/lO0 ml, accelerated and induced, 10.4 mg/lO0 ml.

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lifO.

I10.

'/J/ C'U~,~JLAT IVI~ %

OF TOTALNLI/VlER C~ BABIES 40.

/,'/

20-

TOTALIILmUlilN LEVEL(nl~m/'lO0ml)

Figure 1 Cumulative frequency polygon of neonatal bilirubin concentrations on day three°

W.

CUMULATIVE%

60 .

(3f reAltIES 40.

1

~,

~

I"3 f,

I~ i'6 0

TOTALBILmI~IN LEVEL(e'~lm/lO0el)

Figure ii Cumulative frequency polygon of neonatal bilirubin concentrations on day six.

OCTOBER 1975

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PROSTAGLANDINS

Mean Bilirubin Concentrations Table 1 shows the mean b i l i r u b i n concentration in the studied groups. T h e r e was no significant difference in the mean b i l i r u b i n c o n c e n t r a t i o n following s p o n t a n e o u s labour, compared with either that following induced labour, or for that following a c c e l e r a t e d labour on either day 3 or day 6 (t test p > 0°05 in all instances). In addition, one-way analysis of variance on the b i l i r u b i n c o n c e n t r a t i o n s in all three groups gave the f o l l o w i n g results:D a y 3: ~ = 1.89 (2 and 444 dot.). significant ( p > 0.05),

This is not

D a y 6: ~ = 1.47 (2 and 340 d.f.). This also is not s i g n i f i c a n t ( p > 0.05). I n c i d e n c e of neonates with or i0 m @ / 1 0 0 ml or more

Bilirubin Concentrations

A f t e r s p o n t a n e o u s labour the i n c i d e n c e was 9.6 per cent, a c c e l e r a t e d labour 16o4 per cent, and induced labour 14o7 per cent. These d i f f e r e n c e s are not s t a t i s t i c a l l y s i g n i f i c a n t (Chi 2 on appropriate c o n t i n g e n c y table p > 0oi)o (Table II)o R e i a t i 0 n s h i p B e t w e e n Birthweight Levels of i0 m g / 1 0 0 ml or more

and B i l i r u b i n

Table III i l l u s t r a t e s the d i s t r i b u t i o n o f neonates with b i l i r u b i n levels of i0 m g / 1 0 0 ml or m o r e against birthweight. No significant a s s o c i a t i o n was d e m o n s t r a t e d between b i l i r u b i n levels of I0 m g / 1 0 0 ml or m o r e and birth weight when an i n d e p e n d e n t analysis of each of the three groups was p e r f o r m e d (Chi for linear t r e n d p > 0°05 for all three groups)°

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PROSTAGLANDINS TABLE

I

M e a n B i l i r u b i n Concentrati0,ns,,,,,in,' m g / 1 0 0 the three studied,.~rpup,, s Day Spontaneous (no PGE2) Accelerated

Induced

TABLE

5.59

with

with

PGE 2

PGE 2

3

ml ± SD in

Day 6 +- 3 o 1 5

4.29

+- 3 . 0 7

(n = 188)

(n = 141)

6°45

4.82

(n = 55)

4-_ 3 . 6 9 (n = 38)

6 . 0 7 +- 3o10 (n = 204)

4.83 + 3.36 (n = 164)

+- 3 o 1 4

II

I n c i d e n c e of N e o n a t e s w i t h B i l i r u b i n of I0 m @ / 1 0 0 ml or more in the three 001

VOL. 10 NO. 4

705

o

©

©

©

~D 0%

30(204)

18(188)

TOTAL

0(I)

0(1)

- 4°99

4.5

6(13)

0(8)

- 4.49

7(54)

12(102)

5(34)

4.0

3(47)

12(83)

3(49)

Induced with PGE 2

- 3.99

- 3.49

- 2.99

Spontaneous

a Bilirubin

3.5

3.0

2.5

Birthwei@ht (kg)

N u m b e r of N e o n a t e s w i t h o f IO m ~ / i O 0 ml or m o r e

9(55)

0(i)

0(2)

3(13)

5(20)

1(19)

Accelerated with PGE 2

level

D i s t r i b u t i o n qf N e o n a t e s w i t h B i l i r u b i n C o n c e n t r a t i o n q f I0 m @ / 1 0 0 ml o r more in r e l a t i o n to B i r t h w e i @ h t (The total number of n e o n a t e s in e a c h w e i g h t c l a s s is shown in p a r e n t h e s e s )

T A B L E III

C~

r~

>

O0

O

PROSTAGLANDINS

Relationship between Prosta@landin E 2 Dosage B i l i r u b i n L e v e l s of i0 m @ / 1 0 0 ml or m o r e

and

T h e m e a n dose o f P r o s t a g l a n d i n E 2 u s e d to i n d u c e a n d a c c e l e r a t e l a b o u r is s h o w n in T a b l e IV. T h e m e a n total dose o f P r o s t a g l a n d i n E 2 u s e d to i n d u c e l a b o u r was 0 ° 5 8 8 ± 0.366 mg in t h o s e n e o n a t e s who h a d b i l i r u b i n l e v e l s less t h a n l0 mg p e r i00 mlo A g r e a t e r m e a n t o t a l dose of P r o s t a g l a n d i n E 2 was u s e d to e f f e c t d e l i v e r y in t h o s e n e o n a t e s w h o s e b i l i r u b i n levels r e a c h e d or e x c e e d e d i0 mg p e r I00 ml. This d i f f e r e n c e was s i g n i f i c a n t at the 5 per cent l e v e l (t test 0.02 < p < 0.05). No such t e n d e n c y was d e m o n s t r a t e d f o l l o w i n g a c c e l e r a t e d l a b o u r (t test p > 0.05). T h e p r o p o r t i o n of n e o n a t e s who h a d b i l i r u b i n l e v e l s of IO mg per I00 ml or m o r e was d i s t r i b u t e d a g a i n s t the d o s e o f P r o s t a glandin E 2 received. Following induced labour there was a t e n d e n c y for t h o s e n e o n a t e s w i t h b i l i r u b i n l e v e l s of i0 mg per i00 ml or m o r e to be in g r e a t e r p r o p o r t i o n in the h i g h e r dose r a n g e s of P r o s t a g l a n d i n E 2 u s e d ( T a b l e V). T h i s t e n d e n c y was s i g n i f i c a n t at the 5 per cent l e v e l (Chi 2 for l i n e a r t r e n d 0 ° 0 2 < p < 0.05; W i l c o x o n test b e t w e e n m e a n r a n k s 0 . 0 2 < p < 0.05). No s u c h t e n d e n c y was o b s e r v e d f o l l o w i n g a c c e l e r a t e d l a b o u r (Chi 2 for l i n e a r t r e n d p > 0.05). The Pearson product-moment correlation coefficient b e t w e e n t h e P r o s t a g l a n d i n E2 d o s e s a n d the b i l i r u b i n l e v e l s w e r e not s i g n i f i c a n t l y d i f f e r e n t f r o m zero for a n y o f the g r o u p s s t u d i e d (Table V I ) . Duration

of L a b o u r

N o s i g n i f i c a n t r e l a t i o n s h i p was d e m o n s t r a t e d b e t w e e n the d u r a t i o n of l a b o u r a n d t h e p r o p o r t i o n o f n e o n a t e s w i t h b i l i r u b i n levels of i0 mg p e r I00 ml or m o r e f o l l o w i n g s p o n t a n e o u s or a c c e l e r a t e d l a b o u r (Chi 2 for l i n e a r t r e n d p > 0oi). (Table VII). Following induced labour s i g n i f i c a n t at the 5 per cent l e v e l s of I0 mg per i00 ml or w i t h an i n c r e a s e d d u r a t i o n o f t r e n d 0 . 0 2 < p < 0.05).

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t h e r e was a t e n d e n c y , level, for b i l i r u b i n m o r e to be a s s o c i a t e d l a b o u r (Chi 2 for

707

IV

©

©

0.734

Mean

© (~ 0.382)

n = 30

o f PGE 2

(mg)

dose

i0 m g / 1 0 0 or m o r e

ml

Labour

Bilirubin Concentration

Induced

n = 174

(~ 0 ° 3 6 6 )

0.588

< i0 m g / 1 0 0

ml

n = 9

(~ 0 . 1 6 6 )

0.464

i0 m g / l O 0 or m o r e

Accelerated ml

ml

n = 46

(~ 0 . 1 8 9 1

0.368

< i0 m g / 1 0 0

Labour

M e a n dose of P r o s t a @ l a n d i n E 2 (T SD) r e c e i v e d by M o t h e r s of N e o n a t e s with[ B i l i r u b i n C o n c e n t r a t i o n of i0 m ~ / 1 0 0 m! or m o r e a n d < !0 m @ ~ 1 0 0

TABLE

©

00

ml

UP

©

O

©


1.5

-

0

1.49

.99

.49

Dose of PGE2 received by mothers (m9)

Distribution i0 m @ / l O 0 m l Prosta@landin

TABLE

6

21

83

94

0

0

7 0

17

38

15

8

No. of babies

No. of babies

of

0

0

5

4

No. of babies with bilirubin of i0 m9 per i00 ml or more

Accelerated

Induced No. of babies with bilirubin of I0 mg Der i00 ml or more

of Neonates with a Bilirubin Concentration or m o r e i n R e l a t i o n to t h e T o t a l D o s e o f E 2 received by mothers

>

© ~n

c

©

&a

©

©

c~

VI

36

53

162

202

d.f.

Levels

0.534

0.616

0+155

0°053

(two tailed)

and Bilirubin

coefficient

0.6277

0.5049

1.4270

1.9482

~

E 2 Dosa@e

correlation

+0.1027

+0.0692

+0.1114

+0.1358

Correlation ~ Coefficient

Prostaglandin

product-moment

38

Accelerated (Day 6)

Pearson,s

55

164

Induced (Day 6)

Accelerated (Day 3)

204

Induced (Day 3)

Correlation ' between

TABLE

OD

>

>

OD

P

©

©

©

VII of

Neonates

with

a

Bilirubin

Concentration

of

0(2) 18(188)

is

TOTAL

1(19)

9(81)

Spontaneous

I0 - 14.9

Labour

8(86)

-

5

of

with

or"'more

9(55)

0(5)

0(8)

7(33)

2(9)

with PGE 2

Accelerated

ml

of Neonates

I0 m ~ / l ' O 0

9.9

s




0~

PROSTAGLANDINS

DISCUSSION O u r f i n d i n g s are at v a r i a n c e w i t h those r e p o r t e d by C a l d e r et al (3). We f o u n d no s i g n i f i c a n t d i f f e r e n c e b e t w e e n the m e a n s e r u m b i l i r u b i n concentrations following spontaneous, accelerated or i n d u c e d labour. T h i s is in a g r e e m e n t w i t h the f i n d i n g s of de H e m p t i n n e a n d c o - w o r k e r s (4). H o w e v e r , a s t r i c t c o m p a r i s o n w i t h this s t u d y is not p o s s i b l e as s e r u m b i l i r u b i n m e a s u r e m e n t s w e r e done on c o r d b l o o d o b t a i n e d at d e l i v e r y . In a d d i t i o n ~ oral a n d not i n t r a v e n o u s P r o s t a g l a n d i n E2 was u s e d to i n d u c e labour. Following induced labour a difference s i g n i f i c a n t at the 5 per cent l e v e l was f o u n d b e t w e e n the m e a n t o t a l dose of P r o s t a g l a n d i n E 2 r e c e i v e d by m o t h e r s w h o s e n e o n a t e s d e v e l o p e d b i l i r u b i n l e v e l s of I0 mg or m o r e per I00 ml and those mothers whose neonates had bilirubin levels b e l o w i0 mg per i00 ml. Nevertheless, a significant c o r r e l a t i o n was not d e m o n s t r a t e d b e t w e e n the dose o f P r o s t a g l a n d i n E 2 a n d the s e r u m b i l i r u b i n c o n c e n trationo The p o s s i b i l i t y o f n e o n a t e s d e v e l o p i n g b i l i r u b i n l e v e l s o f i0 mg or m o r e per I00 ml a p p e a r e d to i n c r e a s e s l i g h t l y the l o n g e r the d u r a t i o n o f i n d u c e d labour° H o w e v e r , the e v i d e n c e of P r o s t a g l a n d i n E 2 e x e r t i n g a s t r o n g d o s e d e p e n d e n t e f f e c t on n e o n a t a l j a u n d i c e s e e m s u n l i k e l y as of the six m o t h e r s who r e c e i v e d l a r g e doses of P r o s t a g l a n d i n E 2 to i n d u c e l a b o u r (more than 1.5 mg), n o n e o f the r e s u l t i n g n e o n a t e s d e v e l o p e d b i l i r u b i n l e v e l s o f I0 mg or m o r e p e r i00 ml. We f o u n d no e v i d e n c e to s u g g e s t a d o s e d e p e n d e n t e f f e c t on the n e o n a t a l b i l i r u b i n c o n c e n t r a t i o n f o l l o w i n g a c c e l e r a t e d labour° O n e p o s s i b l e e x p l a n a t i o n for the lack o f a d o s e d e p e n d e n t r e l a t i o n s h i p to the i n c i d e n c e o f h y p e r b i l i r u b i n a e m i a is the k n o w n r a p i d i t y w i t h w h i c h P r o s t a g l a n d i n s are m e t a b o l i s e d . Ninety per c e n t of E a n d F P r o s t a g l a n d i n s are i n a c t i v a t e d in a s i n g l e p a s s a g e t h r o u g h the lungs° It has b e e n d e m o n s t r a t e d in the h u m a n s u b j e c t that 90 per cent of 3H l a b e l l e d P r o s t a g l a n d i n E 2 i n j e c t e d

712

OCTOBER 1975 VOL. 10 NO. 4

PROSTAGLANDINS

i n t r a v e n o u s l y is i n a c t i v a t e d in 1.5 minutes (6)° In the sense that they undergo such rapid degradation, P r o s t a g l a n d i n s are unlike c i r c u l a t i n g hormones (7). In contrast, oxytocin, a n a t u r a l l y o c c u r r i n g octapeptide, a d m i n i s t e r e d in large p h a r m a c o l o g i c a l doses to induce labour m a y overb u r d e n the fetal liver, whose enzyme systems are p r o b a b l y immature. P r o s t a g l a n d i n E2 by virtue of its rapid i n a c t i v a t i o n would not pose such a problem. The cumulative f r e q u e n c y d i s t r i b u t i o n of n e o n a t a l b i l i r u b i n c o n c e n t r a t i o n on both day 3 and day 6 shows a shift to the right following i n d u c e d and a c c e l e r a t e d labour when c o m p a r e d w i t h that f o l l o w i n g spontaneous labour° This w o u l d suggest that i n d u c e d a n d a c c e l e r a t e d labour is a s s o c i a t e d w i t h a small but definite tendency for the n e o n a t a l b i l i r u b i n level to be higher than when labour is spontaneous° This o b s e r v a t i o n c o u l d be a reflection of the i m m a t u r i t y of the fetal hepatic enzyme systems° It has r e c e n t l y been shown that c o r d blood cortisol levels are higher in neonates born after spontaneous labour than induced labour (8). Furthermore, cortisol is thought to be n e c e s s a r y for the m a t u r a t i o n of the fetal hepatic enzyme systems (9). This could e x p l a i n the trend for serum b i l i r u b i n levels to be slightly higher f o l l o w i n g i n d u c e d labour. If this is the case, i n d u c t i o n of labour itself is p r o b a b l y responsible for the t e n d e n c y to s l i g h t l y higher b i l i r u b i n Ievels when c o m p a r e d with neonatal b i l i r u b i n levels following spontaneous labour. As we have not found s t r o n g evidence to support a dose dependent effect for F r o s t a g l a n d i n E 2 it is s u g g e s t e d that those mothers whose neonates are known to be at risk from developing n e o n a t a l jaundice (Rhesus isoimmunisation, prematurity), if labour is to be i n d u c e d P r o s t a g l a n d i n E 2 is p r e f e r a b l e to oxytocin. Our findings seem to indicate that P r o s t a g l a n d i n E 2 w o u l d also be p r e f e r a b l e for a c c e l e r a t i n g labour in order to reduce the chances of neonatal m o r b i d i t y from h i g h b i l i r u b i n levels° The level o f serum b i l i r u b i n c o n c e n t r a t i o n above which it constitutes a danger %0 the n e o n a t e has not b e e n c l e a r l y defined. There is a n e e d for a long t e r m f o l l o w up of infants who d e v e l o p h y p e r b i l i r u b i n a e m i a to assess the effect, if any~ on their subsequent development.

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REFERENCES

714

I°

Beazley, JoM., Alderman, B. British Journal of Obstetrics and Gynaecology, 1975, 82, 265.

2.

Chalmers, I°, Campbell, H., Turnbull, AoC. British Medical Journal, 1975, 2, 116.

3.

Calder, A°A., Ounsted, MoK., Moat, V°A=, Turnbull, A°C., Lancet, 1974, ii, 1339o

4.

de Hemptinne, D., Schuddinck, Lo, Thiery, Mo, Martens, G° International Research Communications System (72-12) 10-14-3.

5.

Beazley, J°Mo, Kurjak, A. Lancet, 1972, 2, 328.

6o

Samuelsson, B., Granstrome, E., Green, K., Hamburg, Mo Metabolism of Prostaglandins. Annals of New York Academy of Sciences, 1971, 180, 138-163°

7.

Embrey, M.Po The Prostaglandins in Human Reproduction, London, Churchill Livingstone, 1975, po13o

8.

Murphy, BoEoP. American Journal of Obstetrics and Gynecology, 1973, 115, 521o

9.

Rose, D°P., Braidman, I.P. Lancet, the Editor), 1970, I, 1117.

OCTOBER 1975

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