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The fetal brain and parturition
63
Animal Reproduction Science, 2 (1979) 63-75 0 Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
THE FETAL BRAIN AND PARTURITION
K.BOER, D.F.SWAAB Netherlands
and M.VISSER
Institute
for Brain Research,
Amsterdam,
The Netherlands
ABSTRACT
The primate mean
fetal brain
length of gestation.
production
appears
chapter
the role of CLIP,
which
the involvement
governing
the switch
In addition,
is produced
a switch
how this switch of labour,
could be related
hormones
corticotropic
production
In
to the posis made
in addition
of the fetal brain in the final timing
in pituitary
the latter.
and a conjecture
by the fetal pituitary
the species
in the fetal pituitary
and ACTH seems to favour
for the induction
Moreover,
neurohypophysial
a-MSH
it is discussed
sible fetal mechanism
the time of birth around
At the end of gestation
of the corticotropics
the present
to adjust
for
to C1-MSH.
of birth
by
and by the release
of
is discussed.
the release
tate the course
of labour,
the fetal brain
appears
of fetal oxytocin
during
labour is thought
to facili-
not only in man but also in the rat, in which
not to be involved
species
in the onset of labour.
INTRODUCTION No intelligent
person
would
commit his fate entirely
else, not even those of his own mother. differences
the fetal sheep brain, which onset of labour
(11, while
little,
if any, significance
of Heap
(3)). According
and Rhesus
Inasmuch
in the level of brain development
monkey
is relatively
in species
as intelligence
at birth
mature,
to this conjecture,
is primarily
anencephaly
human model
is the anencephalic
is still mentioned
being prolonged.
responsible
the fetal brain
brain maturation
If and how the primate
in species
why
for the is of scheme
like man
fetal brain is involved
in the following
pages.
of parturition
The best available onset of labour
with age,
explain
(2, cf. also the hierarchical
in the onset and course of labour will be discussed
The initiation
matures
(fig. 1) might
like rat and rabbit
in this respect
is intermediary.
into the hands of someone
But Honnebier
for the study of fetal brain involvement fetus. Pregnancy
in the textbooks and Swaab
length in combination
(4) and current
(6), studying
literature
in the with (5) as
a large numberofanencephalic
64
HUMAN CP
1
A
PIG
C
A-
MONKEY
C
2
3
P
10
20
30
WEEKS
P
10
20
30
WEEKS
P
10
20
30
WEEKS
P
10
20
30
40
OAYS
P
IO
20
30
40
DAYS
20
30
40
DAYS
4
YEARS
SHEEP C
GUINEA
PIG --
c
A
RABBIT
C
4-e--
RAT
c
P
10
Fig. 1. The velocity of brain growth (B) in relation to the time of parturition (P) in various species; C = moment of conception. (From95, see also for references, with permission of the North Holland Publishing Company.) gestations
found, on the contrary,
shortened.
Anencephaly,
known
to shorten
gestation.
the remainder
hydramnios,
the case histories
adrenal
studies
of which
centrations
which
(for a recent
The pituitaries release
aplasia
(9) do not point
to the fetus
of cortisol
of labour,
(10). These
review,
Also
of the
mean preg-
unless ACTH or
findings,
and a wealth
of
by a rise in fetal
of the fetal hypothalamo-
see 11).
still contain
some ACTH
by AVP injection
have been found to be low
cortisol
(39.7 weeks).
the absence
to an increased
is likely under the control
of anencephalics
with
with those in the sheep, where hypophysectomy
with the occurrence
can be stimulated
in man fetal plasma
length
including
to be
a condition
of the data for anencephalics
showed that in the sheep labour is triggered
release,
complex
by hydramnios,
a normal mean gestation
contrast
are administered
cortisol
pituitary
findings
length in anencephalics
accompanied
(cf. 7), microcephaly
fetus is incompatible
corticosteroids additional
revealed
of acephaly
length. These
of a singlet
the mean gestation
is frequently
After elimination
and pituitary
(8) ,
hypothalamus nancy
however,
may be of maternal
(12, 13, p.243,
(13, p.243).
Umbilical
(15) or low-normal
origin
(18). Moreover,
14), the cord con-
(16, 17), and ACTH treatment,
65
in one of the two anencephalics induced,
did only moderately
sol, oestradiol Because
and oestrone
of the finding
experimental
model
extent
of the fetal brain
distribution
of gestation
high proportion
the sneep did not represent
in agreement
prolonged studies,
we have explored
for man, to the
as compared
however,
a peak around
since the normal
40 weeks, was totally
labour was observed
(20,21). So, also in this respect
to sham-
yet a possible
in the onset of labout was apparent,
lengths,
an optimal
litter were removed
with those obtained
the anencephalic
of both pre- and post-term
this was not the case
Therefore,
of the entire
length was not significantly
(20,21). From
and not at all corti-
(19).
When the brains
term, rat data were
controls
involvement
model.
during which no labour was
urine oestriol,
for the study of human parturition.
that gestation
operated
levels
maternal
in anencephalics,
the rat as an alternative 2 days before
over more than 6 weeks,
increase
lacking.
A
(6). In the rat model
in rat maternal
factors
seem
to be dominant'. A third animal model, the human
anencephalic.
functional primate.
i.e. the decapitated Novy and colleagues
hypophysectomy However,
did not affect
similar
species mean had widened removed
totally
destroyed
while
by means
average
leaving
although
anencephalic
the placenta&situ irradiation
loss of timing
fetus, most approximates
(5) showed in this way that the socalled
the mean gestation
(see also fig. 2). Older
of yttrium-90
fig. 2). The apparent and coworkers,
to the human
Rhesus monkey
length in the sub-human
the peak of births
studies,
in which
(30,31) or where
they still thought
gestation
the
the hypophysis
(32,33) give a similar
of birth after fetectomy
around
the fetus was
impression
did not escape
length to be prolonged,
was (see
Langman on the
(34).
On the basis
of the similarity
tion in particular, adjustment
it appears
of pregnancy
in the Rhesus monkey
Timing
of birth
The fact that the human makes
hibitory
effects
depending
even pre-term
likely that primarily
of fetectomy
and fetal decapita-
the fetal brain
controls
the
in the induction
of
as well.
fetal brain
it reasonable
to the sheep, the human to labour,
the effect
length and is thus in some way involved
labour
gestation
between
to assume
on gestation
adjusts
the time of birth
around
40 weeks
that it has to exert both stimulatory length. Data
fetal hypothalamo-pituitary
are accumulating adrenal
(35-43). Yet in man, administration
of
and in-
that, analogous
axis is stimulated of corticosteroids
prior or
' The peaks of parturitions at noon day 21 and 22 in the rat (20,22) show a strong circadian profile. Since the suprachiasmatic nucleus which is so important for circadian rhythms (23,24), does not contain neurophysin (25) or have any connection with the retina in rat before day 3 post-natal life (26,271, the fetal rat brain is also considered too immature in this respect to be of any significance for the lightinduced labour pattern (28.29).
66
,
??
??
0
0
a.*
o
PS
** I
I
140
150
A
I
100
110
1
I
160 gestation
170 length (days)
190
180
Fig. 2 shows the time of delivery of 1) the Rhesus monkey fetus after destruction of the hypophysis (32 and 33); 0 ;O = also maternal hypophysectomy; s = sham-operated fetuses); 2) the Rhesus monkey fetus after decapitation (5;O) and 3) the Rhesus monkey placenta after fetectomy (30 and 31;~ ). + indicates caesarian sectio. The normal distribution of births is shown by the solid curved line, while the vertical interrupted lines indicate the 5th percentiles (cf. 5). Not shown in the figure are: a) the hypophysectomized stillborn fetuses from ref. 33 that apparently died soon after hypophysis irradiation, b) the delivered placentas from the fetectomy studies, in the three cases that fetectomy was combined with ovariectomy or corpus luteum resection, in the two cases in which fetectomy occurred after a pregnancy length of 139 and 157 days respectively, and in the one case in which the placenta was traumatized. Also not included are the fetectomy studies of Lanman et al. (e.g. 341, since no accurate data were given by these authors. In the referred study, however, they stated that 5 out of 8 placentas were retained post-term, and moreover that it appeared from unpublished observations that also pre-term deliveries occurred. This would even increase the spread of 'gestation lengths' shown above.
corticotropin treatment
corticosteroid These
did not induce pre-term
rather
even tended
treatment
findings
serve to postpone
succesfully
suggest delivery
time that labour is easily The gradually as also occurs
pre-term
induces
pre-term induced
and to advance
(44,50). Only post-term
(51,52).
to sheep, the fetal adrenal would it post-term,
with the help of different,
oxytocin
plasma
oxytocin
thus narrowing e.g. maternal
levels in man during pregnancy
(57), can be such a maternal
used to deny a role of maternal
(47-49) labour. Corticosteroid
labour
labour
that in man, as opposed
rising maternal in the rat
(44-46) or term
to postpone
factor. The arguments
in the induction
the
factors. (53-57), commonly
of labour are no longer
67 valid
(for a review,
The difference
see 57).
between
tropin (pre)termtreatment key-enzymes
sheep and man in the efficacy seems to be based
for the production
of fetal adrenal
oestrogen
production
explained
why labour is postponed
suppress
the adrenal
cursors
enzymes
during
ase (3-8-HSD)
and as a consequence
The prolonged
directly
injected
increase
of this rather
action
factors,
both progesterone
and cortisol
less corticosteroidgenetic by the increased
capability stimulation
ferences
culture
in the proportional
development,
of WMSH
to have
release
species by Challis circulating
of
a-MSH
of ACTH and a-MSH
a-MSH being more active
cortisol.
by higher
at higher
of Challis
amounts
doses
on cortisol
and
amounts
appeared
to
stimulated
This indicates
and coworkers
on the fetal adrenal,
of
action
(61). The cortico-
than of ACIH. This premise
less effect
studies
effect
(60).
the existence
et al.
effect
the former mainly
of cortisol
(cf. 63).Both
(59), and
fetal adrenal
from that of ACTH. The latter hormone
release,
l-24,
production
and oestrone)
in various
(63). The corticotropic
but not of CL-MESHthat even tended fetal adrenal
oestrogen
they found that even small, possibly
(10 pg) were effective
this en-
of ACTH on the
of ACTH
the authors proposed
in the rabbit by Rudman
both in vitro and in vivo,
of the key dehydrogen-
stimulates
effect
pre-
treat-
among which C(-MSH. A corticotropic
of a-MSH has now been demonstrated
(62,63). Recently
of a-MSH
oestradiol-178
small effect
demonstrated
activity
with a depot preparation increased
will
of oestrogen
of A'-38-hydroxysteroid
in the size of the hypoplastic
fetal corticotrophic
of 8-MSH was already
coworkers
treatment
it can even be
of post-term
(cf. 13). ACTH indeed
was found for cortisol,
only a slight
alternative
differ,
6 weeks
and placental
supply
the efficacy
to a stimulated
into the fetus, only moderately
(hardly any increase
As a consequence
of ACTR
of
corticosteroids,asthey
(59), which was even the most prominent
adrenal.
produced
points
e.g. by a priming
under the influence
precursors
of the latter
by exogenous
or cortico-
in the presence
the extraplacental
or corticotropin
late gestation,
zyme in anencephalics
ported
pre-term
(11,42, cf. also 58). If this is accepted,
ment with corticosteroid
tropic
cortisol
see 11,13). Because
(for reviews,
of corticosteroid
upon a difference
a
is supof ACTH,
in the sheep also show dif-
release
during
and ACTH on the adult
adrenal. This finding matches like compound in larger gestation.
amounts Similar
(14): at 15 weeks be present
with those of Silman
is present
than ACTH , while
in the very circumscript
more
and more
scarce.
even in the pituitary
However,
abruptly
present
than a-MSH
of the pituitary
containing
cells were
After birth,
containing
(66)
at the end of gland found to
Later on, ACTH cells were
and the pars intermedia.
a few a-MSH
(64,65) and monkey
and no ACTH containing
pars intermedia.
abundantly
found that an a-MSH-
rather
by immunocytochemistry
only a-MSH
as well, both in the pars distalis
of both man
this ratio reverses
data were obtained of gestation
ACTH cells were much more
and otherswho
in the fetal pituitary
cells,
found
the that became
cells could still be observed
gland of a 79 year old man. The pituitaries
of 7 anencephalics
66 did not contain a-MSH It is suggested, trophic
hormone
absence
therefore,
since
in late gestation of a-MSH
meager
cells at all, while
and the regression
effect
in the pituitary
fetal brain on the development Next to a-MSH, which CLIP
and CLIP workers
of ACIH
recently
the relevance
7-38
cultures.
(i.e. ACTH
supported
in relation
peptide;
extracts
share this effect with CIP and consequently to ACTH production
lated to the initiation
of the changing stimulate centrations effect
on body
to induce
while
of amniotic
during mid-pregnancy
stimulated
function
might
cular interest
of labour.
that the shift from re-
particularly
aqainst
(as a CIP)and
the low con-
both the growth-retarding production
is the reported
which reflects
that intrauterine
in the light
life n-MSH would
growth
reduced
fetal plasma
is stimulated
levels, (6)'.
in favour of ACTH. This would mean that both ACTH with CIP decrease,
and release
Disturbances
for maturation
resulting
growth
is the low incidence
in a
of the lungs
in fetal brain maturation
thus affect both intrauterine in this respect
from
would be intimately
(e.g.71) of corticosteroid
and its competition
corticosteroidgenesis
the induction
of CLIP
safeguard
concentration,
(42), the period
increase
How-
tissue was
CIP) isolated
intrauterine
In favour of this concept
fluid cortisol
Later on, the ratio changes release might
the presence
this period
labour.
and co-
during human
(MV) to the hypothesis
is very attractive
and CLIP. During
(70-72) and brain weight
and its potency decrease
(9),
of ACIH during
of WMSH
(14).
CIP activity
ratios of ACTH/a-MSH
fetal growth
led one of us
by the fetal pituitary
of labour
The idea of CLIP having
the ab-
mechanisms.
on adult rat adrenal
inhibiting
(69). This finding
next to a-MSH
to birth-initiating
effect
(corticotropin
formation
by the data of Silman
that CLIP might (and CLIP)
Moreover,
l-13), the complementary
human pituitary
a-MSH
3) the
in anencephalics,
to a stimulator-y role of the
of CLIP-formation
a corticotropin-inhibiting
for ACTH
points
growth
(68). The simultaneous
from ACTH is for the fetus strongly
demonstrated
cortical
cells.
17-38) is formed
(64-66). Hitherto
cortico-
(see e.g. 67, p. 174), 2) the
of a-MSH on fetal adrenal
is a fragment
(i.e. ACTH
found.
to ACTH production
cortex in anencephalics,
of anencephalics of these
cells were
is the primary
from a-MSH
of the fetal zone
on the fetal adrenal
fetal life has not been discussed ever,
fetus a-MSH
of the switch
and a fetal zone of the adrenal
and 4) the corticotropic
fragment
that in the human
1) the coincidence
result of ACTH treatment
sence of a-MSH
only few ACTH-containing
(44-46) and
influencing
and pregnancy of respiratory
length.
pituitary
Of parti-
distress
(high
' In sheep and rat, where fetal plasma corticosteroid levels have been determined during gestation, the coincidence between a fall in these levels and the start of the fetal growth spurt is even more prominent than in man: in sheep a fall in fetal adrenocortical output is seen between 60-90 and 90-120 days (75) and an increasing fetal growth between 73-70 and 77 and 84 days (76); in the rat the fetal corticosterone plasma level drops between 19 and 20 days (77), the same day that the intrauterine growth spurt commences (78,79).
69
cortisol babies
Final
release
prior
to delivery-ACTH?)
in pre-term
low-weight
(a-MSH deficit?)
(73 - table III; 74 - fig. 5).
trigger
Liggins
(80) recently
mechanism" length,
determines
proposed
rather
subsequently
during
observed
following
induced
labour
release,
since oxytocin
since an oxytocin
by data,
uterine
is considered
during
(84,85), has CHF activity
the sheep fetus were even reported Taken
together,
gestation,
an increased
effect
tion of fetal oxytocin for the induction metrial
which
labour
and oestrogen
in fetal plasma
also exists
study of Dawood
by the authors,
is in-
from the fetal site and inhibiting
is also released
factor
(in
by the fetus given to
(67 - fig. 1). hormone
might
from CX-MSH to ACTH production,
cortisol
the
since it was not
(86). High amounts of vasopressin
to induce
of labour, because
PGF release
contractions
fetal neurohypophysial
of the switch
on fetal adrenal
from the recent
to act as an o-MSH
On the other hand, vasopressin
conjectured
like the increase
not so interpreted
the rat: 83). labour
Nevertheless,
not caused by labour
apparent
although
can induce
fragment
and the "maternal
(81; cf. 42). A similar phenomenon
as became
($2). This observation,
triguing
"adrenal mechanism"
is, however,
"membrane
clock the species mean gestation
for a "final trigger".
is suggested
labour, which
for fetal oxytocin et al.
no need exists
of a final trigger
cortisol
that the local fetal
as a biological
refined by the fetal
mechanism". In his concept existence
for primates,
crudely
release.
Furthermore,
release
(via cortisol)
strengthen
a time-related
of their very potent
the
at the end of stimula-
would be very profitable
combined
effect
on myo-
(in sheep: 1).
The course of labour role of the fetus in the course
The possible
It would be interesting fetuses
of which
because
of the intact
fetus then will interval
to know for instance
one is hypophysectomized.
but no quantitative
or the duration
In man, expulsion
lasted nearly removal
University
three times
longer
was required
Clinic).
stage III, a purely
occurs
at term
(87). The hypophysectomized
data are available
mechanical
of anencephalics the expulsion
(21). Moreover,
with respect
to the
factors
(stage IV)
of manual
stage IV was even more protracted is very unlikely.
are considered
The more so, since a protracted
in the rat after removal
hydramnios
pla-
value of less than 2% in the
cause for the protraction brain
without
of the placenta
a high percentage
an overall
Since in anencephalics
for this disturbance.
also observed
while
(10% versus
fore, the lack of stimulatory sible
first
in literature.
in sheep twin
of parturition.
(stage III of labour)
lasted twice as long as in controls,
cental
proceeds
In this case delivery
fetus that is also born
follow,
of labour is neglected
how delivery
of the fetal brain
to be primarily
than
Thererespon-
course of labour was (20,21). A negative
effect
70 of the previous
abdominal
to have an accelerated Various
observations
this respect.
High
as indicated
S.C. during
labour
lease of oxytocin since higher
in man point
for vasopressin
in human
and spontaneous might
umbilical higher
vaginal
also be increased
fluid,
hypoxia
in
(9,84,85)
(9,82
cord blood.
These
concentrations
delivery,
pituitary
increase
plasma
fetal life
levels were found
release
has been shown
'release'
of oxytocin,
Seppala
and coworker
content
1312 11 10 -
**
ZQ.;
8-
$7:s0 0 57 F4 32ln=42
n=48
before labour
during labour
dur S.C.
(82,851. The re-
that jeopardize
oxytocin
(90). An additional
oxytocin
levels
respectively
in conditions venous
and oxytocin
found in elective
seems to occur by fetal defecation.
Fetal
rats tended
role of fetal oxytocin
(89). In sheep fetus a similar
due to maternal
i.e. into amniotic
to a stimulatory
cord than maternal
with asphyxia
as sham-operated
course of labour.
of both vasopressin
by the step-wise
umbilical
in connection
could be excluded,
than a protracted
concentrations
85,88) have been detected labour,
surgery
rather
Fig. 3 shows the median pituitary oxytocin contentper 100 g body weight in rat fetuses before expulsion, in respectively mothers that only showed behavioural signs (belly contractions, vaginal bleeding) of imminent delivery and mothers that had delivered up to 5 new-horns. For reasons of comparison only the first six removed fetuses of each litter were assayed for this figure. A significant decrease in pituitary oxytocin content (~9: p< 0.001); Mann-Whitney-U-test) is seen as labour has proceeded.
71 (91) showed that meconium
itself
the relativelyhighoxytocin Fetal
oxytocin
contractions
concentration
injected
(19) and oxytocin
(92). The route via which
large amounts
into the human administration
fetal oxytocin
(11). In support
fluid
an accelerated
presence
In the rat a role for fetal oxytocin like maternal labour
however,
(93), fetal pituitary
(941, which
A recent
on this subject,
shows that the fetal pituitary
labour is significantly fetal release prior
enigma-
such as via
et al.
observed
amniotic
fluid (91). as, un-
content was not found to decrease of an enhanced
of which preliminary oxytocin
lower than before
to or during
contractures
remains
are considered,
of meconium-stained
uterine
in the course of labour was doubted
oxytocin
would have been indicative
experiment
fetus elicited
reach the myometrium
fluid.
the course of
to the sheep fetus uterine
circulation
explains
amniotic
of this route might be that Seppala
courseoflabourinthe
which
to accelerate
anencephalic
would
tic, and routes other than via the maternal amniotic
of oxytocin,
they foundingreen-stained
to have the potency
seems, moreover,
since oxytocin
labour,
contains
content
oxytocin
during
release.
data are given in fig. 3,
of the unborn
labour has started,
fetuses
during
and thus indicates
a
labour in the rat as well.
ACKNOWLEDGEMENTS We are grateful to H.F.Pronker
to the Foundation
for his valuable
of Medical
technical
Research
assistance,
FUNGO
for financial
and to Miss J.Sels
support,
for typing
the manuscript.
REFERENCES 1. Liggins, G.C., Fairclough, R-J., Grieves, S.A., Forster, C.S.andKnox, B.S., 1977. Parturition in sheep. In: J.Knight and M.O'Connor (Eds.), The Fetus and Birth, Ciba Fdtn. Symp. No. 47. Elsevier, Amsterdam, pp. 5-30. 2. Fuchs, A.-R., 1978. Hormonal control of myometrial function during pregnancy and parturition. Acta Endocrinologia, 89: Supplementum 221. 3. Heap, R.B., Galil, A.K.A., Harrison, F.A., Jenkin, G. and Perry, J.S., 1977. Progesterone and oestrogen in pregnancy and parturition: comparative aspects and hierarchical control. In: J.Knight and M.O'Connor (Ed?,.), The Fetus and Birth, Ciba Fdtn. Symp. No. 47. Elsevier, Amsterdam, pp. 127-157. 4. Potter, E.L. and Craig, J.M., 1975. Pathology of the Fetus and the Infant. 3rd Ed. Year Book Medical Publishers, Inc., p. 525. 5. Navy, M.J., Walsh, S.W. and Kittinger, G.W., 1977. Experimental fetal anencephaly in the Rhesus monkey: effect on gestational length and fetal and maternal plasma steroids. J. Clin. Endocrin. & Metab., 45: 1031-1038. 6. Honnebier, W.J. and Swaab, D-F., 1973. The influence of anencephaly upon intrauterine growth of fetus and placenta and upon gestation length. J. Obstet. Gynaecol. Brit. Cwlth., 80: 577-588. 7. Liggins, G.C., 1974. The influence of the fetal hypothalamus and pituitary on growth. In: K.Elliot and J.Knight (Eds.), Size at Birth. Ciba Fdtn. Symp. No. 27. Elsevier, Amsterdam, p. 173. 8. Swaab, D.F., Boer, G.J. and Visser, M., 1978. The fetal brain and intrauterine growth. In: D.Barltrop (Ed.), Paediatrics and Growth, Unigate Paediatric Workshops. Fellowship of Postgraduate Medicine, London, pp. 63-69. 9. Swaab, D.F., Boer, G.J., Boer, K., Dogterom, J., Van Leeuwen, F.W. and Visser, M., 1978. Fetal neuroendocrine mechanisms in development and parturition. In: M.A. Corner et al. (Eds.1 , Maturation of the Nervous System. Progr. in Brain Res., vol. 48. Elsevier, Amsterdam, pp. 277-290.
72
10. Liggins, G-C., 1969. The foetal role in the initiation of parturition .in the ewe. In: G.E.W.Wolstenholme and M.O'Connor (Eds.), Foe&l Autonomy. Ciba Fdtn. Symposium, Churchill, London, pp. 218-244. 11. Nathanielss, P-W., 1978. Endocrine mechanisms of parturition. Ann. Rev. Physiol., 40: 411-451. 12. Begeot, M., Dubois, M.P. and Dubois, P.M., 1977. Growth hormone and ACTH in the pituitary of normal and anencephalic human fetuses: immunocytochemical evidence for hypothalamic influences during development. Neuroendocrinology, 24: 208-220. 13. Challis, J.R.G. and Thorburn, G.D., 1976. The fetal pituitary-adrenal axis and its functional interactions with the neurohypophysis. In: R.W.Beard and P.W. Nathanielss (Eds.), Fetal Physiology and Medicine. M.B.Saunders Co., Ltd., London, pp. 232-253. 14. Visser, M. and Swaab, D.F., 1979. Life span changes in the presence of a-melanocyte stimulating hormone containing cells in the human pituitary. J. Developm. Physiol., in press. 15. Miyakawa, I., Ikeda, I., Nakayama, M. and Maeyama, M., 1976. Plasma concentrations of cortisol, progesterone and unconjugated oestradiol and oestriol in women with live anencephalic foetuses before, during and after labour. J. Endoer., 69: 291-292. 16. Sybulski, S., 1977. Umbilical cord plasma cortisol levels in association with pregnancy complications. Obstet. & Gynecol., 50: 308-312. 17. Goldkrand, J.W., Schulte, R.L. and Messer, R.H., 1976. Maternal and fetal plasma cortisol levels at parturition. Obstet. & Gynecol., 47: 41-45. 18. Tervilb, L., Teramo, K. and Rajam&ki, A., 1969. Some aspects of the transfer of cortisol from maternal to foetal blood during normal labour. Ann. Chir. Gynaecol. Fenn., 58: 264-266. 19. Honnebier, N.J., Jobsis, A.C. and Swaab, D.F., 1974. The effect of hypophysial hormones and human chorionic gonadotropin (HCG) on the anencephalic fetal adrenal cortex and on parturition in the human. J. Obstet. Gynaecol. Brit. Cwlth., 81: 423-438. 20. Boer, K., 1976. The foetal brain and labour in the rat. In: The rat hypothalamoneurohypophysial system: its involvement in the onset and course of labour. Diss .,Univ. of Amsterdam, pp. 126-136. 21. Swaab,D.F., Boer, K. and Honnebier, W.J., 1977. The fetal hypothalamus and pituitary in the onset and the course of parturition. In: J.Knight and M.O'Connor (Eds.), The Fetus and Birth, Ciba Fdtn. Symp. No. 47. Elsevier, Amsterdam, pp. 379-400. 22. Boer, K., Lincoln, D.W. and Swaab, D.F., 1975. Effects of electrical stimulation of the neurohypophysis on labour in the rat, J. Endocr., 65: 163-176. 23. Van den Pol, A.N., 1977. The role of the hypothalamic suprachiasmatic nucleus as a circadian oscillator in rat. Sot. Neurosci. Abstr., 3: 167. 24. Moore, R.Y. and Eichler, V.B., 1972. Loss of circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res., 42: 201-206. 25. Wolf, G. and Trautmann, B., 1977. Ontogeny of the hypothalamo-neurohypophysial system in rats - an immunohistochemical study. Endokrinologie, 2: 222-226. 26. Stanfield, B. and Cowan, W-M., 1976. Evidence for a change in the retinohypothalamic projection in the rat following early removal of one eye. Brain Res., 104: 129-136. 27. Mason, C.A., Sparrow, N. and Lincoln, D.W., 1977. Structural features of the retinohypothalamic projection in the rat during normal development. Brain Res., 132: 141-148. 28. Mitchel, J.A. and Yochim, J.M., 1970. Influence of environmental lighting on duration of pregnancy in the rat. Endocrinology, 87: 472-480. 29. Lincoln, D.W. and Porter, D.G., 1976. Timing of the photoperiod and the hour of birth in rats. Nature, 260: 780-781. 30. Van Wagenen, G. and Newton, W.H., 1943. Pregnancy in the monkey after removal of the fetus. Surg. Gynecol. Obstet.,77: 539-543. 31. Van Wagenen, G., Catchpole, H-P.., Negri, J. and Butsko, D., 1965. Growth of the fetus and placenta of the monkey (Macaca mulatta). Amer. J. Physiol. Anthrop., 23: 23-34.
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75 15. Wintour, E.M., Brown, E.H., Denton, D.A., Hardy, K-J., McDougall, J.G., Oddie, C.J. and Whipp, G.T., 1975. The ontogeny and regulation of corticosteroid secretion by the ovine foetal adrenal. Acta Endocrinol., 79: 301-316. 76. Stegeman, J.H.J., 1974. Placental development in the sheep and its relation to fetal development. Dissertation, Univ. of Amsterdam. 77. Cohen, A., for reference see: Jost, A., 1973. Does the fetal hypophyseal-adrenal system participate in delivery in rats and in rabbits? In: K.S.Comline et a.2. (Eds.1, Foetal and Neonatal Physiology; Proc. of the Sir Joseph Barcroft Centenary Symposium. Cambridge Univ. Press, pp. 589-593. 78. Csapo, I. and Wiest, W-G., 1969. An examination of the quantitative relationship between progesterone and the maintenance of pregnancy. Endocrinology, 85: 735-746. 79. Swaab, D.F. and Honnebier, W.J., 1973. The influence of removal of the fetal brain upon intrauterine growth of the fetus and the placenta and on gestation length. J. Obstet. Gynaecol.Brit. Cwlth., 80: 589-597. 80. Liggins, G.C., 1977. Control of parturition in man. Biol. Reprod., 16: 39-56. 81. Murphy, B.E.P. and Diez D'Aux, R.C., 1972. Steroid levels in the human fetus: cortisol and cortisone. J. Clin. Endocrinol., 35: 678-683. 82. Dawood, M-Y., Wang, C-F., Gupta, R. and Fuchs, F., 1978. Fetal contribution to oxytocin in human labor. Obstet. Gynecol., 52: 205-209. 83. Celis, M.E., 1977. Hypothalamic peptides involved in the control of MSH secretion. Identity, biosynthesis and regulation of their release. In: F.J.H.Tilders,'D.F.Swaab and Tj.B.vsn Wimersma Greidanus (Eds.), Melanocyte Stimulating Hormone: Control, Chemistry and Effects. Karger, Basel, pp. 69-79. 84, Hoppenstein, J.M., Miltenberger, F.M. and Moran, W.H., 1968. The increase in blood levels of vasopressin ininfantsduring birth and surgical procedures. Surg. Gynec. Obstet., 127: 966-974. 85. Chard, T., 1973. The posterior pituitary and the induction of labour. In: A. Klopper and J-Gardner (Eds.), Endocrine Factors in Labour. Cambridge Univ. Press, pp. 61-76. 86. Saffran, M. and Schally, A-V., 1977. The status of corticotrophin releasing 24: 359-375. factor (CRFF). Neuroendocrinology, 87. Liggins, G.C., Kennedy, P.C. and Holm, L.W., 1967. Failure of initiation of parturition after electrocoagulation of the pituitary of the foetal lamb. Amer. J. Obstet. Gynecol., 98: 1080-1086. P., Han, G.S., Anandarangam, P.B. and Vasicka, A., 1975. Oxytocin in 88. Kmaresan, maternal and fetal blood. Obstet. Gynecol., 46: 272-274. 89. Vasicka, A., Kumaresan, P., Han, G.S. and Kumaresan, M., 1978. Plasma oxytocin in initiation of labor. Amer. J. Obstet. Gynecol., 130: 263-273. 90. Alexander, D.P., Forsling, M.L., Martin, M.J., Nixon, D.A., Ratcliffe, J.G., Redstone, D. and Turnbridge, D., 1972. The effect of maternal hypoxia on fetal pituitary hormone release in the sheep. Biol. Neonate, 21: 219-228. 91. SeppBlZ, M., Aho, I., Tissari, A. and Ruoslahti, E., 1972. Radioimmunoassay of oxytocin in amniotic fluid, fetal urine, and meconium during late pregnancy and delivery. Amer. J. Obstet. Gynecol., 114: 788-795. 92. Nathanielsz, P.W., Comline, R.S. and Silver, M., 1973. Uterine activity following intravenous administration of oxytocin in the foetal sheep. Nature, 243: 471-472. 93. Fuchs, A.-R. and Saito, S., 1971. Pituitary oxytocin and vasopressin content of pregnant rats before, during and after parturition. Endocrinology, 88: 574578. 94. Forsling, M.L., for figure see Fuchs, A.-R., 1973. Parturition in rabbits and rats. In: A.Klopper and J.Gardner (Eds.1, Endocrine Factors in Labour. Cambridge Univ. Press, pp. 163-185, fig. 12. 95. Querido, A. and Swaab, D.F. (Eds.), 1975. Brain Development and Thyroid Deficiency. North-Holland Publishing Company, Amsterdam, p. 39.
Animal Reproduction Science, 2 (1979) 63-75 0 Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
THE FETAL BRAIN AND PARTURITION
K.BOER, D.F.SWAAB Netherlands
and M.VISSER
Institute
for Brain Research,
Amsterdam,
The Netherlands
ABSTRACT
The primate mean
fetal brain
length of gestation.
production
appears
chapter
the role of CLIP,
which
the involvement
governing
the switch
In addition,
is produced
a switch
how this switch of labour,
could be related
hormones
corticotropic
production
In
to the posis made
in addition
of the fetal brain in the final timing
in pituitary
the latter.
and a conjecture
by the fetal pituitary
the species
in the fetal pituitary
and ACTH seems to favour
for the induction
Moreover,
neurohypophysial
a-MSH
it is discussed
sible fetal mechanism
the time of birth around
At the end of gestation
of the corticotropics
the present
to adjust
for
to C1-MSH.
of birth
by
and by the release
of
is discussed.
the release
tate the course
of labour,
the fetal brain
appears
of fetal oxytocin
during
labour is thought
to facili-
not only in man but also in the rat, in which
not to be involved
species
in the onset of labour.
INTRODUCTION No intelligent
person
would
commit his fate entirely
else, not even those of his own mother. differences
the fetal sheep brain, which onset of labour
(11, while
little,
if any, significance
of Heap
(3)). According
and Rhesus
Inasmuch
in the level of brain development
monkey
is relatively
in species
as intelligence
at birth
mature,
to this conjecture,
is primarily
anencephaly
human model
is the anencephalic
is still mentioned
being prolonged.
responsible
the fetal brain
brain maturation
If and how the primate
in species
why
for the is of scheme
like man
fetal brain is involved
in the following
pages.
of parturition
The best available onset of labour
with age,
explain
(2, cf. also the hierarchical
in the onset and course of labour will be discussed
The initiation
matures
(fig. 1) might
like rat and rabbit
in this respect
is intermediary.
into the hands of someone
But Honnebier
for the study of fetal brain involvement fetus. Pregnancy
in the textbooks and Swaab
length in combination
(4) and current
(6), studying
literature
in the with (5) as
a large numberofanencephalic
64
HUMAN CP
1
A
PIG
C
A-
MONKEY
C
2
3
P
10
20
30
WEEKS
P
10
20
30
WEEKS
P
10
20
30
WEEKS
P
10
20
30
40
OAYS
P
IO
20
30
40
DAYS
20
30
40
DAYS
4
YEARS
SHEEP C
GUINEA
PIG --
c
A
RABBIT
C
4-e--
RAT
c
P
10
Fig. 1. The velocity of brain growth (B) in relation to the time of parturition (P) in various species; C = moment of conception. (From95, see also for references, with permission of the North Holland Publishing Company.) gestations
found, on the contrary,
shortened.
Anencephaly,
known
to shorten
gestation.
the remainder
hydramnios,
the case histories
adrenal
studies
of which
centrations
which
(for a recent
The pituitaries release
aplasia
(9) do not point
to the fetus
of cortisol
of labour,
(10). These
review,
Also
of the
mean preg-
unless ACTH or
findings,
and a wealth
of
by a rise in fetal
of the fetal hypothalamo-
see 11).
still contain
some ACTH
by AVP injection
have been found to be low
cortisol
(39.7 weeks).
the absence
to an increased
is likely under the control
of anencephalics
with
with those in the sheep, where hypophysectomy
with the occurrence
can be stimulated
in man fetal plasma
length
including
to be
a condition
of the data for anencephalics
showed that in the sheep labour is triggered
release,
complex
by hydramnios,
a normal mean gestation
contrast
are administered
cortisol
pituitary
findings
length in anencephalics
accompanied
(cf. 7), microcephaly
fetus is incompatible
corticosteroids additional
revealed
of acephaly
length. These
of a singlet
the mean gestation
is frequently
After elimination
and pituitary
(8) ,
hypothalamus nancy
however,
may be of maternal
(12, 13, p.243,
(13, p.243).
Umbilical
(15) or low-normal
origin
(18). Moreover,
14), the cord con-
(16, 17), and ACTH treatment,
65
in one of the two anencephalics induced,
did only moderately
sol, oestradiol Because
and oestrone
of the finding
experimental
model
extent
of the fetal brain
distribution
of gestation
high proportion
the sneep did not represent
in agreement
prolonged studies,
we have explored
for man, to the
as compared
however,
a peak around
since the normal
40 weeks, was totally
labour was observed
(20,21). So, also in this respect
to sham-
yet a possible
in the onset of labout was apparent,
lengths,
an optimal
litter were removed
with those obtained
the anencephalic
of both pre- and post-term
this was not the case
Therefore,
of the entire
length was not significantly
(20,21). From
and not at all corti-
(19).
When the brains
term, rat data were
controls
involvement
model.
during which no labour was
urine oestriol,
for the study of human parturition.
that gestation
operated
levels
maternal
in anencephalics,
the rat as an alternative 2 days before
over more than 6 weeks,
increase
lacking.
A
(6). In the rat model
in rat maternal
factors
seem
to be dominant'. A third animal model, the human
anencephalic.
functional primate.
i.e. the decapitated Novy and colleagues
hypophysectomy However,
did not affect
similar
species mean had widened removed
totally
destroyed
while
by means
average
leaving
although
anencephalic
the placenta&situ irradiation
loss of timing
fetus, most approximates
(5) showed in this way that the socalled
the mean gestation
(see also fig. 2). Older
of yttrium-90
fig. 2). The apparent and coworkers,
to the human
Rhesus monkey
length in the sub-human
the peak of births
studies,
in which
(30,31) or where
they still thought
gestation
the
the hypophysis
(32,33) give a similar
of birth after fetectomy
around
the fetus was
impression
did not escape
length to be prolonged,
was (see
Langman on the
(34).
On the basis
of the similarity
tion in particular, adjustment
it appears
of pregnancy
in the Rhesus monkey
Timing
of birth
The fact that the human makes
hibitory
effects
depending
even pre-term
likely that primarily
of fetectomy
and fetal decapita-
the fetal brain
controls
the
in the induction
of
as well.
fetal brain
it reasonable
to the sheep, the human to labour,
the effect
length and is thus in some way involved
labour
gestation
between
to assume
on gestation
adjusts
the time of birth
around
40 weeks
that it has to exert both stimulatory length. Data
fetal hypothalamo-pituitary
are accumulating adrenal
(35-43). Yet in man, administration
of
and in-
that, analogous
axis is stimulated of corticosteroids
prior or
' The peaks of parturitions at noon day 21 and 22 in the rat (20,22) show a strong circadian profile. Since the suprachiasmatic nucleus which is so important for circadian rhythms (23,24), does not contain neurophysin (25) or have any connection with the retina in rat before day 3 post-natal life (26,271, the fetal rat brain is also considered too immature in this respect to be of any significance for the lightinduced labour pattern (28.29).
66
,
??
??
0
0
a.*
o
PS
** I
I
140
150
A
I
100
110
1
I
160 gestation
170 length (days)
190
180
Fig. 2 shows the time of delivery of 1) the Rhesus monkey fetus after destruction of the hypophysis (32 and 33); 0 ;O = also maternal hypophysectomy; s = sham-operated fetuses); 2) the Rhesus monkey fetus after decapitation (5;O) and 3) the Rhesus monkey placenta after fetectomy (30 and 31;~ ). + indicates caesarian sectio. The normal distribution of births is shown by the solid curved line, while the vertical interrupted lines indicate the 5th percentiles (cf. 5). Not shown in the figure are: a) the hypophysectomized stillborn fetuses from ref. 33 that apparently died soon after hypophysis irradiation, b) the delivered placentas from the fetectomy studies, in the three cases that fetectomy was combined with ovariectomy or corpus luteum resection, in the two cases in which fetectomy occurred after a pregnancy length of 139 and 157 days respectively, and in the one case in which the placenta was traumatized. Also not included are the fetectomy studies of Lanman et al. (e.g. 341, since no accurate data were given by these authors. In the referred study, however, they stated that 5 out of 8 placentas were retained post-term, and moreover that it appeared from unpublished observations that also pre-term deliveries occurred. This would even increase the spread of 'gestation lengths' shown above.
corticotropin treatment
corticosteroid These
did not induce pre-term
rather
even tended
treatment
findings
serve to postpone
succesfully
suggest delivery
time that labour is easily The gradually as also occurs
pre-term
induces
pre-term induced
and to advance
(44,50). Only post-term
(51,52).
to sheep, the fetal adrenal would it post-term,
with the help of different,
oxytocin
plasma
oxytocin
thus narrowing e.g. maternal
levels in man during pregnancy
(57), can be such a maternal
used to deny a role of maternal
(47-49) labour. Corticosteroid
labour
labour
that in man, as opposed
rising maternal in the rat
(44-46) or term
to postpone
factor. The arguments
in the induction
the
factors. (53-57), commonly
of labour are no longer
67 valid
(for a review,
The difference
see 57).
between
tropin (pre)termtreatment key-enzymes
sheep and man in the efficacy seems to be based
for the production
of fetal adrenal
oestrogen
production
explained
why labour is postponed
suppress
the adrenal
cursors
enzymes
during
ase (3-8-HSD)
and as a consequence
The prolonged
directly
injected
increase
of this rather
action
factors,
both progesterone
and cortisol
less corticosteroidgenetic by the increased
capability stimulation
ferences
culture
in the proportional
development,
of WMSH
to have
release
species by Challis circulating
of
a-MSH
of ACTH and a-MSH
a-MSH being more active
cortisol.
by higher
at higher
of Challis
amounts
doses
on cortisol
and
amounts
appeared
to
stimulated
This indicates
and coworkers
on the fetal adrenal,
of
action
(61). The cortico-
than of ACIH. This premise
less effect
studies
effect
(60).
the existence
et al.
effect
the former mainly
of cortisol
(cf. 63).Both
(59), and
fetal adrenal
from that of ACTH. The latter hormone
release,
l-24,
production
and oestrone)
in various
(63). The corticotropic
but not of CL-MESHthat even tended fetal adrenal
oestrogen
they found that even small, possibly
(10 pg) were effective
this en-
of ACTH on the
of ACTH
the authors proposed
in the rabbit by Rudman
both in vitro and in vivo,
of the key dehydrogen-
stimulates
effect
pre-
treat-
among which C(-MSH. A corticotropic
of a-MSH has now been demonstrated
(62,63). Recently
of a-MSH
oestradiol-178
small effect
demonstrated
activity
with a depot preparation increased
will
of oestrogen
of A'-38-hydroxysteroid
in the size of the hypoplastic
fetal corticotrophic
of 8-MSH was already
coworkers
treatment
it can even be
of post-term
(cf. 13). ACTH indeed
was found for cortisol,
only a slight
alternative
differ,
6 weeks
and placental
supply
the efficacy
to a stimulated
into the fetus, only moderately
(hardly any increase
As a consequence
of ACTR
of
corticosteroids,asthey
(59), which was even the most prominent
adrenal.
produced
points
e.g. by a priming
under the influence
precursors
of the latter
by exogenous
or cortico-
in the presence
the extraplacental
or corticotropin
late gestation,
zyme in anencephalics
ported
pre-term
(11,42, cf. also 58). If this is accepted,
ment with corticosteroid
tropic
cortisol
see 11,13). Because
(for reviews,
of corticosteroid
upon a difference
a
is supof ACTH,
in the sheep also show dif-
release
during
and ACTH on the adult
adrenal. This finding matches like compound in larger gestation.
amounts Similar
(14): at 15 weeks be present
with those of Silman
is present
than ACTH , while
in the very circumscript
more
and more
scarce.
even in the pituitary
However,
abruptly
present
than a-MSH
of the pituitary
containing
cells were
After birth,
containing
(66)
at the end of gland found to
Later on, ACTH cells were
and the pars intermedia.
a few a-MSH
(64,65) and monkey
and no ACTH containing
pars intermedia.
abundantly
found that an a-MSH-
rather
by immunocytochemistry
only a-MSH
as well, both in the pars distalis
of both man
this ratio reverses
data were obtained of gestation
ACTH cells were much more
and otherswho
in the fetal pituitary
cells,
found
the that became
cells could still be observed
gland of a 79 year old man. The pituitaries
of 7 anencephalics
66 did not contain a-MSH It is suggested, trophic
hormone
absence
therefore,
since
in late gestation of a-MSH
meager
cells at all, while
and the regression
effect
in the pituitary
fetal brain on the development Next to a-MSH, which CLIP
and CLIP workers
of ACIH
recently
the relevance
7-38
cultures.
(i.e. ACTH
supported
in relation
peptide;
extracts
share this effect with CIP and consequently to ACTH production
lated to the initiation
of the changing stimulate centrations effect
on body
to induce
while
of amniotic
during mid-pregnancy
stimulated
function
might
cular interest
of labour.
that the shift from re-
particularly
aqainst
(as a CIP)and
the low con-
both the growth-retarding production
is the reported
which reflects
that intrauterine
in the light
life n-MSH would
growth
reduced
fetal plasma
is stimulated
levels, (6)'.
in favour of ACTH. This would mean that both ACTH with CIP decrease,
and release
Disturbances
for maturation
resulting
growth
is the low incidence
in a
of the lungs
in fetal brain maturation
thus affect both intrauterine in this respect
from
would be intimately
(e.g.71) of corticosteroid
and its competition
corticosteroidgenesis
the induction
of CLIP
safeguard
concentration,
(42), the period
increase
How-
tissue was
CIP) isolated
intrauterine
In favour of this concept
fluid cortisol
Later on, the ratio changes release might
the presence
this period
labour.
and co-
during human
(MV) to the hypothesis
is very attractive
and CLIP. During
(70-72) and brain weight
and its potency decrease
(9),
of ACIH during
of WMSH
(14).
CIP activity
ratios of ACTH/a-MSH
fetal growth
led one of us
by the fetal pituitary
of labour
The idea of CLIP having
the ab-
mechanisms.
on adult rat adrenal
inhibiting
(69). This finding
next to a-MSH
to birth-initiating
effect
(corticotropin
formation
by the data of Silman
that CLIP might (and CLIP)
Moreover,
l-13), the complementary
human pituitary
a-MSH
3) the
in anencephalics,
to a stimulator-y role of the
of CLIP-formation
a corticotropin-inhibiting
for ACTH
points
growth
(68). The simultaneous
from ACTH is for the fetus strongly
demonstrated
cortical
cells.
17-38) is formed
(64-66). Hitherto
cortico-
(see e.g. 67, p. 174), 2) the
of a-MSH on fetal adrenal
is a fragment
(i.e. ACTH
found.
to ACTH production
cortex in anencephalics,
of anencephalics of these
cells were
is the primary
from a-MSH
of the fetal zone
on the fetal adrenal
fetal life has not been discussed ever,
fetus a-MSH
of the switch
and a fetal zone of the adrenal
and 4) the corticotropic
fragment
that in the human
1) the coincidence
result of ACTH treatment
sence of a-MSH
only few ACTH-containing
(44-46) and
influencing
and pregnancy of respiratory
length.
pituitary
Of parti-
distress
(high
' In sheep and rat, where fetal plasma corticosteroid levels have been determined during gestation, the coincidence between a fall in these levels and the start of the fetal growth spurt is even more prominent than in man: in sheep a fall in fetal adrenocortical output is seen between 60-90 and 90-120 days (75) and an increasing fetal growth between 73-70 and 77 and 84 days (76); in the rat the fetal corticosterone plasma level drops between 19 and 20 days (77), the same day that the intrauterine growth spurt commences (78,79).
69
cortisol babies
Final
release
prior
to delivery-ACTH?)
in pre-term
low-weight
(a-MSH deficit?)
(73 - table III; 74 - fig. 5).
trigger
Liggins
(80) recently
mechanism" length,
determines
proposed
rather
subsequently
during
observed
following
induced
labour
release,
since oxytocin
since an oxytocin
by data,
uterine
is considered
during
(84,85), has CHF activity
the sheep fetus were even reported Taken
together,
gestation,
an increased
effect
tion of fetal oxytocin for the induction metrial
which
labour
and oestrogen
in fetal plasma
also exists
study of Dawood
by the authors,
is in-
from the fetal site and inhibiting
is also released
factor
(in
by the fetus given to
(67 - fig. 1). hormone
might
from CX-MSH to ACTH production,
cortisol
the
since it was not
(86). High amounts of vasopressin
to induce
of labour, because
PGF release
contractions
fetal neurohypophysial
of the switch
on fetal adrenal
from the recent
to act as an o-MSH
On the other hand, vasopressin
conjectured
like the increase
not so interpreted
the rat: 83). labour
Nevertheless,
not caused by labour
apparent
although
can induce
fragment
and the "maternal
(81; cf. 42). A similar phenomenon
as became
($2). This observation,
triguing
"adrenal mechanism"
is, however,
"membrane
clock the species mean gestation
for a "final trigger".
is suggested
labour, which
for fetal oxytocin et al.
no need exists
of a final trigger
cortisol
that the local fetal
as a biological
refined by the fetal
mechanism". In his concept existence
for primates,
crudely
release.
Furthermore,
release
(via cortisol)
strengthen
a time-related
of their very potent
the
at the end of stimula-
would be very profitable
combined
effect
on myo-
(in sheep: 1).
The course of labour role of the fetus in the course
The possible
It would be interesting fetuses
of which
because
of the intact
fetus then will interval
to know for instance
one is hypophysectomized.
but no quantitative
or the duration
In man, expulsion
lasted nearly removal
University
three times
longer
was required
Clinic).
stage III, a purely
occurs
at term
(87). The hypophysectomized
data are available
mechanical
of anencephalics the expulsion
(21). Moreover,
with respect
to the
factors
(stage IV)
of manual
stage IV was even more protracted is very unlikely.
are considered
The more so, since a protracted
in the rat after removal
hydramnios
pla-
value of less than 2% in the
cause for the protraction brain
without
of the placenta
a high percentage
an overall
Since in anencephalics
for this disturbance.
also observed
while
(10% versus
fore, the lack of stimulatory sible
first
in literature.
in sheep twin
of parturition.
(stage III of labour)
lasted twice as long as in controls,
cental
proceeds
In this case delivery
fetus that is also born
follow,
of labour is neglected
how delivery
of the fetal brain
to be primarily
than
Thererespon-
course of labour was (20,21). A negative
effect
70 of the previous
abdominal
to have an accelerated Various
observations
this respect.
High
as indicated
S.C. during
labour
lease of oxytocin since higher
in man point
for vasopressin
in human
and spontaneous might
umbilical higher
vaginal
also be increased
fluid,
hypoxia
in
(9,84,85)
(9,82
cord blood.
These
concentrations
delivery,
pituitary
increase
plasma
fetal life
levels were found
release
has been shown
'release'
of oxytocin,
Seppala
and coworker
content
1312 11 10 -
**
ZQ.;
8-
$7:s0 0 57 F4 32ln=42
n=48
before labour
during labour
dur S.C.
(82,851. The re-
that jeopardize
oxytocin
(90). An additional
oxytocin
levels
respectively
in conditions venous
and oxytocin
found in elective
seems to occur by fetal defecation.
Fetal
rats tended
role of fetal oxytocin
(89). In sheep fetus a similar
due to maternal
i.e. into amniotic
to a stimulatory
cord than maternal
with asphyxia
as sham-operated
course of labour.
of both vasopressin
by the step-wise
umbilical
in connection
could be excluded,
than a protracted
concentrations
85,88) have been detected labour,
surgery
rather
Fig. 3 shows the median pituitary oxytocin contentper 100 g body weight in rat fetuses before expulsion, in respectively mothers that only showed behavioural signs (belly contractions, vaginal bleeding) of imminent delivery and mothers that had delivered up to 5 new-horns. For reasons of comparison only the first six removed fetuses of each litter were assayed for this figure. A significant decrease in pituitary oxytocin content (~9: p< 0.001); Mann-Whitney-U-test) is seen as labour has proceeded.
71 (91) showed that meconium
itself
the relativelyhighoxytocin Fetal
oxytocin
contractions
concentration
injected
(19) and oxytocin
(92). The route via which
large amounts
into the human administration
fetal oxytocin
(11). In support
fluid
an accelerated
presence
In the rat a role for fetal oxytocin like maternal labour
however,
(93), fetal pituitary
(941, which
A recent
on this subject,
shows that the fetal pituitary
labour is significantly fetal release prior
enigma-
such as via
et al.
observed
amniotic
fluid (91). as, un-
content was not found to decrease of an enhanced
of which preliminary oxytocin
lower than before
to or during
contractures
remains
are considered,
of meconium-stained
uterine
in the course of labour was doubted
oxytocin
would have been indicative
experiment
fetus elicited
reach the myometrium
fluid.
the course of
to the sheep fetus uterine
circulation
explains
amniotic
of this route might be that Seppala
courseoflabourinthe
which
to accelerate
anencephalic
would
tic, and routes other than via the maternal amniotic
of oxytocin,
they foundingreen-stained
to have the potency
seems, moreover,
since oxytocin
labour,
contains
content
oxytocin
during
release.
data are given in fig. 3,
of the unborn
labour has started,
fetuses
during
and thus indicates
a
labour in the rat as well.
ACKNOWLEDGEMENTS We are grateful to H.F.Pronker
to the Foundation
for his valuable
of Medical
technical
Research
assistance,
FUNGO
for financial
and to Miss J.Sels
support,
for typing
the manuscript.
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