British Journal of Obstetrics and Gynaecology
December 1997,Vol. 104,pp. 1341-1350
REVIEW
Clinical, scientific and ethical aspects of fetal and
neonatal care at extremely preterm periods of gestation
Introduction
As defined by the World Health Organization in 1972,
preterm delivery is delivery which occurs before 37
weeks of gestation; it accounts for 6% to 10% of all
deliveries, depending on the demographic features of
the population examined'. The overall preterm delivery
rate is determined after consideration of all causes of
spontaneous preterm labour and deliberate intervention
to achieve elective delivery. It is therefore caused by
a heterogenous group of disorders occurring in preg-
nancy of which a significant proportion are of unknown
aetiology and poorly defined pathophysiology (e.g.
spontaneous preterm labour, pre-eclampsia, intrauterine
growth restriction, chorioamnionitis).
The majority of centres now report close to 100%
survival for infants born after 32 weeks of gestation,
and hence it is delivery before this time that is of major
perinatal importance. After 27 weeks of gestation intact
survival exceeds 50% and, while short and long term
morbidity are a significant concern, there is general
agreement on the provision of aggressive fetal and
neonatal care with a clear objective to achieve survival
with the optimal quality of life. At extremely preterm
periods of gestation (i.e. < 27 weeks), or what is some-
times referred to as the margin of viability, the progno-
sis is sometimes so poor that the objectives are far from
clear and the decisions regarding management difficult
for the parents, the obstetrician and the neonatal physi-
cian. There is no clear definition of the lower limit
of preterm, but the International Classification of Dis-
eases describes the perinatal period as beginning at 22
completed weeks at a time when the birthweight is
approximately 500 g. In practical terms, the accepted
lower limit of viability may vary from one hospital and
physician to the next but generally lies somewhere
between 23 and 25 weeks of gestation; there are a small
number of cases reported in the literature describing
survival at 22 weeks. While specific cases of nonresus-
citation have been tested in British courts there are
no clear guidelines on this issue. This review will
concentrate on the clinical, scientific and ethical aspects
of perinatal care at these extremely preterm periods of
gestation (23+Oto 26'6 weeks).
0 RCOG 1991 British Journal of Obstetrics and Gynaecology
The extent of the problem
Neonatal mortality
A summary of survival figures relating to delivery since
1985, for each week of gestation from 23" to 26+hare
presented in Table 1 and are shown along with handicap
rates in Fig. 12-8. Because of the small number of
deliveries at each of these weeks, it is only by combin-
ing results from a number of studies that meaningful
conclusions can be made. There is approximately a 3%
daily improvement in survival from 23 to 24 weeks and
a 1% to 2% daily improvement thereafter until 26'6
weeks of gestation. This outlines the importance of
prolonging gestation, even by one day, at these early
periods. After gestational age, birthweight is the next
most important factor in determining surviva16*y.'0 and
at the margins of viability the greatest improvement in
survival occurs with an increase in birthweight from
600 g to 800 g. The importance of birthweight in analy-
sis of gestational age-related data has been highlighted,
leading to construction of birthweight and gestational
age specific mortality charts from 20 to 34 weeks of
gestation9J0.Studies of preterm survival at extremely
early periods of gestation have shown a significantly
worse outcome for male compared with female infants,
and Caucasian in comparison with Afro-Caribbean
infantsy-'I .
As preterm deliveries are the result of different com-
plications of pregnancy, it would be helpful to know
whether outcome, in terms of survival, varied with the
primary condition leading to preterm birth of the infant.
Early reports of outcome in very low birthweight
infantsl2.I3and anecdotal experience have suggested that
the so-called 'stressed' fetus, occurring in association
with pre-eclampsia and intrauterine growth restriction,
had a more favourable outcome than those delivered
because of idiopathic preterm labour or preterm prema-
ture rupture of the membranes. More recent studies
have reported that the pregnancy complication, leading
to very preterm delivery, has no bearing on survival.
Results from a series of 535 liveborn singleton infants
between 500 g and 1400 g delivered because of five pri-
mary complications (e.g. preterm premature rupture of
the membranes, idiopathic preterm labour, antepartum
1341
1342 REVIEW

Table 1. Neonatal survival data from 23+Oto 26t6 since 1985. Values are given as nitotal (%) unless otherwise indicated. UCH = University
College Hospital.

Place Year of birth 23 weeks 24 wceks 25 weeks 26 weeks Reference

~

Minneapolis, Minnesota, USA 1986-1990 12/32 (37) 28/75 (37) 54/90 (60) 72/113 (64) Ferrara et al.
UCH, London, UK 1987-1994 11/33 (33) 31/65 (48) 35/74 (47) 57/84 (68) Unpublished
Baltimore, Maryland, USA 1988-1 991 6/40 (15) 19/34 (56) 31/39 (79) Allen et aL2
Detroit, Michigan, USA 1988-1 991 2/28 (7) 13/40 (32) 11/44 (25) 35/62 (56) Holtrop et aL4
Chapel Hill, N Carolina, USA 1989-1991 0121 (0) 5/11 (46) 14/22 (64) 18/25 (72) Katz and Bose3
Cambridge, UK 1985-1 992 1/9 (22) 13/28 (45) 26/55 (47) 43/80 (54) Rennie"
Western Australia 1990-1991 3/15 (20) 8/18 (44) 14/22 (64) 27/40 (68) Hagan et aL6
Trent Region, UK 1991-1993 1/37 (3) 27/97 (28) 38/104 (36) 731132 ( 5 5 ) Bohin et a1.l
TOTAL 37/215 (17) 1441368 (39) 223/450 (50) 3251536 (61)
95% CI of percent 12-22 3345 44-56 55-67

Table 2. Survival (to discharge) of singleton and twin fetuses between 23+Oand 26+6weeks and of birthweight between 500 g and 1000 g in
250 g intervals from Rosie Maternity Hospital, Cambridge and University College Hospital, London. Values are given as n/total (%) unless oth-
erwise indicated.

Year of birth 23*-26+6 weeks 500-749 g 750-899 g

Singletons
Cambridge 1985-1991 73/132 ( 5 5 ) 25/57 (47) 93/132 (70)
London 1987-1994 11 3/203 (56) 50/116 (43) 112/151 (74)
TOTAL 186/335 (56)* 77/173 (45)t 205/283 (72):
95% CI 49--63 36-54 63-81
Twins
Cambridge 1985-199 1 11/30 (37) 1/7 (14) 27/46 (59)
London 1987-1 994 14/35 (40) 9/27 (33) 17/29 (59)
TOTAL 25/65 (38)* 10/34 (29)t 44/75 (59):
95% CI 24-52 12-46 43-75

* X 2 = 6.357, P < 0.02; tx2= 2.658, P > 0.10; = 5,307, P < 0.05

haemorrhage, pregnancy-induced hypertension and

100 1 other causes) have demonstrated that the primary com-
plication did not influence survival before discharge
fiom hospital14. Iannucci et analysed the findings
for 111 neonates with birthweights between 500 g and
80
800 g and categorised the reasons for delivery into four
groups: idiopathic preterm labour, preterm premature
rupture of the membranes, maternal or fetal indications
60 and multiple pregnancy. They concluded that the reason
s for delivery had no impact on survival.
While twins, as a separate group, have a much higher
40 perinatal mortality rate overall because of the increased
incidence of preterm delivery, there are conflicting
reports in the literature in relation to survival figures for
20

0'
t+ I
23 24
I
25
Weeks of gestation
I
26
I
twin fetuses in comparison to singleton fetuses. Wolf et
al. I 6 have reported no difference in survival for single-
ton and twin fetuses matched for gestational age and
birthweight at the margins of viability. In other stud-
ies9J7twins have suffered a significantly increased mor-
tality in comparison to singletons at these gestations. In
Table 2 the survival (to discharge) data for singleton and
Fig. 1. Weekly survival figures, and rates of handicap among sur-
vivors for infants born between 23 and 26 weeks of gestation2 '. The twin births fiom University College Hospital, London
horizontal bars represent the mean and the vertical bars represent (1 987-1 994) and the Rosie Maternity Hospital, Cam-
95% CI. H = survival; H = handicap. bridge (1985-1991) between 23+O and 26'6 weeks, and

0 RCOG 1997 Br J Obstet Gynaecol 104, 1341-1350

 REVIEW 1343

Table 3. Number of handicappedltotal survivors from 23* to 26f6weeks since 1980. Values are given as nltotal (%) unless otherwise indicated.

Place Year of birth 23 weeks 24 weeks 25 weeks 26 weeks Reference

Liverpool, UK 1980-1 993 318 (38) 12/46 (26) 16/73 (22) Cookel'
Haifa, Israel 1982-1986 215 (40) 112 (50) 218 (25) Weissrnan eta/.l9
Northern Region, UK 1983 011 (0) 216 (33) 2/12 (17) Wariyar et
Vancouver, Canada 1983-1989 619 (66) 16/43 (37) 25/77 (32) Synnes et al."
Oxford, UK 1984-1 986 619 (66) 12/31 (39) Johnson et al.2?
Copenhagen, Denmark 1984-1 987 217 (29) 2/18 (11) Eg-AndersenZ3
Minneapolis, Minnesota, USA 1986-1990 7112 (58) 8/28 (29) 16/54 (30) 23/72 (32) Ferrara et 0 1 . ~
Leiden, Holland 1985-1987 213 (60) 017 (0) 216 (33) RUYSet nl.24
Cambridge, UK 1985-1992 212 (100) 3/13 (23) 8/27 (30) 10143 (23) RennieN
TOTAL 15/23 (65) 34/101 (34) 721235 (31) 691263 (26)
95% CI of percent 34-96 2345 24-38 20-32

for the birthweight groups 500-749 g and 750-999 g
are shown. Comparisons on the basis of gestational
age for this period show a significantly improved sur-
vival for singletons (56%) compared with twins (38%)
( P < 0.02). The increased survival for singletons with a
birthweight between 500-749 g (45%) compared with
twins of equivalent weight (29%) did not achieve
statistical significance, but in the birthweight category
750-999 g the survival for singletons (72%) was signif-
icantly better than for twins (59%) (P < 0-05). These
results suggest that for UK tertiary level neonatal units
survival for twins at extremely preterm gestational ages
is significantly worse than that for singletons.
Neurodevelopmentaldisability and handicap
Neurodevelopmental disability is the worst outcome
for survivors born at extremely early periods of
gestation. The types of disability seen among these sur-
vivors include spastic diplegia, spastic hemiplegia and
quadriplegia with or without intellectual impairment.
Other problems include blindness, deafness and severe
epilepsy. Minor motor problems, specific learning dis-
orders and attention deficits are commonly recognised
among school-age survivors. The numerous studies
reporting outcome for very preterm babies show great
variation in their results, and comparisons between
studies can be difficult. This is due to variations in the
diagnosis and definition of disability, the duration and
timing of follow up, differing years of study, the exten-
sive use of birthweight cutoffs (e.g. < or > 1500 g), the
use of hospital rather than geographical populations,
social and environmental differences, the dificulty in
maintaining follow up leading to missing cases from the
studies and the lack of control groups.
In Table 3 the number of children with major handi-
cap as a proportion of total survivors is shown for deliv-
ery at weekly intervals between 23'O and 26fhweeks of
gestation. These results have been obtained from nine
studies for babies born between 1980 and the early
1990s5.8.'R24and are shown alongside the corresponding
weekly survival rates in Fig. 1. At 23 weeks of gestation
if a child lives it is more likely to be handicapped than
not. At 24 weeks of gestation approximately one-third
of infants who survive will have major handicap and
this figure falls to approximately one-quarter for infants
born at 26 weeks of gestation. The UK EPICURE study,
which is a national study on outcome for infants deliv-
ered between 22 and 26 weeks of gestation, is currently
ongoing, and we look forward to the publication of its
results in relation to mortality and morbidity.
The prevalence of moderately severe or severe cere-
bral palsy is from 1.5 to 2.5 per 1000 live births at all
periods of gestation, but is 25 to 3 1 times higher among
preterm infants who weigh < 1500 g at birth (i.e. preva-
lence of approximately 50 per 1000) than among full-
sized newbornP2'. The rate of cerebral palsy among
very low birthweight groups has increased in recent
years in parallel with improval in survival figures, but
the rate of cerebral palsy per 1000 surviving in these
groups has not i n c r e a ~ e d ~ ~ ,suggesting
'~,~~, that the
neonatal measures that have led to the improved
survival are not a direct cause of cerebral palsy.
Maternal morbidity and mortality
The maternal complications associated with the obstet-
ric management of threatened or imminent preterm
delivery between 23'O and 26'6 weeks of gestation
should not be under-estimated. Delivery at these periods
of gestation does not contribute directly to maternal
mortality figures in developed counties. However, it
must be borne in mind that measures aimed at improv-
ing outcome for the fetus, by either prolonging the preg-
nancy (i.e. ritodrine tocolysis) or delivering the infant
(i.e. anaesthesia and caesarean section with increased
risk of thrombosis, haemorrhage and sepsis), are
directly related to maternal mortality in the UK30.
Maternal morbidity is a more frequent cause for con-
cern. The greater need for classical caesarean section
because of a poorly formed lower uterine segment at
these early periods of gestational age has hazardous

Q RCOG 1997 Br J Obstet Gynaecol 104, 1341-1350

1344 REVIEW
short and long term implications for the mother.
Classical caesarean section is associated with a higher
incidence of severe perioperative bleeding (> 1000 mL),
a greater need for post-operative blood transfusion, and
a higher incidence of postpartum fever than caesarean
section performed using a lower transverse uterine
incision31,32 Women who have had a classical caesarean
section have a 13% incidence of abnormal scars and a
6% incidence of scar dehiscence in a future pregnancy,
compared with a zero or negligible risk for both factors
in a matched control group who had a lower transverse
incision3'. The serious maternal morbidity that may
arise from tocolytic treatment (e.g. chest pain, pul-
monary oedema, cardiac arrhythmias) has been well
d~cumented~~. Chorioamnionitis and the complications
of maternal sepsis may occur with prolonged ruptured
membranes < 26 weeks of gestation34.Finally, whatever
the outcome, the delivery of an infant between 23+Oand
26'6 weeks of gestation constitutes a major adverse life
event for the parents and the psychological effects may
last for many years.
Clinical aspects
General measures
Care of a woman with threatened preterm delivery
between 23 'O and 26+6 weeks of gestation should take
place at a perinatal centre with experience in the care of
very preterm infants, so that her pregnancy can be man-
aged by an obstetrician with an interest in perinatal
medicine and an experienced neonatologist. Before
counselling and development of a plan for care and
delivery, it is important to obtain preliminary informa-
tion. A detailed fetal anomaly scan is a prerequisite if
this has not already been performed or the information
is incomplete or unavailable. Provision of this service
out of normal hours is an essential component of a refer-
ral perinatal centre. Detailed sonographic assessment of
estimated fetal weight, amniotic fluid volume and
Doppler ultrasound of the uterine, umbilical and fetal
vasculature will contribute to the overall picture of fetal
wellbeing and the ultimate prognosis for the neonate.
The missed diagnosis of a lethal abnormality or severe
uteroplacental insufficiency resulting in abdominal
delivery of a nonviable infant should be avoided.
Sonographic assessment of fetal presentation, placental
location and cervical status may all help in planning the
time and mode of delivery.
Induction offetalpulmonary maturation
The two main therapeutic interventions that have been
investigated in recent years for induction of pulmonary
maturation in the preterm fetus are corticosteroids and
thyrotrophin-releasing hormone. Reports have concen-
trated generally on a broad range of preterm gestational
ages. There is unequivocal evidence that antenatal corti-
costeroid administration to women expected to deliver
preterm will reduce respiratory distress syndrome, mor-
tality and intraventricular haemorrhage in the infants.
Most recently this has been shown by C r o ~ l e yin~the ~
Cochrane Library in her review of 3700 babies born to
randomised women in 18 trials which reported clinically
relevant outcomes. The effect on respiratory distress
syndrome was not statistically significant in the sub-
group of infants born < 28 weeks of gestation; Crowley
speculated that this may relate to the small numbers
available for analysis at this gestational age. There was
'no strong evidence' of any adverse effects of cortico-
steroids in these trials except that a subgroup analysis in
one trial suggested that corticosteroid administration
might predispose to fetal death in hypertensive women.
There is therefore no good scientific evidence outlining
benefits, or potential hazards, of corticosteroid adminis-
tration between 23+O and 26'6 weeks of gestation.
Hence, there are no guidelines as to when they should
be given during this period. The use of weekly repeated
doses at this time has never been evaluated in terms of
benefit, and more importantly, safety.
The benefits of thyrotrophin-releasing hormone
given with antenatal corticosteroids have been investi-
gated in many trials since the first reports of its potential
use from Liggins' group in 198836. This topic has
been reviewed in detail in the recent edition of the
Cochrane Library by Crowther and A l f i r e ~ i cAddition
~~.
of thyrotrophin-releasing hormone to corticosteroids,
compared with corticosteroids alone, had no effect on
mortality, the need for oxygen therapy or the incidence
of respiratory distress syndrome. It is therefore not
currently recommended for clinical practice, and there
are no data outlining its use between 23 and 26 weeks of
gestation.
Tocolytics
There are currently a number of agents being used, or
under clinical or scientific evaluation for use, in the
treatment of preterm labour. These include beta-adren-
ergic a g ~ n i s t s prostaglandin
~~, synthetase inhibitors3*,
calcium channel blockers39, magnesium sulphate40,
potassium channel openers4', nitric oxide donors42and
oxytocin antagoni~ts~~. The beta-adrenergic agonist
ritodrine is the most commonly used tocolytic agent in
the United Kingdom and the United States. Ritodrine is
effective in reducing the number of women who deliver
within 24 to 48 hours of commencing treatment but has
no significant beneficial effect on perinatal mortality,
neonatal morbidity, birthweight or in prolonging the
p r e g n a n c ~ ~ ~Some
. ~ . other tocolytic agents have
0 RCOG 1997 Br J Ohstet Gynaecol 104, 1341-1350

achieved comparable results, but none has been shown
to be more effective in any way and all are associated
with serious adverse maternal and fetal effects'. For
women with a singleton pregnancy in threatened
preterm labour with intact membranes at 24+O to 26f6
weeks of gestation, attempts to prolong gestation by 24
to 48 hours must be made after discussion with the
parents, but the presumed benefits of this delay may be
even less at these early periods of gestation in view of
the lack of data to support benefit from corticosteroid
administration at this time. In view of the survival and
handicap figures presented for 23 weeks of gestation in
Tables 1 and 3, and the present literature information on
the benefits of ritodrine therapy, it is the authors' view
that its use should not be considered before 24 weeks
of gestation. Because of the greatly increased risk of
serious morbidity from ritodrine therapy in multiple
p r e g n a n c i e ~ ~and
~ * the
~ ~ ,lack of data to support corti-
costeroid administration both in these pregnancies and
at very early periods of gestation, it is doubtful whether
ritodrine therapy should ever be used in these pregnan-
cies between 23'O to 26+6weeks of gestation. Further
discussion about future prospects for tocolysis will take
place in the scientific section below.
Antibiotics
Evidence for the use of antibiotics for preterm labour
between 23 and 26 weeks of gestation is based on the
results of four t r i a l ~ ~ ~ all
-~O concerning
, preterm labour
generally, which have been combined in a recent
review5'. It was concluded that, apart from the Romero
trial5", the others are of poor quality and provide little
data on infant mortality and morbidity. This latter trials0
found no significant difference between the treated
(with ampicillin and erythromycin) and untreated
groups in maternal outcome (interval to delivery, fre-
quency of preterm delivery, frequency of preterm
premature rupture of the membranes, clinical chorioam-
nionitis and endometritis) or neonatal outcome (e.g.
respiratory distress syndrome, bronchopulmonary dys-
plasia, intraventricular haemorrhage, sepsis and admis-
sion and duration of stay in neonatal intensive care).
Similar results have since been published using cefti-
~ o x i m eHauth
~ ~ . et aLS3have also demonstrated that for
women with idiopathic preterm labour antibiotics did
not lower the preterm delivery rate, but in those who
had bacterial vaginosis there was benefit from treatment
with metronidazole and erythromycin. However, in this
issue of the Journal (pages 1391-1397) McDonald et
al.54 report that treatment in mid-pregnancy of bacterial
vaginosis or heavy growth of Gardnerella vaginalis with
metronidazole does not reduce the preterm birth rate,
although there was a reduction in spontatneous preterm
births among women with a previous preterm delivery.
0 RCOG 1997 Bv J Obstet Gynaecol 104, 1341-1350
R E v I Ew 1345
The ORACLE Trial, a large multicentre trial funded by
the UK Medical Research Council and the UK Regional
Directors of National Health Service Research and
Development, is currently underway to evaluate the role
of co-amoxiclav and erythromycin in idiopathic preterm
labour, and we await its results. In the meantime,
because of insufficient evidence that antibiotic treat-
ment confers more good than harm for idiopathic
preterm labour with intact membranes, their use in
general clinical practice is not indicated.
There is a vast literature on the use of antibiotics
for preterm pre-labour rupture of the membranes. As for
preterm labour with intact membranes these reports
generally apply to a range of preterm gestational ages. A
review of 12 of these trialss5,which included acceptably
controlled comparisons, shows that treatment is associ-
ated with a reduction in the incidence of delivery within
a week and a reduction in maternal and neonatal infec-
tion, but had no effect on the perinatal mortality rate.
While there is a concern that the benefit of a longer time
in utero may be offset by some adverse factor (e.g.
exposure to resistant organisms) the implications for
practice currently are that the benefits of antibiotic
treatment for preterm pre-labour rupture of the mem-
branes appear to outweigh the potential harm and
should be used at 23-26 weeks of gestation.
Emergency cervical cerclage
Consideration of emergency cervical cerclage will
occasionally arise between 23+O and 26+6 weeks of
gestation, and the studies reported have included a large
proportion of cases at this time. Presentation with cervi-
cal dilatation may occur in someone with or without
a history suggestive of cervical incompetence. The
majority of reports on this topic are observational and
retrospective in nature, but mainly conclude that the
procedure does confer benefit. In a series of 19 cases of
emergency cerclage between 16 and 28 weeks of ges-
tation, at cervical dilatation between 3 and 10 cm, gesta-
tion was prolonged between 1 and 19 weeks, with an
overall perinatal survival rate of 63%56.Wong et aLS7
reported a series of 5 1 women, 18 of whom had cervical
dilatation of 1 3 cm, and found a median duration of
time gained of one week in this group with a perinatal
survival rate of 45%. Maternal complications included
chorioamnionitis, cervicovaginal fistula and deep vein
thrombophlebitis. A review of comparable studies
published on this topic between 1980 and 1992 has con-
cluded that emergency cerclage is beneficial, although
the incidence of complications, often due to infection, is
high58. There is only one prospective studys9 to our
knowledge on this subject and the number of subjects is
small. In this study 22 women who underwent cerclage
between 20 and 27 weeks of gestation were compared
1346 REVIEW
with 15 women who chose conservative management
with bedrest. Cervical dilatation was > 4 cm in all
women at presentation. Emergency cervical cerclage
resulted in a longer mean gestational age at delivery, a
shorter period of antepartum hospitalisation, less need
for tocolysis, and fewer preterm membrane ruptures.
The incidence of infection and caesarean section were
similar in both groups. The perinatal mortality in both
groups was similar but those who had undergone
cerclage had had a more advanced gestation and greater
birthweight. In conclusion therefore, with cervical
dilatation in the presence of intact membranes and with-
out evidence of infection, emergency cerclage should be
offered at these early periods of gestation. The role of
amniocentesis to outrule chorioamnionitis prior to such
cerclage is a source of current debate.
Mode of delivery
The optimal mode of delivery for women between 23
and 26 weeks of gestation in preterm labour is
unknown. The numbers recruited for randomised stud-
ies on this subject are too small to allow for reliable
conclusions. This topic has been reviewed60, using
information from the Cochrane Library, in relation to a
policy of elective caesarean delivery compared with
expectant management with recourse to caesarean
section if a clear clinical indication arose. These
findings pertain to delivery < 37 weeks of gestation, and
there are no reliable data concerning mode of delivery
for the subgroup 23O
' to 26+6weeks only. There is there-
fore no evidence that a policy of elective caesarean
section, for cephalic or breech presentation, confers
neonatal benefit between 23 and 26 weeks of gestation.
Neonatal management at delivery
After having met and counselled the parents, a senior
neonatologist should attend the delivery. By this stage a
decision to resuscitate the neonate or not should have
been made. However, the possibility of having to
change course immediately after delivery because of
unexpected circumstances (e.g. the baby is smaller
or larger than expected, or the presence of a major con-
genital malformation) should also have been discussed.
Weighing the baby at birth may be of help because
survival is still very rare in birthweights < 500 g. The
presence of a second experienced neonatologist in the
delivery room can be extremely helpful in order to keep
the parents informed of progress while they see every-
thing is being done. This situation allows for calmer dis-
cussion with the parents, as well as consensus between
two neonatologists. Withdrawal of treatment to allow
the baby to die in its parent's arms can be much easier
for all involved in these circumstances. The outcome
after full cardiopulmonary resuscitation in the delivery
room is so appalling in terms of survival and handicap
that it is doubtful whether it
for very pretexm infants6*p6*
should ever be attempted between 23+O and 26+6weeks
of gestation.
Scientific aspects of very preterm delivery
The large group of primary complications leading to
preterm delivery is poorly understood and much
research, of both a basic scientific and clinical nature, is
being done to address this. It is well beyond the scope of
this review to even give an overview of this research,
but the current difficultiesin understanding the aetiology
of spontaneous preterm labour, and the frustrations
encountered with research attempts to predict and pre-
vent it, will be briefly highlighted.
Unlike some animal models of parturition, the exact
sequence of events leading to human labour is unknown.
There is no causal relation between increasing fetal
cortisol concentrations and the initiation of labour in
humans, as is essential to the progesterone withdrawal
hypothesis so clearly outlined in sheep". The substrate
for cortisol action in the ovine placenta (placental
17-alpha hydroxylase) is absent in the human placenta.
To our knowledge the state of excitability of the human
myometrium during pregnancy is controlled by
a complex network of physiological mechanisms
involving hormones, peptides, cell membrane receptors,
intracellular signalling systems, calcium, neuronal and
metabolic factors, gap junctions and ion channels64.
Advances have been made, even in the last five years, in
clarification of the role of some of these: for example,
calcium channeP5, the nitric oxide pathway66, endo-
theli~~~~.", potassium channel^^^,^^, oxidation-reduction
reactions70and corticotrophin-releasing hormone7'. The
1970s and 1980s saw major advances in understanding
prostaglandin^^^, the adrenergic pathways, steroid hor-
mones, oxytocin and the role of the extracellular
m a t r i ~ ~ . ' ~It. ~remains,
~. however, that the detailed
physiology of human labour (and hence the pathophysi-
ology of preterm labour) are unknown, thus creating a
major barrier to effective therapeutic intervention.
As a result, most attempts to intervene and improve
outcomes for women in early preterm labour have been
unsatisfactory and largely inadequate. Most of these
attempts can be categorised into predictive and preven-
tative measures. Risk scoring clinical or
sonographic cervical a s ~ e s s m e n tand
~ ~uterine
. ~ ~ activity
monitoring' may help to identify some women who
will have a preterm delivery. The presence of fetal
fibronectin in cervico-vaginal secretion^^^, salivary
estriol levels79,relaxido, serum collagenasesgl, serum
metalloproteinases82,CRH83,cervico-vaginal cytokines
and granulocyte e l a ~ t a s ehave~ ~ all been reported as
0 RCOG 1997 Br J Obstet Gynaecol 104, 1341-1350

markers of impending preterm delivery. However, the
best reported sensitivity values are approximately 80% tal care for extremely preterm infants which include
with disappointingly low positive predictive values of
around 30%. For this reason, and the fact that there is no
effective therapeutic intervention, such predictive tests
do not have a clinical role in current practice.
Numerous agents with smooth muscle relaxing prop-
erties have been evaluated for use in the primary and
secondary prevention of preterm l a b o ~ r ~ ~While, ~ ~it- ~ ~needs .
is believed prolonging the pregnancy by 24 to 48 hours,
achieved with the use of these agents is an advantage for
transfer, or to allow for corticosteroid therapy, their use
has not yet been shown to lead to an improvement in
perinatal outcome. At the same time, the serious adverse
effects of these compounds have been well documented. The parents should be counselled about the complica-
As the pharmacokinetic and pharmacodynamic profiles
of many compounds are currently being evaluated in in
vitro preparations of human m y o m e t r i ~ m ~ ' . ~ it ~is. ~ ~ outcome
becoming apparent that the concept of myometrial
selectivity, as is being developed for some compounds
in other smooth muscle systemsR6,is the best way
forward to avoid systemic adverse effects. Sadly, phar-
macological development concerning the myometrium
is not a major priority of the pharmaceutical companies
involved in smooth muscle research. This is because of
the relatively small numbers, in epidemiological terms,
for whom this treatment would be required compared
with other potential uses for these compounds such as
hypertension, angina or asthma. Secondly, there is a
great apprehension about development of compounds
for use in pregnancy and the potentially long term
implications for litigation. There is therefore a great
need for perinatal physicians and scientists interested in
this field to continue basic scientific research bridged
with rigorous clinical appraisal in attempt to reduce the
perinatal wastage associated with early preterm labour.
Ethical aspects of very preterm delivery
The issues that arise at the border of viability (i.e. 23'O
to 26+('weeks of gestation) concerning the ethical basis
of intervention, or the lack of it, are complex from a
general moral viewpoint and in relation to the everyday
decisions required. A fetus, because of its insufficiently
developed central nervous system, has no values or
beliefs of its own in relation to what may be in its best
interests. Decisions are therefore the combined remit of
the parents and the medical caregivers (i.e. the obstetri-
cians and neonatal physicians). The recently publicised
Messenger case in the United States outlines the diR-
culties that may arise in this situationR7.In this case a
dermatologist felt that his child born at 25 weeks of ges-
tation and weighing 780 g, was resuscitated against his
wishes and removed the infant from the ventilator. He
was initially charged with manslaughter but was later
0 RCOG 1997 Br J Obstet Gynaecol 104, 1341-1350
REVIEW 1347
acquitted and has since proposed guidelines for neona-
compassion, care and comfort. Because of the special
relationship between parent and child, the parents are
regarded by society as appropriate for making decisions
regarding the care of their children, but this authority is
not absoluteg8.The obstetrician is responsible for the
wellbeing of the mother and her fetus and occasionally
to decide that the interests of one must take prior-
ity. From the time of delivery the infant's care is the
responsibility of the neonatologist.
Parental counselling
tion leading to imminent preterm delivery, the current
fetal condition, the chances of neonatal survival and the
, ~ ~ , for survivors. The obstetric implications for
the mother should also be discussed. This counselling
should be handled with caution but above all should be
clear in its content. We believe that the parents should
be seen before delivery by a senior obstetrician and pae-
diatrician and that a joint discussion is preferable. We
believe that information similar to that outlined above,
should be given to the parents. The survival and out-
come figures cited for parents should not vary from one
staff member to the next, as is often the case. Each unit
should have an agreed document which includes the fig-
ures they regard as appropriate for counselling parents
for weekly periods of gestation. The basic document
may need to be qualified for small for gestational age
fetuses and multiple pregnancy. This document should
be available to all staff members in the labour ward and
in the neonatal unit, and should be revised annually. It
should be explained to parents that these figures are a
crude outline and that once the baby is born other
factors will immediately influence the chance of intact
survival. These factors include the condition of the baby
at delivery, the sex of the child, the presence or absence
of infection, and later on the occurence or not of a major
intracranial lesion, severe lung disease or retinopathy of
prematurity.
The role of theparents
Parents may have difficulty deciding on what is the best
course of action for them, the fetus and their family
when the risk of impending delivery at these very
preterm gestations is discussed. This may arise from a
lack of medical information, religous or cultural beliefs,
inability to cope with the acutely stressful circum-
stances of hospitalisation or the belief that such
decisions must be taken by doctors. It is much easier
to agree to make every effort to save life and can be
hardest for the parents to understand that death is the
1348 R E V I E W
best decision they can make for their baby. It is there-
fore imperative that accurate and realistic information
about outcome is given in a sensitive way. It is very
important that the parents’ wishes are met in every pos-
sible way as they, more than anyone, are going to suffer
the long term burden of the all too frequent outcome of
death or handicap. Because there is often uncertainty in
relation to outcome the parents must arrive at a level of
certainty at which they feel happy to proceed with
aggressive medical care, or not. However in the extreme
situations (Leea request for all measures up to CPR at
23 weeks of gestation, or for nonresuscitation at 26
weeks of gestation) problems can arise for the obstetric
and neonatal teams, We believe that at 24 and 25 weeks
of gestation a well informed decision from &e parents
goes a long way towards dictating perinatal manage-
ment. Extra information in relation to ktal growth and
wellbeing, and condition at birth, should ideally be
included in this decision.
The role of the doctor
It is inevitable that in many c%es the doetors involved
will make a significant contribution to the decision
about resuscitation. In the United States the use of ante-
natal directives, decided jointly by the obstetrician and
parents, prohibiting neonatal resuscitation has emerged
as an optionx9.On= of the arguments for antenatal direc-
tives is that parents have the right to find doctors whose
philosophy agrees with theirs about medical care at the
borders of viabilty. This agreement is formally signed
antenatally and the paediatrician is not called to the
delivery, thereby ensuring death of the infant after birth.
This arrangement .does not m u r ‘intt-n UK. It has led to
much discussion and has been criticised on the basis
that the obstetrician has an obligation to both the mother
and her fetus, which may lead ro conflict; that the condi-
tion of the infant at birth may be very different to that
predicted antenatally; and that withdrawing treatment
later may be a better option than witholding treatment
(this latter point is controversial). Immediately at deliv-
ery, the neonatologist, who is then in charge of tnedical
care, may have a completely different perspective froin
that of the obstetric team. It has been argued that deci-
sions made by neonatologists may be related to deeply
personal biases about quality versus sanctity of life,
indifference to the hardships of k n g term disability, fear
of failure (i.e death), fear of litigation and even curiosity
to experiment with human lifeg0.In the UK there may
also be a polarisation of views between the obstetric and
neonatal teams, but it is the authors’ experience that
joint consideration of all the variables previously
outlined generally kads to a consensus for perinatal
management.
Conclusion
Perinatal care at very preterm periods of gestational
age has been frustratingly resilient to therapeutic inter-
vention in recent years. There is little in the way of
definitive evidence to support many of the currently
practised antenatal measures. There is a great need for
hrther research to address this problem. Advances in
neonatal care must be considered in light of survival
figures and reliable long term outcome data”. The
ethics of when to act, and when to do nothing, have
raised more questions than answers.
Acknowledgement
The authors would like to thank Dr J. Shaw, Consultant
Neonatologist, University College Hospital, London for
providing neonatal survival figures for inclusion in this
review.
John J. Morrison
Lecturer I Senior Registrar (Feto-Maternal Medicine)
University College London Medical School, London
Janet M. Rennie
Consultant (Neonatal Medicine)
King b College Hospital, Lorldon
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