REVIEW

Review

Preterm delivery

Michael M Slattery, John J Morrison

Preterm delivery and its short-term and long-term sequelae constitute a serious problem in terms of mortality, disability,
and cost to society. The incidence of preterm delivery, which has increased in recent years, is associated with various
epidemiological and clinical risk factors. Results of randomised controlled trials suggest that attempts to reduce these
risk factors by use of drugs are limited by side-effects and poor efficacy. An improved understanding of the physiological
pathways that regulate uterine contraction and relaxation in animals and people has, however, helped to define the
complex processes that underlie parturition (term and preterm), and has led to new scientific approaches for
myometrial modulation. The continuing elucidation of the mechanisms that regulate preterm labour, combined with
rigorous clinical assessment, offer hope for future solutions.

Preterm delivery of infants remains one of the most
intractable problems that contributes to perinatal
morbidity and mortality in obstetric practice in developed
countries.1 Preterm delivery results from a series of
disorders, implicating maternal and fetal disease, some of
which are explained and inter-related, and others of which
are of unknown cause.2,3 Epidemiological risk factors, of
which parental socioeconomic status is among the most
important, have a huge bearing on incidence and outcome
of preterm birth.4–6 Research efforts to address this problem
have risen substantially over the past 10 years, but have not
resulted in improvements in prediction and prevention of
preterm delivery.
For complex reasons, the overall frequency of preterm
births actually seems to be increasing.7 A major drawback
to the development of beneficial interventions to reduce
perinatal wastage, and the long-term sequelae that arise
from preterm delivery, is our poor understanding of the
normal physiology of human parturition. Consequently,
our knowledge of the pathophysiology of disorders that
lead to preterm delivery is limited. However, there have
been great advances in our understanding of the molecular
and cellular pathways operative in reproductive tissues in
the maintenance of uterine quiescence during pregnancy,
and in initiating term and preterm labour. This
understanding has led to the development of new
therapeutic strategies, many of which are undergoing
assessment in clinical trials.
Mortality and morbidity
About 75% of perinatal deaths occur in infants born
prematurely,8–10 with over two thirds of these arising in the
30–40% of preterm infants who are delivered before
32 weeks’ gestation. In recent decades, primarily through
advances in neonatal medicine, there has been an increase
in survival rates for preterm and low-birthweight infants,
especially for those born extremely early on in gestation
(figure 1),9,11–23 and a survival rate of almost 100% can now
Lancet 2002; 360: 1489–97
Department of Obstetrics and Gynaecology, National University of
Ireland Galway, Clinical Science Institute, University College
Hospital Galway, Galway, Ireland (M M Slattery MB,
Prof J J Morrison MD)
Correspondence to: Prof John J Morrison
(e-mail: john.morrison@nuigalway.ie)
be expected in infants delivered at or after 32 weeks’
gestation in developed countries.
Results of studies on survival of preterm twins, by
comparison with preterm singletons matched for
gestational age, are conflicting.9,24,25 For twins born before
28 weeks’ gestation, the outcome in terms of survival is
worse than that for singletons matched for gestational
age.9,24,25 For example, the average survival (to discharge) of
singleton infants born between 23 weeks’ and 26 weeks’
gestation was reported as 56%, compared with 38%
(p<0·02) for twin fetuses over the same interval.9
Furthermore, twins of the same sex seem to have a
consistently poorer prognosis than do twins of different
sexes.25 Between weeks 29 and 37 of gestation the outcome
for twins improves, with equivalent mortality rates
reported for singletons of comparable gestational age.26
The rate of perinatal morbidity does not seem to differ
much between twins and singletons delivered between
24 weeks’ and 34 weeks’ gestation, though there is a higher
prevalence of respiratory distress syndrome reported in
twins than in singletons.24
The overall fall in perinatal mortality has been
reciprocated by an increase in short-term morbidity and
long-term physical and mental disability in infant survivors
of very preterm birth. The EPICure Study Group21
assessed the association between extremely premature
birth and consequent neurological and developmental
disability in a cohort of 811 infants delivered between
22 weeks’ and 25 weeks’ gestation in the UK and Ireland.
They noted that about 54% of infants delivered at
23 weeks’ gestation, followed for a median of 2·5 years,
had either a severe (daily physical assistance required) or
other type of disability. The corresponding figures were
52% at 24 weeks’ and 45% for those born at 25 weeks’
Search strategy
We searched Medline, PubMed, and the Cochrane Library for
published work relevant to this Review with the search terms
“preterm delivery”, “preterm labour”, and “preterm birth”,
alone, and in combination with the terms “epidemiology”,
“reproduction”, “multiple pregnancy”, “twins”, and “perinatal”.
We also did separate searches with the terms “tocolysis” and
“myometrium”. We focused on work published in the past
5 years, but also included commonly referenced and highly
regarded older publications. Recent review articles that
provided comprehensive overviews were also included.

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REVIEW
100
46
80 202 348
969
Survival (%)
60
1283
893
40
434
20
44
0 not an increased tendency to register livebirths at very early
22 23 24 25 26 27 28 29
Gestational age (weeks)
Figure 1: Perinatal survival (%) between weeks 22 and 31 of
gestation
Average total number of neonates9,11–23 for each week of gestation given in
respective bars. Although denominator data in different studies could
vary, the figures presented here are outlined as a proportion of all
livebirths as reported.
gestation.21 There was no relation between the pattern of
morbidity and gestational age. Compilation of data from
registers of people with cerebral palsy, which report
outcome for preterm infants based on birthweight, has
revealed that the prevalence of cerebral palsy is
60–80 times higher in low-birthweight infants (<1500 g),
than in fully grown infants at term.27 Although
interpretation of outcome on the basis of birthweight
introduces the confounding variable of intrauterine growth
restriction, most infants born with a birthweight of less
than 1500 g are preterm. Follow up of low-birthweight
infants (<1500 g) into adulthood (up to age 20 years) has
revealed that they are more likely than infants born
weighing more than 1500 g to have chronic health
problems, such as neurosensory deficits—eg, blindness,
deafness, cerebral palsy—a lower IQ, lower scores on
academic achievement tests, and subnormal height.28
These findings pertain to only one study, however, and
more long-term studies are needed before firm conclusions
can be drawn. Furthermore, the chances of survival for
premature infants born now are much improved due to
aggressive intensive care.29 Whether or not this increased
survival will further adversely affect morbidity in childhood
or adulthood, or both, remains to be seen.
Epidemiology
A child born before 37 weeks of gestation is judged
preterm.30,31 Although there is no set lower limit for this
definition, 23–24 weeks’ gestation is widely accepted,
corresponding to an average fetal weight of 500 g. The
Panel 1: Causes of preterm delivery
Cause
Spontaneous preterm labour
Multiple pregnancy and associated complications
Preterm prelabour rupture of membranes (pPROM)
Hypertensive disorders of pregnancy
Intrauterine growth restriction
Antepartum haemorrhage
Miscellaneous—cervical incompetence,
uterine malformation
1490
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prevalence of preterm delivery varies from 6% to 15% of
104 all deliveries,2,8,32,33 depending on the geographical and
demographic features of the population studied. Although
34 ascertainment of exact statistics at the borders of viability is
difficult, with potential for slight variation between
countries, there has been a tendency towards higher
reported rates in recent years.7,31,34 The factors that
contribute to preterm birth differ between studies, but
generally include one or more of those shown in panel 1.
The rise in reported rates of preterm delivery is a cause
for concern and has been attributed to many factors,
including increased obstetric intervention,35 use of assisted
reproduction techniques,36 high numbers of multiple
births,37,38 raised prevalence of substance misuse in urban
areas,4 and a rise in idiopathic preterm delivery rates heavily
weighted by adverse socioeconomic factors.4–6 Whether or
30 31 gestational ages (20–22 weeks) in some countries has
contributed to the rise in preterm delivery rates is unclear.36
Although the overall rate of preterm delivery is an
important statistic in public-health terms, outcome
measures in terms of morbidity and mortality vary greatly
within this group, depending on actual gestation at delivery.
For this reason, and because neonatal survival is effectively
100% after 32 weeks’ gestation, there is now a trend
towards assessment and reporting of outcome for the 1–2%
of births that arise before 32 weeks’ gestation separately
from those occurring after this time.2,9,11–23
Socioeconomic status
Social disadvantage, whether defined by occupation,
income, or degree of education, is associated with an
increased risk of preterm delivery.4,9,39,40 The reasons for this
trend are not clear, but possible explanations include
worse nutritional status, increased frequency of cigarette
smoking, greater use of recreational drugs such as cocaine,
higher rates of fetal growth retardation, poorer quality and
quantity of antenatal care, higher frequency of genital-tract
infection, physically demanding work, and higher levels of
adverse psychological factors. Attempts to understand
rates of preterm delivery in lower socioeconomic groups
have not yet yielded benefit in terms of providing clues to
the cause of preterm birth in general.4 Furthermore,
attempts at intervention by improvement of social-support
mechanisms in this population have neither resulted in a
decrease in the rates of preterm delivery, nor in
improvement in outcome by any perinatal measure.41,42
Ethnic origin
The preterm birth rate for black women is almost twice that
for white women of comparable age in the USA,8,34,43
irrespective of socioeconomic status.44 This racial gap has
slightly diminished during the past 10 years largely due to
an increase in preterm delivery rates for white infants;31
although preterm birth rates have increased by 3·6% in
black women (from 15·5% in 1975 to 16·0% in 1995), a
rise of 22·3% in white women (from 6·9% to 8·4%) has
been reported over the same interval.34 In black primigravid
women in the USA, rates of preterm delivery increased
Frequency from 1975 to 1990 and began to decline thereafter, whereas
31–50%2,35 among white primigravid women, the rates rose between
12–28%2,24,36 1975 and 1995.34 Why this difference exists is not clear, but
6–40%2,35,37 since the preponderance of preterm deliveries in the black
12%3 population arose in the idiopathic preterm labour group, it
2–4%3 cannot be explained by variation in socioeconomic status,
6–9%3 and hence is suggestive of a biological variation. The US
8–9%3 Department of Health’s objectives for the first decade of
this century, detailed in Healthy People 2010,45 aim to
achieve an incidence of no more than 7·6% for preterm
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birth over the next 8 years, and for the first time all ethnic
groups are expected to approach the Healthy People 2010
objective at similar rates.
Multiple pregnancy
Multiple pregnancy accounts for 12–27% of all preterm
births.2,24 Over the past 20 years there has been a great
increase in the incidence of multiple births, largely as a
result of use of assisted conception technologies. In the
USA, twin livebirth rates increased from 18·9 per 1000 in
1980 to 26·9 per 1000 in 1997.46 Similarly, in the north of
England, the twinning rate increased from 9·9 per 1000
maternities in 1982 to 12·0 in 1994.47 Additionally, the
preterm birth rate among multiple pregnancies has
substantially increased. In Canada, preterm delivery
among all multiple births increased from 40% in 1981–83
to 53% in 1997.48 Although these increases have
contributed much to the overall rise in preterm delivery
rates in developed countries,36 increased intervention to
deliver twins early in the third trimester—ie, induction of
labour or caesarean section—might also have played a
part.49 These changes could be associated with a decrease
in perinatal morbidity and mortality among twin
pregnancies that reach 34 weeks’ gestation.
Age, parity, and past reproductive history
Results of one study34 suggest that the incidence of preterm
delivery in white women is lowest in those aged
20–24 years for the first birth, and 25–29 years for
subsequent births.34 For black women, the lowest rates of
preterm labour, for both the first and second births, arise
between the ages of 25 years and 29 years.34 Women who
give birth at age younger than 20 years, have increased
rates of preterm delivery.50,51 However, first teenage births
do not seem to be independently associated with raised
risk of preterm delivery, whereas second teenage births are
associated with a highly increased risk (6·1%) when
compared with the risk for women aged 20–29 years
(3·5%).51 A previous history of preterm birth or delivery of
a low-birthweight infant are also important risk factors for
subsequent preterm delivery.52,53 Findings of one study54
showed that the risk of preterm delivery in the second
pregnancy was 14·3% if the first birth occurred preterm,
and 28·1% for the third pregnancy if both previous
children were born preterm.54 For each birth that is not
preterm, the risk of a subsequent preterm birth decreases.
Second (but not first) trimester pregnancy loss has been
linked with an increased risk of preterm delivery,55 possibly
because of its known association with cervical
incompetence, whether due to dilatation at induced
abortion or previous cone biopsy. Previous involuntary
termination of pregnancy significantly raises the risk of
preterm delivery.56 After adjustment for potential
confounding variables, and stratification by gravidity, the
odds ratios of preterm singleton livebirths in women with
one, two, or more previous induced abortions are
1·89 (95% CI 1·70–2·11), 2·66 (2·09–3·37), and 2·03
(1·29–3·19), respectively.56
There is also a substantially increased risk of preterm
delivery after assisted conception with in-vitro fertilisation
(IVF) and gamete intrafallopian transfer (GIFT),
especially for singleton gestations. The preterm delivery
rates for singleton pregnancies after IVF and GIFT are of
the order of 20%,57–59 and these higher rates could be
attributed to various factors, including cervical trauma,
disturbed implantation, infection, uterine malformations,
and associated infertility factors. No further increase in
rates was observed with oocyte donation.60,61 For twin
pregnancies conceived after IVF or GIFT,62 there was no
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REVIEW
significant difference in the frequency of preterm delivery,
or mean gestational age at delivery, by comparison with
twins conceived spontaneously,62 a factor which could be
associated with the reduced incidence of monozygotic
twinning in the assisted reproduction technology group.
That the raised rates of multiple pregnancy associated with
assisted conception technologies, and that the increased
preterm delivery rate among singleton pregnancies arising
from such technologies, have played a part in the overall
increased rate of preterm delivery is, however, clear.
Whether or not the increased risk of congenital birth
defects associated with assisted reproduction (odds
ratio 2·0; 95% CI 1·3–3·2)63 has a further bearing on
preterm delivery is unclear.
Substance misuse
Substance misuse during pregnancy has consistently been
shown to increase the risk of preterm delivery, but what is
not clear is how much of this increase risk is due to the
actual substance, and how much it is related to other
adverse socioeconomic factors. About 25% of women who
use multiple drugs have a preterm labour.64 Findings for
individual substances vary greatly between reports. Many
studies65–69 have outlined a clear association between cocaine
use and increased preterm delivery rates. However, making
sound conclusions in terms of the cause of preterm delivery
is difficult, since the populations studied are generally
highly selected, studies do not control for potential
confounding variables, and different criteria are used as
evidence of drug misuse—eg, self-reporting, medical record
documentation, or urine assays. Other studies have not
shown an increase in preterm birth rates with cocaine use
during pregnancy70,71 and suggest that many other lifestyle
risk factors in cocaine users could account for adverse
pregnancy outcomes. Likewise, the occasional use of
marijuana during pregnancy is not apparently associated
with increased risks of preterm delivery70,72 or perinatal
morbidity or mortality,73 although in one report73 a possible
association between frequent and regular use of marijuana
throughout pregnancy was associated with small
decrements in fetal birthweight. Narcotic use, high alcohol
intake, caffeine consumption, and cigarette smoking are all
more prevalent among the socially disadvantaged, but these
factors have not been shown to exert an independent
adverse effect by increasing the risk of delivery preterm.4,74,75
Infection
Any systemic maternal infection—eg, pyelonephritis,76
pneumonia77—that arises at a preterm period of gestation
can trigger onset of labour, and the association between
genital-tract infection and particularly intrauterine
infection, and spontaneous preterm labour has been widely
researched. Despite this work, the exact frequency of
preterm delivery related to intrauterine infection, and the
specific organisms involved, are poorly understood.
Intrauterine infection can be present without clinical signs
of maternal infection, which has led to hypotheses of fetal
or choriodecidual inflammatory syndromes causing
preterm delivery, without objective evidence of infection.78
By use of amniocentesis in women with preterm labour
and intact membranes, a mean rate of positive amniotic
fluid cultures of 12·8% has been reported.79 The two most
common organisms are Mycoplasma hominis and
Ureaplasma urealyticum, followed by Gardnarella vaginalis,
peptostreptococci, and bacteroides species.79–82 These
organisms found in the genital tract are all of fairly low
virulence. Bacterial vaginosis, which is associated with
preterm labour,83 serves to highlight vaginal carriage of
these organisms, and hence is a marker of potential
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Uterotonic pathways Uterorelaxant pathways

Receptor (?)
+ agonist

Peptides:
Cell membrane
VIP (?)
RhoA RhoA CGRP (?)
GDP GTP Cytoplasm

Rho Kinase
Oxytocin + Cl– channel GTP
P
NOS
Depolarisation MP (inhibited) cGMP NO Nitrates
MP (active)
Oestrogen Progesterone
P
Uterine stretch MLC MLC Relaxation
Contraction
Prostaglandin E2/F2␣ Ca2+
ATP
receptors Ca2+, Mg2+- ATPase
[Ca2+]
Endothelin Ca-Cam + MLCK K+
ET1/ET2/ET3
receptors
Passive entry PGs Inhibition
Na+ Na+/Ca2+
SR
Calcium channels COX exchanger
(Ca2+ store) cAMP
(VOC/AOC) ATP
AA Ca2+
ACh receptor
IP3 + DAG
+ agonist Inhibition Adenylate
cyclase
GS PIP2 Gi GS Peptides:
CRH
Polyamines
Oxytocin receptor PTHrP
␣1 adrenergic ␤2/␤3 adrenergic
+ agonist
receptor + agonist receptor + agonist

Figure 2: Major physiological pathways mediating myometrial contraction and relaxation

Uterotonic pathways (solid red arrows)—Myometrial contraction and relaxation result from the phosphorylation or dephosphorylation of myosin light chains
(MLC), respectively. Phosphorylation, by the enzyme myosin light chain kinase (MLCK), in the presence of adenosine triphosphate (ATP), is regulated by
intracellular calcium concentrations ([Ca2+]i ), in conjunction with the intermediate protein calmodulin (Cam), which together form the calcium-calmodulin
(Ca-Cam) complex. Calcium channels (voltage and agonist operated channels VOC/AOC), membrane endothelin (ET) receptors (ET1, ET2, ET3), passive entry,
membrane prostaglandin receptors (E2, F2α) and stretch, all facilitate an increase in intracellular Ca2+ concentration (↑[Ca2+]i) and result in smooth muscle
contraction. Agonist-mediated activation of membrane acetylcholine (Ach) and oxytocin receptors stimulate the production of the second messenger
D-myoinositol 1,4,5-triphosphate (IP3), the latter through the action of the enzyme phosphoinositidase C (coupled to the oxytocin receptor by a stimulatory
G-protein [Gs]), on the plasma membrane constituent phosphatidyl-inositol 4,5-bisphosphate (PIP2). IP3 releases Ca2+ from the sarcoplasmic reticulum (SR)
thus increasing [Ca2+]i and resulting in cell contraction. A byproduct of IP3 synthesis, the second messenger diacylglycerol (DAG) might promote cell
contraction via intracellular prostaglandin synthesis from arachidonic acid (AA) by cyclooxygenase (COX) enzymes. The steroid hormone oestrogen
promotes cellular contractility by up-regulating COX enzymes, particularly the COX-2 isoform. The active isoform of myosin phosphatase (MP)
dephosphorylates MLC, promoting cell relaxation. Receptor-agonist binding and the formation or upregulation of intracellular RhoA or Rho kinase could
result in a shift in the equilibrium of intracellular MP in the direction of the inactive isoform, resulting in enhanced cell contraction—ie, calcium
sensitisation. Agonist binding of the ␣1 adrenergic receptor stimulates inhibitory G-proteins (Gi), which inactivate the adenylate cyclase mediated production
of cAMP from ATP. cAMP results in cell relaxation in many ways, including inhibition of MLCK and the efflux of [Ca2+]i through sodium/calcium (Na+/Ca2+)
exchanger channels. Chloride (Cl-) channels, which might be activated by oxytocin, exert their uterotonic effect by depolarisation of the smooth muscle cell
membrane.
Uterorelaxant pathways (broken arrows)—Activation of beta-2 (β2) and β3 adrenergic receptors increases intracellular cAMP via Gs-mediated activation of
adenylate cyclase, resulting in cell relaxation. Endogenous or exogenous nitrates are converted to nitric oxide (NO) within myometrial cells by nitric oxide
synthase (NOS). The action of NO is mediated by activation of soluble guanylate cyclase which, in the presence of guanosine triphosphate (GTP), produces
cyclic guanosine monophosphate (cGMP). cGMP activates protein kinases, ultimately leading to smooth muscle relaxation. Vasoactive intestinal peptide
(VIP) and calcitonin gene-related peptide (CGRP) exert uterorelaxant effects by increasing concentrations of cGMP. Polyamines act via calcium antagonism,
while the peptides corticotrophin-releasing hormone (CRH) and parathyroid hormone-related peptide (PTHrP) promote cell relaxation by increasing
concentrations of cAMP. Cytosolic calcium-ATPase and magnesium-ATPase enzymes exert a uterotonic effect by decreasing [Ca2+]i.

intrauterine colonisation.84 In preterm prelabour rupture of
the membranes (pPROM),2,24,37 positive amniotic fluid
cultures are detected in about 32% of women. Microbial
invasion of the amniotic cavity does not explain the raised
risk of preterm delivery associated with twin pregnancy,
being present in only 11·9% of cases.85 PCR could help to
identify more accurately a possible infectious cause in the
30–40%86,87 of preterm births currently classified as
idiopathic.
Therapeutic intervention
Tocolytics
The molecular and cellular processes involved in the onset
and maintenance of human parturition are complex and
incompletely understood. A detailed review of these
mechanisms is beyond the scope of this Review. However,
the salient physiological pathways that mediate myometrial
contractility and relaxation are shown diagrammatically in
figure 2.88–102 Many of the pathways have been elucidated
over the past 10–15 years and, although the mechanism of
labour onset is reasonably well understood in mammalian
and non-human primate systems, the precise sequence of
events in people is unclear.103,104 Similarly, the exact
pathophysiology that underlies preterm labour is
unknown.
Attempts to use drugs to delay the onset of, or inhibit,
preterm labour have, therefore, been less than successful.
Most of these efforts have involved development of

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 REVIEW

Panel 2: New strategies for myometrial relaxation and their stage of development
Preclinical studies Clinical studies References
In vitro In vivo (type)
Drug
Atosiban ✓ ✓ RCTs 112, 114, 115
␤2 agonists ✓ ✓ RCTs 105, 111, 114–116
␤3 agonists ✓ - - 101
Calcium channel antagonists ✓ ✓ RCTs 116
COX-2 inhibitors ✓ ✓ CR 100, 118
Glyceryl trinitrate ✓ - RCTs 111
Human chorionic gonadotropin ✓ ✓ RCTs 119–121
Indometacin ✓ ✓ RCTs 113
Magnesium sulphate ✓ ✓ RCTs 107
Peptides
Parathyroid hormone-related peptide ✓ - - 97
Vasoactive intestinal peptide ✓ ✓ - 108
Calcitonin gene-related peptide ✓ - - 93
Potassium channel openers ✓ - - 106
Protein kinase inhibitors ✓ - - 91
Rho kinase inhibitors ✓ - - 99
Tyrosine kinase inhibitors ✓ - - 91
COX-2=cyclooxgenase-2. RCTs=randomised controlled trials. CR=case report.

agonists of the uterorelaxant pathway, or antagonists of the
uterotonic pathways. Historically, ␤2 adrenergic agonists
have been the most widely used agents in clinical
practice,105 but at high cost in terms of adverse effects. For
this reason, and the fact that the delay in delivery achieved
by their use did not translate into objective perinatal
benefit (as measured by mortality or morbidity), much
scientific and clinical research has focused on the
development of new tocolytic agents (panel 2).106–108 Of the
available agents, ␤ mimetics, indometacin, atosiban, and
nifedipine all significantly delay delivery after the onset of
preterm labour for longer than 24 h and 48 h compared
with placebo or no treatment.105,109–116 However, neonatal
outcome, as measured by perinatal death, respiratory
distress syndrome, birthweight, patent ductus arteriosus,
necrotising enterocolitis, intraventricular haemorrhages,
seizures, hypoglycaemia, or neonatal sepsis did not differ
greatly in treatment and control groups.
So should tocolytic drugs ever be prescribed? No
available tocolytic drug provides significant neonatal
benefit compared with placebo. Furthermore, data from
the EPICure group117 show that tocolytics, though
associated with a decrease in death before discharge (odds
ratio 0·57; 95% CI 0·41–0·79), are associated with a rise in
the frequency of severe neonatal brain scan abnormalities
(2·02; 1·04–3·94) and severe chronic lung disease (2·53;
1·42–4·51). We therefore recommend that, until novel
methods of tocolysis of proven benefit are avalable,
pharmacological agents with a minimum profile of adverse
effects—ie, atosiban112,114,115 or nifedipine116—should
constitute the first line of treatment.
Whether or not pharmacological methods of myometrial
modulation being developed will provide potential for
perinatal benefit in the treatment of preterm labour
remains to be seen. No overall difference between glyceryl
trinitrate and ritodrine in reduction of preterm delivery
rates has been noted,111 and the limited clinical data
available118 with respect to the use of cyclooxygenase-2
(COX-2) inhibitors suggest that serious adverse neonatal
effects could arise. Results of some studies119 indicate that
human chorionic gonadotropin (hCG) plays a part in
maintenance of uterine quiescence in the third trimester,
and hence could be an endogenous tocolytic agent. hCG
exerts a potent myometrial relaxant effect in human
myometrium in the third trimester (figure 3),119 and
inhibits preterm delivery in animals.120 However, although
findings of provisional observational clinical studies121 have
suggested that hCG could have a role in treatment of
preterm labour, this notion has not been tested in
randomised controlled trials.
Glucocorticoids
The routine administration of glucocorticoids
(dexamethasone or betamethasone) to women at risk of
preterm delivery before 34 weeks’ gestation has greatly
reduced mortality, respiratory distress syndrome, and
intraventricular haemorrhage in preterm infants.122 The
beneficial effects of corticosteroids on fetal lung
maturation have been reported within 48 h of initial
administration and, for babies born between 24 h and
7 days after treatment, there is a significant reduction in
respiratory distress syndrome, from 25% in controls to
12% in the treated group (odds ratio 0·38,
95% CI 0·25–0·57).122 No beneficial effect has been
reported after the administration of corticosteroids before
28 weeks’ gestation or if neonates are delivered more than
30 min
2g
0·001 0·01 0·1 1·0 10
hCG (IU/mL)
Figure 3: In-vitro uterorelaxant effect of cumulative
administration of human chorionic gonadotropin (hCG) to
human myometrial tissue from a pregnant woman
hCG was added in a cumulative manner (at concentrations ranging from
0·001 to 10 IU/mL) at 30 min intervals to isolated biopsies of
myometrial tissue obtained from pregnant women. Myometrial tissue was
maintained under a constant resting tension of 2 g. A significant,
concentration-dependent relaxant effect resulted.119 Reproduced by
permission of Elsevier Science.

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REVIEW
7 days after initiation of treatment. Additionally, the small
numbers of neonates from twin pregnancies included in
the trials122 do not allow for a confident statement with
respect to the effect of corticosteroid prophylaxis in
multiple pregnancy.
The administration of further courses of corticosteroids
each week to mothers who have not delivered within
1 week of the initial dose has become common obstetric
practice in many centres. However, the risk-benefit ratio of
this practice has not been borne out in the conclusions of
several randomised controlled trials, which report that
multiple weekly administration of antenatal corticosteroids
does not confer an advantage over single-course treatment
in terms of composite neonatal morbidity (0·80;
0·59–1·10).123–25 Because of the lack of knowledge with
respect to potential harmful effects of repeated doses of
glucocorticoids to the developing fetus, such regimens
should be reserved for women enrolled in randomised
controlled trials until further data are available to guide
clinical practice.
Antibiotics
Considerable research effort has been focused on the
potential for antibiotic prophylaxis in the management of
women at increased risk of preterm delivery. Meta-
analyses126–128 of reports from randomised controlled trials
on the efficacy of different combinations of antibiotics in
the prevention and treatment of preterm labour are
inconsistent. However, results of a large multicentre
randomised controlled trial128 of 6295 women in
spontaneous preterm labour did not support a role for
routine antibiotic prophylaxis in the management of such
women. Because of its size and quality, the findings of this
trial overrule the uncertainties of previous trials.
The beneficial effect of prophylactic antibiotic regimens
in pPROM is better defined. The findings of the
ORACLE I study129 indicated favourable outcomes,
including a significant prolongation of pregnancy and
improved neonatal outcome in a large cohort of mothers
treated with erythromycin.
Speculative screening of asymptomatic mothers for
microbes associated with an increased frequency of preterm
birth, in particular those responsible for bacterial
vaginosis,130,131 does not seem to be worthwhile.132 The
treatment of established bacterial vaginosis in early
pregnancy decreases neither the incidence of preterm
delivery nor the prevalence of peripartum infections (with
the reported exception of mothers with a history of preterm
labour133). The empirical or blind treatment of all patients
for bacterial vaginosis in the first trimester could even be
harmful, with some reports134 suggesting that application of
2% clindamycin cream to pregnant women with normal
vaginal flora stimulates the development of vaginosis.134
Cervical cerclage
Reports of the potential value of prophylactic or
therapeutic cervical cerclage in the management of women
at risk for cervical incompetence and preterm labour are
conflicting. Early data135 showed that in women at risk of
cervical incompetence during pregnancy, prophylactic
introduction of a cervical suture greatly reduced the rate of
delivery before 33 weeks’ gestation (13% with cerclage vs
17% with no cerclage). However, no great risk reduction
was noted between 33 weeks’ and 36 weeks’ gestation, and
the insertion of surgical sutures was reported to double the
risk of puerperal pyrexia.135 Results of three randomised
controlled trials136–39 have not clarified this situation further.
Two of the trials reported no advantage in terms of
perinatal outcome in women with clinical evidence of
1494
For personal use. Only reproduce with permission from The Lancet Publishing Group.
cervical incompetence before 24 weeks’ gestation.136,137 The
other trial reported a benefit from insertion of cervical
cerlage by reducing the rate of preterm delivery before
34 weeks’ gestation.138,139 This benefit was observed in
women who had short cervical length (<25 mm) or risk
factors for preterm delivery, and occurred with or without
additional bed rest as a treatment regimen for the
women.138,139 No significant increase in the risk of materno-
fetal complications associated with cerclage was reported.
Larger randomised controlled trials than those completed
and systematic reviews are still needed to definitively
outline the role of cerclage in high-risk pregnancies, but
evidence suggests that women with previous risk factors, or
short cervical length, could benefit from the procedure.
Enhanced social support
The intrinsic role of socioeconomic factors in the cause of
preterm labour has resulted in numerous studies, assessing
the contribution of enhanced antenatal care and increased
social support during pregnancy. The methods by which
social support was improved varied between reports, and
included an increase in the number of antenatal visits, bed
rest programmes, home visits by midwifes, social worker
and psychological counselling sessions, and nutritional
education.140 To date, no large improvement in perinatal
outcome, or length of gestation achieved, has been linked
with any of these interventions.
Future directions
The main aim of future research is to reduce the
prevalence of preterm delivery that does not confer fetal
or maternal benefit. Improved understanding at the
molecular level of the events that surround labour, term
and preterm, and the development of novel
pharmacological methods for clinical assessment, are
essential to such progress. The use of new DNA
microarray techniques should allow for the comparison of
simultaneous RNA expression of thousands of individual
genes in human reproductive tissues (myometrium,
deciduas, fetal membranes, and placenta) at the time of
preterm labour. Such global analysis of feto-maternal gene
expression, followed by systematic examination of
plausible candidate genes in terms of RNA and protein
expression, could provide clues to the cause of preterm
delivery and indicate the most relevant therapeutic
approach. In practice, the identification of potentially
preventable preterm deliveries on a large scale would be a
major leap forward, however, whether this is realistically
achievable remains to be proven. Importantly, novel
interventions should be subjected to rigorous clinical
assessment—ie, multicentre randomised controlled
trials—to allow for the heterogenous nature of the
condition, and the potential for a significant placebo
effect.
The delivery of an infant preterm can be a devastating
event with great long-term health and social implications
in childhood, and beyond, for the offspring and their
family. Therefore, despite the frustrating absence of
objective benefit in outcome of available treatments,
perinatal scientists and clinicians should be encouraged to
continue to search for solutions to this problem.
Conflict of interest statement
None declared.
Acknowledgments
We thank the Health Research Board of Ireland and the Higher Education
Authority of Ireland for research funded into preterm delivery at the
Department of Obstetrics and Gynaecology, National University of
Ireland, Galway. The funding sources did not contribute to the writing of
the report.
THE LANCET • Vol 360 • November 9, 2002 • www.thelancet.com

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