8

Pharmacological prevention of prematurity

Katie M. Groom
*
MBBS, BSc
Research Fellow
Department of Obstetrics and Gynaecology, University of Auckland, School of Population Health (Building 730),
Faculty of Medical and Health Science, University of Auckland Tamaki Campus, Private Bag 92019,
Auckland, New Zealand
The acute treatment of premature labour is successful for delaying delivery for short periods of
time. Acute tocolysis does not have a signicant impact on perinatal outcome. This is likely to be
because the process leading to labour occurs over a longer timeframe and therefore therapies
instigated as preventative measures are more likely to be successful in delaying delivery. Identi-
cation of women at risk of preterm birth is essential to ensure therapies are targeted appro-
priately. Risk assessments for prediction include previous obstetric history, previous episode of
threatened preterm labour, fetal bronectin status and cervical length.
Several groups of pharmacological agents have been studied for the prophylactic treatment of
preterm labour. There is no evidence to support the use of tocolytics such as b-mimetics and
oxytocin receptor antagonists. Current studies of calcium channel blockers are too small to
draw nal conclusions. Non-steroidal anti-inammatory drugs are associated with side effects
on the fetal renal system and ductus arteriosus, making them suitable only for long term use
in pregnancy with close ultrasound surveillance. Antibiotics used early in pregnancy in women
with abnormal vaginal ora may reduce the risk of preterm birth; however, in women with other
risk factors for preterm birth, metronidazole may be associated with an increased risk. The use
of progesterone in women with a history of very early preterm labour is likely to be benecial
for preventing preterm labour.
Key words: premature labour; prevention; tocolysis; maintenance therapy; NSAI drugs; antibi-
otics; progesterone.
Prematurity continues to be a major obstetric problem, accounting for up to 80% of all
neonatal morbidity and mortality. There is a wide variety of tocolytic drugs available for
the acute treatment of threatened preterm labour. Although the majority of these do
delay delivery, allowing time for antenatal corticosteroid administration and in utero
transfer if required, they have not been shown to have a signicant impact on outcome.
1
* Tel.: 64 21528369.
E-mail address: katiegroom@xtra.co.nz
1521-6934/$ - see front matter 2007 Elsevier Ltd. All rights reserved.
Best Practice & Research Clinical Obstetrics and Gynaecology
Vol. 21, No. 5, pp. 843856, 2007
doi:10.1016/j.bpobgyn.2007.03.010
available online at http://www.sciencedirect.com
Prevention of premature labour is likely to be more successful in reducing preterm
birth than acute treatment of an episode of threatened preterm labour. It is now well
established that the inammatory cascade leading to labour is a complex process
involving multiple feedforward mechanisms that occur over several weeks.
2,3
It is likely
that this cascade is too far advanced to be reversed once contractions have started
and therefore therapeutic options for preventing preterm birth should be considered
before, or early in, the inammatory cascade. Several groups of pharmacological
agents have been used for the prevention of preterm birth but for them to be effective
those women at risk of preterm labour need to be accurately identied.
PREDICTION OF PRETERM LABOUR
There is a variety of methods for predicting preterm labour which can be used in a gen-
eral low risk population or more specically targeted at women with recognised risk
factors. Sensitivity, specicity and predictive values of these tests are greater in those
women identied to be at risk. However, tests for predicting women at risk before an
episode of threatened preterm labour occurs are still limited. Consequently, many
therapies for preventing preterm labour are only instigated after an episode of threat-
ened preterm labour has been successfully treated with acute tocolysis and is often
referred to as maintenance therapy. Thus, an episode of threatened preterm labour
is regarded by itself to be a predictor of preterm labour.
Risk scoring and home uterine monitoring
Women with a history of preterm birth, second trimester loss or induced abortion are
at increased of preterm labour.
46
Previous obstetric history has been combined with
socio-economic factors, gynaecological and medical history, and pattern of daily activ-
ity to create risk scoring systems such as the Creasy score.
7
These types of scoring
systems have relatively low positive predictive values and sensitivities but are simple
and low cost, making them useful for identifying women who may benet from newer
but more intensive screening tests. They are unlikely to be appropriate tests alone on
which to base the instigation of therapies that may prevent preterm labour.
Monitoring of uterine contractility has been used to predict preterm delivery.
Although the likelihood of preterm delivery increases with increased frequency of
contractions, the positive predictive value and sensitivity of this test is very low.
8
It is therefore an unsuitable clinical test for predicting preterm delivery.
Fetal bronectin and other biochemical markers
Fetal bronectin (fFN) is an extracellular matrix protein found in the decidua basalis
next to the placental intervillous space. It acts like a glue attaching the fetal mem-
branes to the uterine decidua. Mechanical or inammatory mediated damage to the
placenta or membranes may result in its release into the cervico-vaginal uid. Fibro-
nectin is often found in cervico-vaginal uid before 18 weeks gestation and at the
end of term pregnancy; however, it is not normally present from 22 to 37 weeks
and is associated with an increased risk of preterm birth.
There have been many studies assessing the accuracy of fFN as a predictive test for
preterm labour in both symptomatic and asymptomatic women. It is widely accepted
844 K. M. Groom
as a good test for excluding preterm birth in those presenting with threatened pre-
term labour due to its strong negative predictive value: <0.5% deliver within 710
days after a negative test.
9
However, in asymptomatic women, although a positive
fFN test is associated with an increased risk of preterm delivery at <34 weeks (LR
4.01, 95% CI 2.935.49 with a positive result, compared to LR 0.78, 95% CI 0.72
0.84 with a negative result), it is not a good test for the general population due to
its low sensitivity. Only 18% of women with a positive result deliver before 34 weeks
gestation.
9
In asymptomatic women with risk factors for preterm labour, fFN is likely
to be a better predictive test (sensitivity 69%, 95% CI 20100%) for delivery at < 34
weeks than in a low risk population (sensitivity 49%, 95% CI 890%), but with reduced
test specicity (74%, 95% CI 46100%, compared to 90%, 95% CI 8397%).
10
Many biochemical markers, such as a-fetoprotein, human chorionic gonadotrophin,
oestriol
11
, progesterone, C-reactive protein, tumour necrosis factor-a (TNF-a), inter-
leukin (IL)-6
12
, IL-8
13
, corticotrophin releasing hormone (CRH)
14
and matrix metallo-
proteinases (MMPs), have been measured in a variety of maternal uids and secretions
as predictors of preterm delivery. These biochemical markers are currently only used
in a research setting and are unlikely to be suitable tests for widespread clinical use.
Cervical length
Transvaginal measurement of cervical length is a reproducible
15
and safe technique.
Since the mid 1990s there has been an enormous amount of work on its use as a pre-
dictor of preterm delivery.
Within a low risk population, delivery before 33 weeks gestation occurs in
approximately 50% of women with a cervical length 15 mm measured at 23 weeks
16
or during the second trimester.
17
However, a cervical length 15 mm at 23 weeks
occurs in <2%of the population. Thus, although this appears to be a good test to identify
patients at risk, the incidence of a positive test in a population with a low prevalence of
preterm delivery is too low for it to be introduced routinely into clinical practice.
Studies of women at high risk for preterm delivery are smaller but suggest im-
proved sensitivity
18
at longer cervical lengths. In the largest study of high risk women
(n 469) serial cervical length measurement from 15 to 24 weeks demonstrated a cer-
vical length of 25 mm had a sensitivity of 94%, negative predictive value 99% and
positive predictive value 10% for delivery before 28 weeks (83%, 98%, and 15%, re-
spectively, for 32 weeks).
19
The majority of cervical length studies in high risk populations include interventions
when cervical length was short, thus making predictive values less accurate. Cervical
length measurement does not full all the criteria for an ideal screening test. However,
it is probably the most widely accepted and used test currently available, particularly
within a high risk population, to detect those women at risk of early delivery who may
benet from preventative therapies.
PHARMACOLOGICAL AGENTS FOR PREVENTION OF PREMATURITY
Tocolytics
A variety of tocolytic drugs is used in the acute treatment of preterm labour. Some
have also been investigated for the prevention of premature labour or to reduce
recurrence once an episode of threatened preterm labour has occurred.
Pharmacological prevention 845
b-Mimetics
b-Mimetics stimulate b2 adrenergic receptors in smooth muscle. These receptors act
via cAMP to reduce sensitivity to and absolute levels of intracellular calcium, causing
myometrial relaxation. Although b-mimetics reduce contractions, they have no effect
on cervical ripening or the fetal membranes.
There is a considerable number of studies assessing the use of oral b-mimetics
(ritodrine, terbutaline and salbutamol) for maintenance tocolysis after an episode of
threatened preterm labour. Comparators are placebo or no treatment
20
, indometha-
cin
21
, or magnesium.
20
Individual studies are too small to draw conclusions. A recent
meta-analysis of 11 studies including 1238 women using oral preparations of b-mimetics
concluded that available evidence does not support their use for maintenance.
20
In the
eight trials comparing oral b-mimetics (ve terbutaline and three ritodrine) to placebo
or no treatment there was no difference in the rate of preterm birth, perinatal morbid-
ity or mortality. As with acute treatment there was an increased risk of maternal side
effects (Table 1).
Subcutaneous pump infusions of terbutaline have been used for maintenance tocol-
ysis. The potential advantages of a continuous infusion include an overall lower dose
with fewer side effects. However, their use is not associated with a reduction in pre-
term birth, perinatal morbidity or mortality when compared to placebo
22,23
or oral
terbutaline.
23
The use of oral b-mimetics for the prevention of preterm labour without a prior
episode of threatened preterm labour has been studied in twin pregnancies. In
a meta-analysis of ve trials including 344 twin pregnancies and comparing oral
b-mimetics with placebo, treatment commenced from 20 to 34 weeks and continued
up to a maximum of 38 weeks gestation or the onset of labour.
24
There was no
reduction in the incidence of delivery at <37 weeks (RR 0.85, 95% CI 0.651.10) or
delivery at 34 weeks (RR 0.47, 95% CI 0.151.50). Correspondingly, there was no
reduction in neonatal mortality (RR 0.80, 95% CI 0.351.82).
Oxytocin receptor antagonists
Atosiban is a competitive oxytocin/vasopressin receptor antagonist. Inhibition of the
oxytocin receptor leads to a reduction in extracellular calcium inux as well as release
of calcium from intracellular stores and therefore inhibition of contractility. Like
Table 1. Outcome data from meta-analysis of trials of oral b-mimetics vs placebo or no treatment.
20
Outcome and side effects b-mimetics vs placebo or
no treatment (95% CI)
Delivery <37 weeks RR 1.08 (0.88e1.32)
Mean difference in birthweight 4.13 g (91.89e100.16)
Admission to neonatal intensive care RR 1.29 (0.64e2.60)
Perinatal mortality RR 2.41 (0.86e6.74)
Respiratory distress syndrome RR 1.10 (0.61e1.98)
Maternal tachycardia RR 1.55 (1.02e2.37)
Maternal hypotension RR 1.80 (1.08e3.01)
Maternal palpitations RR 5.67 (1.32e24.40)
846 K. M. Groom
b-mimetics, atosibans mode of action is on myometrial contractility and it has no
effect on other aspects of the labour process.
Long term treatment with atosiban has been used for maintenance therapy. In
a randomised placebo controlled trial in 513 women, Valenzuela et al demonstrated
that continuous subcutaneous infusion of atosiban prolonged the interval from the
start of maintenance treatment to rst recurrence of symptoms of labour (27.6
days vs 32.6 days, p 0.02). However, there was no effect on preterm delivery rate
(delivery <32 weeks 12% vs 14%, 95% CI 10 to 7) or neonatal outcome (neonatal
intensive care admission 21% vs 26%, 95% CI 11 to 3).
25
Calcium channel blockers
Calcium channel blockers inhibit transmembrane inux of calcium through voltage de-
pendent channels, leading to a reduction in intracellular calcium and therefore contrac-
tility. In a small trial of 74 women, nifedipine maintenance therapy was compared to no
treatment following an episode of threatened preterm labour. It led to an increase in
time to delivery (37 days vs 33 days, p 0.04) but this had no impact on mean gesta-
tional age at delivery, preterm delivery rates or neonatal outcome.
26
In a similar sub-
sequent trial of a further 73 women, nifedipine also caused a signicant increase in
time from initiation of maintenance therapy to delivery (27 days vs 16 days,
p 0.007) and mean gestation at delivery (37.0 weeks vs 35.1 weeks, p 0.003); how-
ever, there was again no difference in perinatal outcomes.
27
Larger studies are re-
quired to see if this delay in delivery will lead to an overall improvement in outcome.
Magnesium sulphate
Magnesium sulphate acts as a calcium antagonist at the neuromuscular junction. De-
spite little evidence to support its use in the acute treatment of preterm labour, mag-
nesium sulphate is the most commonly used tocolytic drug in the USA. It has also been
used for maintenance treatment following an episode of threatened preterm labour
but like other tocolytic drugs, it appears to have little impact on outcome.
28
Tocolytic drugs have not been shown to be benecial in preventing preterm labour
and current recommendations conclude that there is insufcient evidence regarding
maintenance tocolysis following an episode of threatened preterm labour and so
should not be used in routine practice.
29
All these tocolytic drugs act primarily to in-
hibit myometrial contractility. Contractions do not occur until the end stages of the
complex process leading to labour. It is likely that tocolytic drugs either used for acute
treatment or for prevention are unlikely to be successful in improving outcome as by
only exerting an effect on contractions they do not delay delivery for long enough to
have a signicant impact. Drugs that inhibit earlier stages of the labour process and/or
have effects on the cervix and fetal membranes as well as contractility are more likely
to be benecial.
Non-steroidal anti-inammatory (NSAI) drugs
NSAI drugs inhibit the cyclo-oxygenase (COX) enzymes responsible for the conver-
sion of arachidonic acid to prostaglandins. Prostaglandins are central to the inamma-
tory process of labour and have effects not only in the myometrium but also upon the
cervix and fetal membranes. Within the myometrium, PGF
2a
promotes gap junction
formation
30
and upregulation of the oxytocin receptor (OTR), and has a direct effect
Pharmacological prevention 847
on myometrial contractility via its own receptor. PGE
2
is used clinically for cervical rip-
ening for induction of labour
31
and is known to act as a chemoattractant promoting
MMP activation and leading to cervical ripening and membrane rupture.
Therefore, COX inhibitors are likely to be successful not only at halting contrac-
tions but also at stopping the early phases of the preparation for labour. This makes
them a suitable potential candidate to be given before or early in the inammatory
process for the prevention of preterm labour.
Indomethacin
Indomethacin is a non-specic COX inhibitor, an NFkB inhibitor and a calcium channel
blocker. In vitro it inhibits prostaglandin production in fetal membranes
32
and has a re-
versible inhibitory effect on myometrial contractility.
33,34
Indomethacin can be administered orally, rectally or vaginally. Its use for the acute
treatment of preterm labour is well documented. It is one of the few tocolytic drugs to
delay delivery for 710 days and reduce the rates of delivery at <37 weeks gestation
and the incidence of low birthweight (<2500 g). However, it has no signicant impact
on the incidence of neonatal death.
35
Concerns over fetal side effects have limited its use for long term preventative treat-
ment. In a randomised trial comparing oral indomethacin and terbutaline for mainte-
nance tocolysis after threatened preterm labour, treatment continued to 37 weeks
gestation (the indomethacin group transferred to terbutaline at 34 weeks or earlier if
oligohydramnios or fetal ductus arteriosus constriction was observed). The authors
suggested both drugs were effective long term tocolytics (despite the lack of a placebo
control group) but indomethacin was associated with signicant fetal side effects.
21
Indomethacin is known to have an effect on fetal kidneys. In a study assessing its
effect with prolonged use (mean of 15 days) there was a signicant reduction in fetal
urine production and a corresponding fall in amniotic uid volume.
36
Amniotic uid
volume re-accumulated within 1 week after discontinuation of treatment, suggesting
the effect is reversible.
Both PGE
2
and prostacyclin are expressed in the fetal ductus arteriosus and are
necessary for maintaining ductal vasodilatation and patency. Indomethacin may there-
fore induce constriction of the fetal ductus arteriosus in utero. Fetal echocardiography
has shown that constriction of the ductus arteriosus occurs with indomethacin in up
to 50% of cases.
3740
However, this side effect is gestation dependent, occurring in
only 510% of cases at <32 weeks gestation but 50% (95% CI 2065%) at 32 weeks
gestation. The effect is reversible, with discontinuation of treatment leading to a return
to non-constricted ductal ow and no adverse neonatal outcomes.
38,40
There have also been concerns regarding indomethacin and risks of necrotising en-
terocolitis
41,42
and intraventricular haemorrhage.
41
However, data are conicting with
some studies showing no increased risk.
43,44
A risk/benet analysis suggests that the
benets of indomethacin as a tocolytic outweigh the adverse effects at gestational
ages 32 weeks.
45
This is based on its use for acute treatment and it is likely that
the risks for the fetus of prolonged use are too high to consider preventative therapy
in a clinical setting.
Selective COX inhibitors
The COX enzyme exists in at least two forms. COX-1, the constitutive form, pro-
motes production of eicosanoids which are responsible for physiological processes,
whereas COX-2, the inducible form, is responsible for changes seen with inammation
848 K. M. Groom
and therefore labour. It is well established that COX-2 and not COX-1 upregulation
occurs with the onset of labour.
4648
It has been proposed that COX-2 selective or
specic inhibitors will prevent preterm labour and may not cause changes in physiolog-
ical functions that lead to fetal side effects.
49
Sulindac, although a non-selective COX inhibitor, is less potent than indomethacin
for COX-1. In addition it is absorbed via the gastric mucosa as a biologically inactive
prodrug and is excreted in an inactive form in the urine. The placenta is permeable
to sulindac but less so to its active sulphide metabolite. It could therefore be associated
with a reduction in fetal side effects. The use of sulindac for maintenance tocolysis has
been studied in two randomised placebo controlled trials. Sulindac was prescribed for
7 days
50
or until 34 weeks gestation
51
but failed to improve outcome compared to
placebo, except in a subgroup of women delivering at <37 weeks gestation in whom
sulindac was associated with a longer interval from start of treatment to delivery.
50
The reported fetal side effect prole of sulindac is variable. Even with prolonged use,
Humphrey et al found no signicant effect on fetal urine production and amniotic uid
measurements when used up to 34 weeks gestation
51
, but other studies using similar
doses and for shorter durations have shown signicant reductions.
52,53
Similar variable
ndings are seen with measurements of the ductus arteriosus. Carlan et al compared in-
domethacin and sulindac, and despite signicant increases in systolic and diastolic veloc-
ities with indomethacin, sulindac had no effect.
54
Conversely, in a comparative study of
the short term use of indomethacin, sulindac and placebo, both drugs lead to signicant
reductions in the pulsatility index of the ductus arteriosus.
53
Over the last few years there has been signicant interest in the potential of COX-2
selective or specic drugs. These were initially developed and marketed by the phar-
maceutical industry for conditions such as rheumatoid arthritis and osteoarthritis.
It was hoped that COX-2 specic drugs may be effective at preventing preterm labour
without the fetal side effects.
The use of nimesulide (516 fold selective for COX-2 compared to COX-1) for the
prevention of preterm labour was rst described in a single case report with a very
encouraging outcome.
55
Further case series and reports suggested it was an effective
prophylactic therapy for women at very high risk but it was still likely to have fetal side
effects which may cause signicant harm.
5658
Rofecoxib (COX-2 specic at therapeutic concentrations) has been used in the
only randomised placebo controlled trial of a COX-2 specic inhibitor as a prophylactic
treatment in women at high risk of preterm labour.
59
The study was powered to as-
sess both fetal side effects and outcome (delivery at <30 weeks gestation). Ninety-
eight women at very high risk of preterm delivery were recruited. Risk assessment
was based on obstetric history, cervical length and/or need for emergency cerclage.
Treatment continued to 32 weeks gestation with all women undergoing close ultra-
sound surveillance. Rofecoxib was associated with a reversible effect on the fetal
kidneys causing a reduction in hourly fetal urine production rates (L34%, 95%
CI L13 to L50%, p 0.004) and amniotic uid index (L2.2, 95% CI L3.2 to
L1.2, p<0.001). It also caused an increase in maximum systolic velocity (0. m/s,
95% CI 0.030.16, p 0.02) and minimum diastolic velocity (0.007 m/s, 95%
CI 0.00070.013, p 0.03) of ow in the ductus arteriosus. This effect, suggesting
constriction of the ductus arteriosus, increased with time on treatment but was
reversed with discontinuation and had no long term clinical sequelae.
There was no difference in preterm delivery rates at < 30 weeks gestation (28% on
placebo vs 33% on rofecoxib, MantelHaenszel [MH] 1.11, 95% CI 0.671.87). How-
ever, more surprisingly, there were more deliveries at < 37 weeks gestation in those
Pharmacological prevention 849
on rofecoxib (40% vs 67%, M-H adjusted risk 1.59, 95% CI 1.092.32) with rates of
preterm prelabour rupture of membranes higher in those on rofecoxib (RR 2.5,
95% CI 1.34.7). It is not clear why this occurred but as the increase in the number
of preterm deliveries occurred after 30 weeks (at the time of stopping drug treatment)
it may be that the withdrawal of COX-2 inhibition precipitated labour.
The results of this study along with the withdrawal of some COX-2 inhibitors from
the market due to concerns over long term effects in the adult population
60,61
mean
further investigation into the use of COX-2 inhibitors for the prevention of preterm
labour is unlikely and probably unnecessary.
Antibiotics
Antibiotic use for the prevention of preterm delivery remains contentious. There are
many studies assessing different antibiotics, routes of administration and treatment reg-
imens. Results vary according to the pre-existing risk of each population. Most studies
have concentrated on women with abnormal bacterial ora or with positive fFN results.
In a low risk general obstetric population, the use of metronidazole in the second
trimester following a diagnosis of bacterial vaginosis did not reduce preterm delivery
(12.2% vs 12.5% with placebo).
62
However, in a population with additional risk factors,
metronidazole and erythromycin appeared to reduce delivery at <37 weeks gesta-
tion (26% vs 36% with placebo).
63
These ndings were conrmed in a meta-analysis of 3969 women from ten studies
of asymptomatic women with bacterial vaginosis treated with antibiotics. Regimens
used included oral metronidazole erythromycin and vaginal or intravenous clindamy-
cin. There was no reduction in delivery at <37 weeks gestation (OR 0.83, 95% CI
0.571.21) for all patients, although subanalysis of high risk patients treated with
oral regimens for 7 days did show a reduction (OR 0.42, 95% CI 0.270.67).
64
Inter-
estingly, this meta-analysis failed to demonstrate signicant reductions in preterm
delivery in almost 1300 women treated with clindamycin.
More recently two studies have shown improved success with the use of clindamy-
cin. Lamont et al randomised 409 women with abnormal genital tract ora in the
second trimester to vaginal clindamycin or placebo and found a reduction in delivery
at <37 weeks gestation from 10% to 4%.
65
A criticism of this study may be the
low rate of preterm delivery (in a moderate risk population) which was reduced
even further. Ugwumadu et al also demonstrated a reduction in late miscarriage and
preterm delivery for women with abnormal vaginal tract ora (including bacterial vag-
inosis) with oral clindamycin (15.7% vs 5.3%).
66
The effect of antibiotics in women with a positive fFN test in pregnancy has also
been studied. In a general asymptomatic obstetric population of 16,317 women, 715
with a positive fFN test at 2126 weeks gestation received metronidazole and eryth-
romycin or placebo. There was no effect on preterm delivery below 37, 35 or 32
weeks.
67
More interestingly, subgroup analysis of 76 women with a history of previous
preterm delivery showed an increased risk in those taking antibiotic treatment (<37
weeks 46.7% vs 23.9%, RR 1.95, 95% CI 1.033.71). A similar nding was seen in a UK
population of high risk women with a positive fFN test treated with metronidazole in
the late second and early third trimesters (delivery at <30 weeks gestation 21% vs
11% on placebo, RR 1.9, 95% CI 0.725.09; <37 weeks gestation 62% vs 39% on
placebo, RR 1.9, 95% CI 1.052.40).
68
Metronidazole has also been associated with
increased risk of preterm delivery in women with Trichomonas vaginalis. In a study
850 K. M. Groom
by Klebanoff et al, 617 women were treated at 1623 weeks gestation. Metronidazole
was associated with an increase in rate of delivery at <37 weeks from 10.7% to 19%
(RR 1.8, 95% CI 1.22.7).
69
It is not clear why antibiotics may increase the risk of early delivery but it is possible
that their eradication of normal bacterial vaginal ora allows growth of harmful organ-
isms, leading to ascending infection, stimulation of the inammatory process and early
delivery. These studies demonstrate the diverse effects of antibiotic treatment. At
present their use for the prevention of preterm labour should be carefully considered
and widespread indiscriminate use of antibiotics in pregnancy should be avoided.
Progesterone
Progesterone is the predominant pro-pregnancy hormone and has a suppressive ac-
tion on pro-labour genes. It has a negative regulatory effect on many of the contraction
associated proteins (such as connexin 43), preventing the formation of myometrial gap
junctions. It also decreases uterine sensitivity to oxytocin, probably via a direct effect
on the oxytocin receptor.
70
In addition, progesterone exerts an inhibitory effect on
prostaglandin activity via an effect on prostaglandin dehydrogenase (the main enzyme
responsible for inactivation and metabolism of prostaglandins).
71
The overall inhibitory
effects of progesterone on pro-labour factors allows enlargement of the uterus with-
out increasing uterine contractility. For many years it has been known that pro-
gesterone withdrawal is the stimulus for labour in many animal models. In humans
a functional withdrawal of progesterone is likely to be integral to the onset of labour
and administration of exogenous progesterone may be benecial in preventing pre-
term labour.
A meta-analysis by Keirse in 1990 demonstrated a reduction in preterm delivery
(OR 0.5, 95% CI 0.300.85) associated with 17 a-hydroxyprogesterone caproate (nat-
ural metabolite of progesterone) but with no corresponding improvement in perinatal
morbidity or mortality.
72
More recently the prophylactic use of progesterone in high
risk populations has been further assessed in two randomised placebo controlled tri-
als. In 142 women randomised to receive 100 mg progesterone or placebo as a vaginal
suppository from 24 to 34 weeks gestation there was a signicant reduction in
preterm delivery rates at <37 weeks (13.8% vs 28.5%, p 0.03) and at <34 weeks
(18.6% vs 2.8%, p 0.002).
73
This study did not report on neonatal outcomes.
A larger study in the USA assessed the efcacy of injections of 250 mg 17 a-hydrox-
yprogesterone caproate in 463 women recruited at 1620 weeks gestation with a
history of preterm delivery. Treatment was given weekly until delivery or 36 weeks.
There was a signicant reduction in delivery rates before 37, 35 and 32 weeks
(36.3% vs 54.9%, OR 0.66, 95% CI 0.540.81; 20.6% vs 30.7%, OR 0.67, 95% CI
0.480.93; 11.4% vs 19.6%, OR 0.58, 95% CI 0.370.91, respectively). There was
also a reduction in the incidence of birthweight <2500 g, necrotising enterocolitis, in-
traventricular haemorrhage and the need for supplemental oxygen, but not perinatal
death, birthweight <1500 g or respiratory distress syndrome.
74
Subsequent data
analysis suggests the effect of 17 a-hydroxyprogesterone caproate on prevention of
preterm birth is only signicant for those women regarded to be at the highest risk
of preterm birth (i.e. previous very early delivery at 2028 or 2834 weeks but
not with only moderate risk (i.e. previous delivery at 3437 weeks).
75
These studies have led to greater interest in the potential use of progesterone as
a prophylactic treatment. However, despite a relatively moderate predened risk, the
Pharmacological prevention 851
overall rates of preterm delivery were high (54.9%) and remained so even with
treatment (36.3%)
74
, The two progesterone trials have now been included in meta-
analyses and suggest a reduction in preterm birth and the incidence of low birthweight
<2500 g.
7678
However, despite prolongation of gestation, signicant improvements in
perinatal morbidity and mortality have still not been demonstrated. In addition, there is
insufcient data regarding optimal dose, and route and timing of administration of
progesterone to advocate its use in a clinical setting outside of a supervised trial.
SUMMARY
There is no evidence to support the long term use of tocolytic drugs to prevent pre-
term labour. The long term use of NSAI drugs including COX-2 selective and specic
inhibitors is limited by concerns over fetal side effects. Antibiotics may be benecial in
some women for preventing preterm birth but in others they may be associated with
an increased risk and therefore should only be used with caution. Progesterone is
likely to be the best potential drug at present for prevention of preterm birth but
further investigation is still required.
Practice points
use of pharmacological agents for prevention of preterm labour should only be
considered in women at high risk
risk assessments used include previous obstetric history, previous episode of
threatened preterm labour, abnormal vaginal ora, positive fFN and short
cervical length
evidence is insufcient to support maintenance therapy with tocolytic drugs
such as b-mimetics, atosiban and nifedipine following an episode of threatened
preterm labour
NSAI drugs should only be used long term in pregnancy under close ultrasound
surveillance
antibiotics in women with a history of preterm birth may further increase risk
of premature delivery
prophylactic administration of progesterone to women at high risk of preterm
labour is likely to prevent subsequent premature delivery
Research agenda
further investigation of reliable tests for the accurate prediction of preterm
birth
larger randomised controlled trials further to assess the effectiveness of
calcium channel blockers for maintenance therapy following an episode of
preterm labour
further studies to ascertain the optimal dose, route and timing of administra-
tion of progesterone before advocating its widespread clinical use
852 K. M. Groom
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