Primary predictors of preterm labour

Francois Goffinet
Spontaneous preterm birth accounts for 60% of all preterm births in developed countries. With the increase in
multiple pregnancies, induced preterm birth and the progress in neonatal care for extremely preterm neonates,
spontaneous preterm birth for singleton pregnancies in developed countries has probably decreased over the
past 30 years. This decrease is likely to be related to better prenatal care for all pregnant women because the
recognition of primary risk factors in early or late pregnancy remains a basic part of prenatal care. The failure
to distinguish between induced and spontaneous preterm labour in most population-based studies makes it
difficult to interpret results with respect to the primary predictors of preterm labour. Many such primary
predictors of preterm labour have been used over the past 2030 years. These include individual factors,
socio-economic factors, working conditions and obstetric and gynaecological history. Risk scores have been
proposed in order to produce these data. Unfortunately, the predictive value of these scores, especially their
specificity, is poor, mainly because all of these factors are indirect. We still cannot identify the mechanisms
that lead to preterm labour and birth. New markers more directly related to preterm labour have recently been
proposed, some of which relate to direct causes of preterm labour such as cervical ultrasound measurement,
fetal fibronectin (FFN), salivary estriol, serum CRH and bacterial vaginosis. Several of these have predictive
values, which are potentially useful for clinical practice. Nonetheless, pregnant women in developed countries
are already closely monitored throughout pregnancy. Before proposing new screening tests to be applied
systematically to all pregnant women, their advantages and drawbacks must be fully evaluated.
INTRODUCTION
The primary predictors for spontaneous labour and preterm
birth currently used are based on either risk factors (e.g. socio-
economic, history, lifestyle) or clinical information that
becomes available during the course of pregnancy (e.g.
digital cervical examination, uterine contractions, bleed-
ing).
1,2
The benefits of considering these factors in prenatal
surveillance have not yet been demonstrated. In recent years,
newmarkers for the risk of pretermbirth have been proposed
as primary predictors in low risk populations. Although some
may be principally aetiological in nature, most are purely
symptomatic markers. They may be more relevant than
standard markers and thereby improve the efficacy of our
management of spontaneous pretermlabour by enabling more
precise and earlier diagnosis of women at very high risk.
STANDARD PRIMARY PREDICTORS OF PRETERM
LABOUR: DEMOGRAPHIC, SOCIO-ECONOMIC
AND PSYCHOSOCIAL FACTORS
Although some studies have found that women who
are short and thin before pregnancy have an increased risk
of preterm birth, this association seems less clear after
adjusting for the principal confounding factors (ethnic
group, socio-economic status, etc.).
3,4
The multivariate anal-
ysis of a prospective study, nonetheless, appears to showthat
(Caucasian) women with a low body mass index (BMI) have
an elevated risk of preterm birth.
5
Most studies report a clear association between low
maternal weight gain and preterm birth.
1,4
This effect is
not associated with hyperemesis gravidarum, which is not
associated with preterm birth.
6
Even after adjustment for the other known risk factors,
black women have a risk of preterm birth twice that of white
women.
4,5,7
A recent French study reports that preterm birth
rates are significantly higher among women born in the
overseas French districts in the Caribbean and Indian Ocean
and in sub-Saharan Africa. This study also found that this
excess risk was greatest for early preterm births.
8
Although
socio-economic and medical factors probably play a role,
this difference may be in part genetic, just as the several-
day difference in the mean duration of gestation between
black and white women is also possibly genetic.
7
Different studies define socio-economic status in various
ways, by criteria linked to education, employment or family
environment. Moreover, these criteria are highly related to
all the other demographic, ethnic and environmental factors.
Although all studies find that low socio-economic status is
associated with preterm birth,
1,3,4
it is difficult to isolate
specific risk factors. While living alone is reported to be a
risk factor for preterm birth by all studies taking it into
consideration,
9,10
it may be considered a socio-economic
marker by some and a psychosocial marker by others.
Psychological factors and lifestyle are also defined
variably in different studies. They are often based on
BJOG: an International Journal of Obstetrics and Gynaecology
March 2005, Vol. 112, Supplement 1, pp. 3847
D RCOG 2005 BJOG: an International Journal of Obstetrics and Gynaecology www.blackwellpublishing.com/bjog
Department of Obstetrics and Gynaecology, Maternity
Port-Royal, Cochin-Saint Vincent-de-Paul Hospital, Paris, France
Correspondence: Professor F. Goffinet, Epidemiological Research Unit
on Women and Childrens Health, INSERM U 149, 123 Bd de Port-Royal
75014 Paris, France.
criteria related to anxiety, such as a womans attitude to-
wards her pregnancy, various life events and social sup-
port. Older studies appear contradictory, probably because
of the difficulty in measuring these criteria precisely.
4
In a
study of 2593 women, Copper et al.
11
found an association
between stress (measured on a stress scale) and preterm
birth, but the OR was only 1.16. More recent studies report
an association between preterm birth and anxiety, stress
and depression.
12
Dole et al.
13
examined a comprehensive array of psy-
chosocial factors, including life events, social support,
depression, pregnancy-related anxiety, perceived discrimi-
nation and neighbourhood safety in relation to preterm birth
(<37 weeks) in a prospective cohort study of 1962 preg-
nant women. The risk of preterm birth was elevated among
women with high levels of pregnancy-related anxiety (risk
ratio [RR] 2.1), with negative life events (RR 1.8)
and with the perception of racial discrimination (RR 1.4).
The association between high levels of pregnancy-related
anxiety and preterm birth was reduced but not eliminated
when the analysis was restricted to women without medical
comorbidities. Similarly, Haram et al.
12
found a high cor-
relation between domestic violence and major social and
lifestyle risk factors for spontaneous preterm labour.
Most recent studies show those women who are
employed have a lower risk of preterm birth.
14,15
In those
studies that control for the key confounding factors, some
characteristics related to physically or psychologically de-
manding work are associated with preterm birth.
4,1518
The EUROPOP multicentre study found that specific
working conditions affect the risk of preterm birth.
19
A
moderate excess risk (adjusted) was observed among those
who worked more than 42 hours a week (OR 1.33, CI
1.11.6), stood more than 6 hours a day (OR 1.26, CI
1.11.5) or were dissatisfied with their job (OR 1.27,
CI 1.11.5), compared with all working women.
Neither dieting nor inadequate calorie intake appears
to be associated with preterm birth. Most recent studies
report no association between anaemia and preterm birth,
except among populations from developing countries.
Some studies report associations between preterm birth
and deficiencies in iron, zinc or other minerals, but they
rarely adjust for the major confounding factors. Trials
that test mineral supplements most often reach negative
results.
4
Solid evidence shows that smoking is moderately asso-
ciated with preterm birth. The more the mother smokes, the
greater the risk.
4
It appears clear that alcohol consumption does not create
a risk of preterm birth, except in cases of very high
consumption.
4,5,20,21
A recent study in Denmark among
40,892 women found no association between preterm birth
and alcohol intake level or type of beverage drunk after
adjusting for other factors.
22
Among women who had seven
or more drinks per week, the relative risk of preterm birth
was 3.26 (95% CI 0.8013.24) (Table 1).
HISTORY
History of previous preterm birth or second trimester
pregnancy loss is the most important risk factor of preterm
birth even after adjustment for the standard confounding
factors.
1,35
This risk increases with the number of previ-
ous events. It has been proposed that this finding may be
related to cervical incompetence.
The studies on the effects of parity and of a short interval
between two pregnancies are very contradictory. Alone,
these criteria are not risk factors. However, on the other
hand, it is probable that the association is due to other fac-
tors and that only some subgroups of nulliparae or grand
multiparae are at high risk of preterm birth.
Most studies report no association between preterm
birth and a history of one or two abortions, spontaneous
or elective.
4,5
The results are contradictory, however,
when the number reaches three or more. One pathophys-
iologic hypothesis is that cervical incompetence may
Table 1. Risk factors for preterm delivery and possibility of prevention.
Association with
spontaneous
preterm birth
Intervention
possible
Risk factors: individual,
socio-economic and behavioural
Black No
Young mother (<1519 years) Yes
Lives alone No
Domestic violence Yes
Low socio-economic status ?
Stress, depression, life events Yes
Hard work Yes
No or inadequate prenatal care Yes
Smoking, cocaine Yes
Alcohol, caffeine
Low maternal weight before pregnancy No
Weight gain during pregnancy
Short No
Gynaecological and obstetric history
Preterm delivery or second trimester
pregnancy loss
Yes
Previous cone biopsy ?
Mullerian abnormality No
Parity
Short interval between the two last
pregnancies
?
Family history (genetic factors) No
Warning signs during prenatal surveillance
IVF Yes
Multiple pregnancy Yes
Placenta praevia ?
Bleeding No
Cervicovaginal infections Yes
Uterine contractions Yes
Cervical modifications Yes
Risk scores Yes
PRIMARY PREDICTORS OF PRETERM LABOUR 39
D RCOG 2005 BJOG: an International Journal of Obstetrics and Gynaecology 112 (Suppl. 1), pp. 3847
result from trauma at the moment of the dilatation and
curettage.
The risk of preterm birth appears to be multiplied by a
factor ranging from two to five in the case of in utero
diethylstilbestrol exposure. This excess risk may be asso-
ciated with cervical or uterine malformations and with the
incompetence with which it is frequently associated.
4
Women who become pregnant as a result of IVF have a
higher risk of preterm birth, even after adjustment for the
multiple pregnancies.
4
The results are contradictory for
simple infertility. The hypotheses concern unknown under-
lying causes of infertility that may be associated with
preterm birth. Others have suggested hypotheses of greater
medical interventionism in this group of pregnancies.
PRENATAL SURVEILLANCE AND SYMPTOMS
DURING PREGNANCY
Patients with no or minimal prenatal care (few consulta-
tions, no consultation until the end of the second trimester)
have an increased risk of preterm birth.
23
This association
may be due to other factors especially common in these
women (psychosocial, economic, etc.). Programmes in-
tended to improve prenatal surveillance have reached con-
tradictory conclusions about their impact on preterm birth.
It is difficult to demonstrate a beneficial effect.
24
The U.S.
National Center for Health Statistics natality data set shows
that the absence of prenatal care is associated with elevated
preterm birth rates, after adjusting for key confounding
factors.
25
Risks range from 1.6- to 5.5-fold for different
antenatal high risk conditions.
The assessment of the number and intensity of uter-
ine contractions measured by self-palpation is very dis-
appointing because it is very poorly correlated with
monitoring.
26
Routine recording of uterine contractions
is not useful for assessing the risk of preterm birth in the
general population.
27
Although its predictive value is best in
symptomatic populations, its interest remains very limited
because a significant relation is found only very late, in the
24 hours preceding preterm birth.
28
Cervical change is associated with preterm birth.
2,29,30
In
a general population, a shortened or open cervix between
24 and 28 weeks indicates an elevated risk.
31
Significant
associations must not, however, be confused with predic-
tive value because there are many false positives and false
negatives. Various studies reach quite contradictory con-
clusions about the relevance of clinical examination as a
screening method.
31,32
The rate of false positives frequently
ranges between 20% and 60%, and false negatives be-
tween 40% and 60%. One reason is the imprecision and
lack of reproducibility of this examination. Systematic dig-
ital cervical examinations do not appear to reduce the
number of preterm births. A European randomised con-
trolled trial of 5600 women found similar rates of preterm
birth in the group that underwent an average of six digital
examinations during pregnancy, and the group with an av-
erage of one.
33
It was suggested long ago that risk scores could be used
to identify a group at high risk of preterm birth at the
beginning of pregnancy.
1,34,35
These scores use criteria
from the patients history, social background and lifestyle.
Some also considered symptoms during pregnancy. Despite
the favourable impression of the first studies, the predic-
tivity of these scores is low.
4,36,37
The likelihood ratios
found in the studies evaluating these risk scores (in the
general population) ranged from 1.3 to 8.3.
37
One reason is
that many preterm births occur in women with no risk
factors identified by standard markers.
4
In practice, sensi-
tivity is very often less than 50%, or even 25% with a
positive predictive value (PPV) between 20% and 40%.
Consequently, fewer than half the women who will give
birth preterm are identified, and most of the women with a
high risk score will undergo a large number of useless and
expensive interventions.
37
This is linked in part to the sub-
stantial weight that all these scores attribute to a history of
preterm birth, while nearly half of all preterm births occur
in nulliparae. In the American preterm prediction study,
the authors used a population of 2929 women from the gen-
eral population to construct the best possible model based
on the criteria associated with preterm birth in the study.
38
After analysis of more than 100 parameters, the criteria
retained in the model were race, history of preterm birth,
low BMI, uterine contractions in the past two weeks, vag-
inal bleeding during pregnancy and a high Bishop score.
Unfortunately, this score still identifies only a minority of
the women who will give birth preterm. The sensitivity was
24.2% for nulliparae and 18.2% for multiparae, with PPVs
of 28.6% and 33.3%, respectively.
38
NEW MARKERS AS PRIMARY PREDICTORS IN
LOW RISK POPULATIONS?
The prognostic value of the primary markers currently
available for predicting the risk of preterm birth is insuf-
ficient, and the diagnosis of preterm labour comes too late.
It is probably for these reasons that treatments based on
these markers have not reduced the number of preterm
births. These treatments are applied to many women with
only a slightly elevated risk (numerous false positives) and
not applied to many women who would have benefited
from them or who benefit too late (numerous false neg-
atives). The principal objective of developing new primary
markers is to identify more precisely the women at high
risk of preterm birth with few false positives and false
negatives. The practical advantages of those currently
under consideration are their ease of use, their reproduc-
ibility and their often modest cost. They are defined as
primary predictors because they can be used directly in an
unselected population without another screening before, for
example, the standard primary predictors.
40 F. GOFFINET
D RCOG 2005 BJOG: an International Journal of Obstetrics and Gynaecology 112 (Suppl. 1), pp. 3847
Fetal fibronectin (FFN) is an extracellular glycoprotein
located on the decidua and the fetal membranes, secreted at
the maternal fetal interface by the trophoblast, a tissue
layer formed by the cells of the outer wall of the ovum.
FFN is present in the membrane that surrounds the egg
and ensures the blastocytes adhesion to the endometrium.
Its presence in the cervicovaginal secretions, placenta and
amniotic fluid is normal through to the 20th week.
39
Once
the membranes fuse at 22 weeks, FFN is not normally
released in vaginal mucus except when the membranes
rupture, when it is found so often that it has been sug-
gested as a diagnostic test for rupture. At the end of
pregnancy, it undergoes glycosylation and loses its adhe-
sive properties. From 38 weeks of gestation onwards, it
progressively stops serving as the glue between the mem-
branes and the uterine wall.
Two mechanisms may explain the presence of FFN in
vaginal secretions in cases of spontaneous preterm labour.
The separation of the chorion from the deciduous mem-
brane of the lower uterine segment may allow its release.
Alternatively, FFN may be secreted in the cervical canal in
response to chorionic inflammation (and accompanying
proteolysis).
The assay used to measure FFN levels is performed with
a specific antibody (FDC-6), and the threshold of 50 ng/mL
seems the most useful. Its disadvantage is that the results
are not available for several hours. Some studies have
therefore assessed rapid bedside tests, some not requiring
a speculum. They have been compared with the quantita-
tive assay, but their predictive value for spontaneous
preterm labour has been assessed only rarely.
4042
These
studies show good correlation between the laboratory find-
ings and the qualitative test, but some false positives and
false negatives result from the difficulty of assessing the
borderline colorimetric results.
Numerous clinical studies have assessed the predictive
value of the FFN assay for preterm birth. Differences in the
study populations, protocols and methodological quality
make it difficult to compare results. Here we present the
results of two meta-analyses.
43,44
Both rigorously assessed
the methodology of the studies retained, especially as to
selection bias, double-blinding of the test results and the
precision of term. The inclusion period most often ran from
24 to 34 weeks; a quantitative test used 50 ng/mL as the
cutoff for a positive determination.
The predictive values of the results reported in Table 2
are good, with likelihood ratios similar to those found in
high risk populations. The predictive value is especially
interesting for preterm births before 28 and 32 weeks, as
Goldenberg et al.
45
reported in a study of nearly 3000 women.
Nonetheless, reviewing all of these studies, Khan et al.
46
showed that the authors conclusions about the diagnostic
Table 2. Adjusted OR for preterm birth related to working conditions among women working after the third month of pregnancy in three subgroups of
countries in the EUROPOP study.
Countries A-1, adjusted
OR (95% CI)
Countries A-2, adjusted
OR (95% CI)
Countries A-3, adjusted
OR (95% CI)
Total adjusted
OR (95% CI)
Term births (n) 1833 1600 616 4049
Preterm births (n) 936 859 534 2329
Weekly working hours >42 1.12 (0.81.5) 1.40 (1.01.9) 1.65 (1.02.7) 1.33 (1.11.6)
Standing position >6 hours 1.06 (0.81.3) 1.38 (1.11.7) 1.55 (1.12.3) 1.26 (1.11.5)
Dissatisfied with job 1.42 (1.11.8) 1.10 (0.81.4) 1.28 (0.81.9) 1.27 (1.11.5)
Countries A-1 child mortality rate <8 per thousand and long prenatal leaves frequent.
Countries A-2 long prenatal leaves infrequent.
Countries A-3 child mortality rate >10 per thousand and long prenatal leaves frequent.
Table 3. Characteristics and results of studies in low risk populations to
assess the prediction of delivery before 37 weeks gestation by fetal
fibronectin.
Authors (year) % PD Nb Sen Spe LR
test ()
LR
test ()
Single samples
Faron et al. (1997)
47
9.9 162 31 95 6.5 0.7
Inglis et al. (1994)
48
17.8 73 15 85 1.0 1.0
Rozenberg et al. (1996)
49
14.2 141 60 96 14.5 0.4
Goldenberg et al. (1996)
45
10.3 2929 10 98 5.0 0.9
Vercoustre (1996)
50
1.7 58 100 89 9.5 0.3
Summary LR
*
(Chien et al., 1997
43
)
3.2
(2.24.8)
0.8
(0.70.9)
Summary LR
*
(Faron et al., 1998
44
)
7.5
(4.612.3)
0.7
(0.41.0)
Serial sampling
Lockwood et al. (1993)
51
11.4 429 61 72 2.2 0.5
Hellemans et al. (1995)
52
9.6 136 54 85 3.7 0.5
Goldenberg et al. (1997)
53
9.0 1870 25 90 2.6 0.8
Greenhagen et al. (1996)
54
9.9 111 64 85 4.2 0.4
Langer (1997)
55
3.4 206 57 89 5.4 0.5
Summary LR
*
(Faron et al. 1998
44
)
3.0
(2.24.1)
0.6
(0.40.9)
PD preterm delivery before 37 weeks of gestation; Nb number of
women included in the study; Sen sensitivity; Spe specificity; LR
likelihood ratio for positive test result; LR likelihood ratio for negative
test result.
*
Summary likelihood ratios are presented with their 95% confidence
intervals. Chiens meta-analysis included three studies, Farons 4.
PRIMARY PREDICTORS OF PRETERM LABOUR 41
D RCOG 2005 BJOG: an International Journal of Obstetrics and Gynaecology 112 (Suppl. 1), pp. 3847
value of FFN met the gold standard in only 26% of cases
and that 66% of the authors over-estimated the diagnostic
value of their test.
Most studies in general populations conclude that FFN
alone does not provide enough information (Table 3).
Combining FFN with a clinical score (essentially based
on history and digital examination), Crane et al.
56
found
that the likelihood ratio increased from 3.3 with FFN alone
to more than 10 for the two tests together. Logistic
regression produces the most significant OR for the clinical
score (OR 6.9 [3.092.8]) and FFN (OR 8.0 [1.6
38.3]). Table 4 summarises the performance of the various
combinations.
The theoretical benefits of transvaginal sonography
compared with digital cervical examination are as follows:
the increased reproducibility of transvaginal sonography
examination of the complete cervix (in particular, the
supravaginal portion that cannot be explored by digital
cervical examination), and the morphology of the internal
os, which cannot always be (or is not always) explored
during digital examination.
Iams et al.
57
showed that among f3000 patients from
the general population that were evaluated twice (24 and
28 weeks), cervical length measured by transvaginal ultra-
sound was continuously associated with delivery before
35 weeks. The comparison of its predictive value with the
Bishop score seems to show a slight advantage for ultra-
sound in the various general population-based studies
(Table 5).
There has been an explosion in publications on this topic
over the past decade. Some authors conclude that this
examination should be used systematically in prenatal
surveillance. The number of publications is not synony-
mous with a definitive conclusion. Many issues make it
difficult to interpret these results. The populations studied
and study designs often differ as to whether the physicians
know the results of the test: predictive values for sim-
ilar studies can be very different. Honest et al.
62
reviewed
33 studies in asymptomatic women. They concluded that
transvaginal cervical sonography identifies women who are
at higher risk of preterm birth, although the studies vary
widely with respect to gestational age at testing and thresh-
old of abnormality. With testing at <20 weeks of gestation
and a cervical length cutoff of 25 mm, the authors reported a
summary LR of 6.29 with a corresponding LR of 0.79.
In this way, there is convincing evidence, as there is for
FFN, that a short cervix in the second trimester indicates an
increased risk of preterm birth in an unselected population.
This information does not help us decide which interven-
tion should be used.
Estriol begins to appear during the ninth week of
pregnancy, and its plasma concentration continues to in-
crease throughout the course.
63
Estrogens have been shown
to directly affect myometrial contractility, modulate the ex-
citability of myometrial cells and increase uterine sensitivity
Table 4. Combination of preterm birth risk score and fibronectin test for
prediction of preterm delivery in a low risk population (Crane et al.
56
).
*
Sen Spe PPV NPV LR
test ()
LR
test ()
Preterm birth risk score 78 80 21 98 3.9 0.3
FFN 56 83 18 96 3.3 0.5
Preterm birth risk score
and FFN
44 98 57 96 19.4 0.6
Preterm birth risk score or
FFN
89 66 15 99 2.6 0.2
Sen sensitivity; Spe specificity; PPV positive predictive value;
NPV negative predictive value; LR likelihood ratio for positive test
result; LR likelihood ratio for negative test result.
* n 140 low risk pregnant women assessed between 20 and 24 weeks of
gestation. Bacterial vaginosis was not associated with preterm delivery in
this study; preterm birth risk score included the following criteria: previous
preterm delivery, multiple gestation, suspected preterm labour, bleeding
after 12 weeks, cervical dilatation >1 cm and cervical length <1 cm.
Table 5. Comparison of the diagnostic value of cervical ultrasound and
digital cervical examination for pretermdelivery in a population at low risk.
Authors (year) % PD Nb Sen Spe LR
test ()
LR
test ()
Andersen et al. (1990)
58
18 113
lg TVS <34 mm
(25th centile)
47 84 2.9 0.6
lg clin. <15 mm
(25th centile)
36 76 1.5 0.8
Tongsong et al. (1995)
59
35 mm 12 730 66 62 1.7 0.5
Iams et al. (1996)
57
4.3
*
2915
24 weeks
cl 25 mm 37 92 4.6 0.7
cl 30 mm 54 76 2.3 0.6
protrusion 25 94 4.2 0.8
Bishop 4 28 91 3.1 0.8
28 weeks
cl 25 mm 49 87 3.8 0.6
cl 30 mm 70 68 2.2 0.4
protrusion 32 92 4.0 0.7
Bishop 4 42 82 2.3 0.7
Hasegawa et al. (1996)
60
lg 1 SD 3 729 47 85 3.1 0.6
Taipale et al.
61
2.4 3694
(1822 weeks)
lg 29 mm 19 97 6.3 0.8
IO 5 mm 16 99 16.0 0.8
cl cervical length; IOwidth internal os; SDstandard deviation; PD
delivery before 37 weeks; Nb total number of patients included in study;
Sen sensitivity; Spe specificity; LR likelihood ratio for a positive
test; LR likelihood ratio for a negative test.
Note that in this study, the comparison of the two examinations was
not performed on exactly the same women: 95 ultrasound examinations
and 72 digital cervical examinations.
*
<35 weeks.
42 F. GOFFINET
D RCOG 2005 BJOG: an International Journal of Obstetrics and Gynaecology 112 (Suppl. 1), pp. 3847
to oxytocin.
64,65
Plasma and salivary estriol levels peak three
to five weeks before labour onset both in term deliveries and
also in preterm births.
65
Fetal precursors are the source of maternal estriol and
this reinforces the hypothesis that the fetus plays a prepon-
derant role in triggering parturition. It may thus be that the
fetus responds in cases of stress or signals and initiates a
process that leads to preterm birth several weeks later.
The estriol concentration in saliva very precisely reflects
the free estriol concentration in plasma.
66
The advantages
of saliva are the ease and non-invasiveness of its collection,
the stability of the concentration during transport and a
reliable and reproducible assay technique (immunoassay).
63
McGregor et al.
65
reported a prospective study in which
salivary estriol was measured every week from 22 weeks for
241 pregnant women. The study endpoint was preterm birth
before 35 weeks, preceded by signs of spontaneous preterm
labour and without PROM (prevalence 9.5%). The authors
observed a sensitivity of 71% and a specificity of 77%
(likelihood ratio 3.1) with a cutoff point of 2.3 ng/mL. The
same team showed that this test discriminated better than
Creasys clinical score and, in a second study, that salivary
estriol identified 61% of the women who delivered preterm
within two weeks.
34,63
They conclude that this new test
might be useful in a population of asymptomatic but high
risk women in order to determine precisely which women
are really at risk of preterm birth. The noticeable advantage
over corticotropin-releasing hormone (CRH) is technical.
The salivary test is reliable, simple and stable but other
studies are needed before any definitive conclusion can be
made, particularly because the specificity is poor. In addi-
tion, all three existing clinical studies come from a single
team, so this new marker should be used only as part of a
research protocol.
Corticotropin-releasing hormone may play a role in pre-
term labour. Data suggest that it is involved in myometrial
contractility, through the expression of myometrial receptors
(CRH-R1 and R2), and in prostaglandin production.
67,68
Initial studies showed an association between a high CRH
level and preterm birth.
69,70
Maternal plasma CRH trajec-
tories appear to vary according to the cause of preterm
birth.
71
Clinical studies have shown that CRH produces
poor results in screening for preterm birth.
7275
Moreover,
CRH concentrations seem to be associated with numerous
factors, including ethnicity, stress and hormonal placental
modifications.
67,74
Until prospective studies using a precise
and reproducible assay technique report their results there
is, however, no point in discussing the practical use of this
marker.
To date, numerous serum markers have been reported. In
general, authors report significant associations between a
marker and preterm birth in studies with a small number
of subjects. The routine use of these markers cannot be
considered until more convincing studies are available. Re-
cent markers include maternal serum collagenase, serum
ferritin and placental alkaline phosphatase.
76,77
Any substance that, like fibronectin, is derived from
proteolytic activity and degradation of the extracellular
matrix of the choriodecidual zone around the cervix may
deserve study, and a number of such substances have been
examined. Besides cytokines, which are discussed elsewhere,
the most important of these are granulocytic elastase-a1-
antiprotease, prolactin and sialidase.
7881
A recent study
reports a significant association between preterm birth and
an elevated beta-human chorionic gonadotrophin (h-hCG)
concentration in the cervicovaginal secretions.
82
All of these
initial results call for confirmation by other studies with
more subjects.
Bacterial vaginosis (BV) is the only infectious marker
that can be used as a primary predictor in an unselected
population. Strong scientific evidence supports the exis-
tence of a relation between BV and spontaneous preterm
labour and preterm birth. In a large recent meta-analysis of
more than 20,000 women, Leitich et al.
83
report that BV
more than doubled the risk of preterm birth, and that higher
risks were reported when BV screening was performed
before 1620 weeks of gestation. Nonetheless, the studies
of the efficacy of antibiotic treatment after screening in low
risk populations are contradictory, and in the large study
of the National Institutes of Child Health and Human De-
velopment, oral metronidazole therapy did not prevent
spontaneous preterm labour and preterm birth in a mixed
population. In fact, in the high risk subgroup, it was shown to
increase it.
84,85
Infection markers are important in the battle against
preterm birth because an aetiological treatment is available
against infections. The use of these markers in current
practice is limited by their lack of simplicity, mediocre
reproducibility and high cost; all issues as fundamental in
daily practice as their capacity to identify preterm births
due to infection.
The most interesting new markers are ultrasound sonog-
raphy and fetal fibronectin, but some conditions have not
yet been met. It remains uncertain as to whether they pro-
vide any benefit over those from standard prenatal care. It
also must be remembered that adding a new screening test
before complete evaluation in everyday practice may be
harmful.
Adequate evaluation of other new markers is only be-
ginning today, and none can be proposed systematically in
prenatal surveillance.
IS THEUSEOF PRIMARYPREDICTORS EFFECTIVE?
The absence of any scientific proof of the efficacy of
these primary factors leaves many clinicians sceptical.
Studies assessing programmes to prevent preterm birth re-
port contradictory results. Several difficulties may explain
this absence of proof. Many studies combine spontaneous
and induced preterm birth, which do not respond to the
same prevention activities. In addition, the usual prevention
PRIMARY PREDICTORS OF PRETERM LABOUR 43
D RCOG 2005 BJOG: an International Journal of Obstetrics and Gynaecology 112 (Suppl. 1), pp. 3847
policies are probably only slightly (if at all) effective for
women at high risk.
31
In view of the intensive standard
prenatal surveillance currently provided and the rates of
spontaneous preterm labour and preterm birth, the effect
observed is only slight. It is also difficult, ethically and
practically, to compare two groups, one without any basic
prenatal surveillance. Until these primary factors are
replaced by more specific or even more aetiological fac-
tors, management will remain solely symptomatic and will
be needlessly applied to many patients. Current preventive
measures are ineffective or (occasionally) incorrectly ap-
plied at a regional or national scale. Finally, it is still dif-
ficult to show effects in countries where prevention policies
are especially well applied. As a result of this, the EURO-
POP multicentre study assessed and described the frequen-
cy with which work leave was prescribed in 17 countries
and studied hard work as a primary factor for preterm
births.
19
Hard work was not associated with preterm birth
in countries with policies of frequent prenatal work leave
but was significantly associated with it in other countries,
even after adjustment for other socio-economic factors
(Table 2).
Due to the absence of definitive proof, the primary
factors are not generally considered to participate in the
battle against preterm birth. It is often forgotten that the
recognition of the women at high risk within a general
population is one foundation of the current healthcare
system. These women present many psychosocial risk
factors for disorders other than preterm birth, and consid-
eration of these primary factors should allow them to be
integrated into more appropriate treatment circuits. Specific
examples show that appropriate prenatal management can
be effective in different subgroups identified on the basis of
these primary factors. In a historical study of 16,000 women,
the prevention policy for preterm birth reduced the preterm
birth rate among women at intermediate risk levels iden-
tified with standard primary predictors.
31
In an observation-
al study of 3073 low-income women, those women who
received psychosocial services had a reduced risk of low
birthweight babies, even after controlling for the number of
prenatal visits and gestational age.
86
A prenatal nutrition
and education programme for twin pregnancies reduced the
rate of preterm prelabour rupture of the membranes and
delivery before 36 weeks.
87
Other studies report an im-
proved outcome for twins associated with specialised pre-
natal care.
88,89
Two types of management can be proposed to high risk
women identified by screening with primary markers. The
first treats the cause, making it especially effective for both
prevention and treatment. This management can be offered
to very specific aetiologic subgroups, which represent only
a portion (sometimes quite small) of women among all
preterm births. Examples include cerclage for cervical
incompetence and antibiotics for infection. Such specific
treatment can never be effective for the entire group of high
risk women. Within each of these subgroups, it is probably
the most effective method for reducing the risk of preterm
birth.
The second type of management provides symptomatic
management of the threatened (or actual) preterm labour.
Nearly all cases of preterm birth are preceded by signs and
symptoms of spontaneous preterm labour. Consequently,
these symptoms, regardless of their cause, must be treated
in all cases in which it is appropriate to prolong the preg-
nancy. Randomised controlled trials of early screening
programmes for threatened preterm labour have shown an
increase in early diagnosis and, according to some authors,
a reduction in the number of preterm births.
90,91
This symp-
tomatic management (monitoring of uterine contractions at
home by a midwife, rest, tocolytics) has been the object of
much criticism, but although it does not always lead to a
reduction in the rate of preterm birth, it has reduced neo-
natal consequences, especially for extreme preterm birth.
Tocolytics prolong pregnancy for an average of several
days and therefore allow corticosteroids to be administered
and/or the mother to be transferred to a tertiary hospital
with neonatal intensive care facilities.
One reason for the ineffectiveness of treatment to reduce
preterm births is that its cause is rarely determined during
prenatal care and therefore it will remain difficult to reduce
preterm births if their causes are not acted upon. The
aetiology of preterm birth also remains difficult to define
because it is most often multifactoral, especially in the case
of spontaneous preterm labour leading to preterm birth.
92
One of the principal objectives in prevention is to discover
early aetiologic markers that would allow us to identify
subgroups of patients at high risk of preterm birth and to
manage them with more appropriate and thus more effec-
tive strategies. Recent results in this direction (e.g. infec-
tious markers, cervical ultrasound for early diagnosis of
incompetence) are encouraging.
This strategy can be effective from a public health
perspective only if it can identify as precisely as possible
the women at elevated risk among the entire population of
pregnant women. The accuracy of this screening depends
on the identification of different subgroups at risk of pre-
term birth due to different causes, with markers identified
that are appropriate to each cause.
CONCLUSION
Little progress has been made in identifying the mech-
anism at the origin of spontaneous preterm labour leading
to preterm birth, or in its treatment. Nonetheless, if we take
into account the increase in multiple pregnancies and
induced preterm birth, and the progress in neonatal care
for extremely preterm neonates, spontaneous preterm birth
for singleton pregnancies in developed countries has prob-
ably decreased over the past 30 years.
9395
This decrease in
preterm birth is undoubtedly related to better prenatal care
for all pregnant women. The recognition of primary risk
44 F. GOFFINET
D RCOG 2005 BJOG: an International Journal of Obstetrics and Gynaecology 112 (Suppl. 1), pp. 3847
factors in early or late pregnancy constitutes a part of basic
prenatal care.
New markers such as FFN and cervical ultrasound con-
stitute undeniable progress in the identification of patients
at risk of preterm birth, both in the general population and
in the population with threatened preterm birth. No man-
agement has yet been demonstrated to be effective, espe-
cially in a general population. Any recommendations for
their systematic use are precipitated. Future studies must
evaluate their advantages and disadvantages in everyday
practice. A retrospective study of 16,540 births of infants
with birthweight above the 10th centile of the reference
curves sought to determine the consequences of false
positives diagnosed with intrauterine growth retardation
(IUGR) by ultrasound.
96
The rate of preterm elective
caesarean birth was 12.7% among neonates for whom
IUGR was erroneously diagnosed, compared with 1.2%
among those for whom IUGR was not diagnosed. Associ-
ation between preterm caesarean and misdiagnosis of
IUGR still existed (OR 5.2, 95% CI 2.112.9) after
obstetric history and hypertension during pregnancy were
taken into account. This example illustrates that the assess-
ment of a diagnostic procedure must always include a prag-
matic evaluation, carried out in conditions close to those of
usual practice.
Another benefit to research on new markers is that it
improves understanding of the mechanisms of preterm la-
bour. An aetiological approach may someday lead to treat-
ments appropriate to each mechanism or cause.
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