Download Management of women with a previous preterm birth

PROBLEM-BASED LEARNING IN OBSTETRICS
Management of women with
a previous preterm birth
Although the survival of preterm infants has improved over
the last 20 years, the rate of long-term disability has not. Little
advance has been made in the prevention and treatment of PTB.
Indeed, the rate of PTB is increasing, and consequently the
prevalence of long-term disability attributed to PTB is also
increasing. The challenge of managing PTB at an individual or
community level is that of reducing the proportion of mothers
who deliver before 32 weeks. It is in this context that two case
scenarios are discussed, highlighting the management principles
that should inform care.
Dilly OC Anumba
Abstract
Preterm birth (PTB) is the principal cause of perinatal morbidity and
mortality of non-anomalous fetuses. It poses major health economic
burdens on families and society. Extreme PTB is associated with a high
risk of long-term ill-health and disability. Although advances in neonatal
care and use of antenatal corticosteroids have improved the survival of
preterm babies over the last two decades, the incidence of PTB and its
long-term sequelae remain relatively unchanged. Recent strategies for
identifying women at risk of PTB include ultrasound assessment of the
cervix and the detection of fetal fibronectin on genital swabbing.
Progestogen therapy in women at risk may prolong gestation and
improve neonatal outcomes, but the optimal regimen and the women
most suitable for this therapy remain to be clarified. Further work is
required to identify screening methods with high positive predictive
values, and to formulate effective therapies that substantially prolong
gestation and minimise the proportion of extremely premature births.
Case 1: idiopathic spontaneous preterm birth
A 21-year-old woman in her third pregnancy presents to the
antenatal clinic for booking at 13 weeks’ gestation. She has had
two previous preterm deliveries, the first at 25 weeks’ gestation
culminating in early neonatal death and the second at 27 weeks.
The latter baby survived and has developmental delay at 3 years
of age. She is concerned that she will deliver prematurely and
that the baby may have problems if it survives. She hopes that
you can do something to minimise this risk. How would you
manage her pregnancy?
This case illustrates the typical presentation of women at risk
of PTB and the management dilemmas associated with previous
PTB. Provision of appropriate counselling and a strategy for care
is predicated on a working understanding of the epidemiological
issues, and the existing evidence base, pertaining to the
prevention, diagnosis and treatment of preterm labour. Up to
75% of PTBs are spontaneous, while the rest arise from medical
indications. Spontaneous PTB occurs when the process of labour
begins in the absence of any obvious maternal or fetal illness. It
may result from spontaneous labour, incompetent cervix,
premature rupture of membranes (PROM) or intrauterine infection. Approximately one-half of spontaneous PTBs have no
associated identifiable risk factors; the other half are associated
with risk factors such as multiple gestation, a history of previous
PTB, second-trimester bleeding, genitourinary tract infections,
cigarette smoking, low body mass index and age below 18 years.
It is prudent to elicit these associations in any woman booking for
antenatal care.
This case demonstrates risk factors for PTB such as teenage
pregnancy (the first birth at 25 weeks’ gestation was in the earlier
teenage years) and two previous PTBs (associated with a 25–30%
risk of recurrence). A clear history of the sequence of events
preceding each of the two previous births may shed light on
potential aetiological associations with recurrent PTB: continuing
substance misuse, cigarette smoking, genitourinary infection,
PROM, or previous cervical surgery or uterine malformation.
Such information could prove useful in outlining a care plan.
Previous cold-knife cervical biopsy, particularly if repeated, may
lower the threshold for considering elective cervical cerclage.
PTB associated with infection may require genitourinary infection screening at the booking visit, and throughout pregnancy.
There is a strong association between genital tract infection and
preterm labour, and it is often impossible to determine whether
chorioamnionitis is the cause or the consequence of PTB.
However, a careful evaluation of the history may clarify the
sequence of events. Previous PTB is associated with a sixfold
Keywords preterm birth; pregnancy; labour
Introduction
A fetus is preterm when it is born before 37 completed weeks of
gestation. Most morbidity and mortality occurs in infants born
before 32 weeks’ gestational age with birth weight below 1500 g.
The consequences of such premature delivery are most severe
when birth occurs at the borders of fetal viability, between 23 and
28 weeks’ gestation. The socioeconomic burden of preterm birth
(PTB) includes the high cost of neonatal intensive care and the
long-term care of disabled survivors. Worldwide data on the
incidence of PTB are unreliable, but the incidence ranges
between 5% in developed countries and 25% in developing
countries. Higher PTB rates are recorded among blacks and
women at the extremes of reproductive age. The principal
aetiological associations include infection, iatrogenic delivery
(mainly due to hypertension and pre-eclampsia), multiple
pregnancy, intrauterine growth restriction, substance dependence
and maternal stress.
Dilly OC Anumba FWACS MRCOG MD LLM(Medical Law) is at the Section of
Endocrinology and Reproduction, Academic Unit of Reproductive and
Developmental Medicine, Obstetrics and Gynaecology, University of
Sheffield, Sheffield, UK and Senior Clinical Lecturer/Consultant in
Obstetrics and Gynaecology, Subspecialist in Fetomaternal Medicine,
Section of Endocrinology and Reproduction, Academic Unit of
Reproductive and Developmental Medicine, Obstetrics and Gynaecology,
University of Sheffield, Sheffield, UK.
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increased risk of PROM and a 20-fold increased risk of PTB
without PROM.
Medically indicated premature delivery is often the result of
disorders such as pre-eclampsia, fetal growth restriction, placenta
praevia and a history of stillbirth. If either of the previous births
was artificially induced for any of these indications, the risk of
recurrence would depend on the persistence of the underlying
medical condition. Evaluation for these disorders early in the
antenatal period should ensure that appropriate care plans are
put in place.
A strong positive history of PTB as illustrated by this case is
associated with a high recurrence risk. One study has suggested
that a history of two consecutive PTBs is associated with a
recurrence risk of 25–30% (relative risk 6.5) compared with 2.6%
in a woman who has had two previous term deliveries (relative
risk 0.6) and no history of PTB. A history of one PTB is associated
with a 10–17% risk of recurrence (relative risk 3.9). A woman
considered to be at high risk of recurrent PTB requires closer
surveillance during pregnancy and consideration of interventions
that may reduce the risk or the impact of PTB on the health of the
child. However, there is no consensus on how those at risk
should be managed during a future pregnancy.
the cervical internal os. A cervical length of 25 mm or less (below
the 10th percentile) measured at 24 weeks’ gestation is associated
more strongly with preterm labour than digital examination. To
predict PTB before 35 weeks’ gestation, a cervical length of
25 mm of less is associated with a sensitivity of 47% and a
positive predictive value of 37%. At all cervical lengths, the risk
of PTB increases as the cervical length declines. The low
sensitivity of cervical length relates to the low prevalence of
PTB in low-risk populations. In a high-risk cohort of women with
a prevalence of PTB of more than 30%, the sensitivity of cervical
length monitoring is 79%, compared with 19–39% in a low-risk
population with a prevalence of PTB of less than 4%. In most
studies, however, in both low- and high-risk women cervical
length is associated with a high negative predictive value. Thus,
this assessment helps to avoid unnecessary tocolysis, reduces
hospitalisation time, and may facilitate more accurate selection of
women who require corticosteroid treatment for fetal lung
maturation.
There is no consensus regarding which women are at sufficient
risk of PTB to be suitable for cervical length monitoring. Based on
recurrence risks, most practitioners would agree on the appropriateness of cervical monitoring in a woman with a history of
two previous PTBs. The lower predictive value of this screening
tool as the risk of PTB declines would make such monitoring
cost-ineffective in women with a history of only one previous
PTB, particularly at later gestations. An algorithm for cervical
monitoring is shown in Figure 1. Several variations of this model
exist, but further evidence is required to determine who to scan,
when to scan, how frequently to scan, and when to discontinue
scanning as pregnancy progresses.
Qualitative determination of FFN in cervicovaginal secretions
has found worldwide appeal for screening for the risk of PTB.
FFN is an extracellular matrix protein that acts as an adhesive
between the fetal membranes and the decidua. It is commonly
found in cervical secretions in the first half of pregnancy, and its
presence after 20 weeks’ gestation is thought to represent
disruption of the maternal–fetal interface. When FFN is found
in cervical secretions between 24 and 30 weeks’ gestation, the
sensitivity for predicting delivery before 35 weeks’ gestation is
low (o30%), as is the positive predictive value. In contrast, the
negative predictive value for delivery within 2 weeks of the test is
more than 90%. FFN determination is useful in the screening of
serially monitored, asymptomatic, high-risk women. A negative
FFN test identifies patients at low risk of PTB, but a positive test
has limited predictive value.
Simultaneous use of cervical length assessment and FFN
determination improves the overall prediction of PTB. In one
study, cervical length less than 25 mm and a positive FFN test are
associated with a risk of delivery before 35 weeks of more than
60%, compared with a risk of 25% with cervical length less than
25 mm and negative FFN. Another study showed that, when the
FFN test is positive at 23 weeks, the risk of delivery before 33
weeks’ gestation is 75% if the cervical length is 15 mm or less,
compared with 3% if it is more than 15 mm.The same study
showed that when FFN is negative, the risk of PTB before 33
weeks is 11% if the cervical length is 15 mm or less, compared
with 0.5% if it is more than 15 mm. Data of this kind are
increasingly incorporated into simple management decision trees
for women attending PTB clinics. Ultimately, whether to use
The evidence base for several screening tools used to predict
PTB is weak.
Although a woman may have been identified to be at increased
risk of PTB, effective prevention is often unproven.
Many women who will not have PTB undergo screening and
treatment in an attempt to defer labour in the few women who
will.
In the given clinical scenario, in which the risk of repeat PTB is
high, careful monitoring in a designated specialist clinic will be
helpful. Regardless of whether there was associated infection in
either of her previous pregnancies, screening for genitourinary
infection at booking and throughout pregnancy is advisable.
Since the infections associated with PTB are unclear, which
organisms warrant treatment remains controversial. There is
some agreement that organisms that cause bacterial vaginosis,
and sexually transmitted infections such as chlamydia, should be
treated promptly. Further swabs should confirm clinical cure after
appropriate antibiotic therapy has been completed. Although the
role of group B haemolytic streptococcal infection in the genesis
of PTB remains unclear, women who screen positive during
pregnancy should receive antibiotics intra-partum to reduce the
risk of neonatal infection.
Screening by ultrasonography and fetal fibronectin
There is an emerging consensus that cervical ultrasonography
and qualitative determination of fetal fibronectin (FFN) in
cervicovaginal secretions are valuable screening methods for
idiopathic spontaneous PTB in women considered to be at high
risk. In contrast, and despite extensive clinical trials, monitoring
of uterine activity is not of value in the prediction of preterm
labour.
Assessment of the cervix by transvaginal ultrasonography is
increasingly used in women at risk of preterm labour and PTB.
Indices that correlate with risk of PTB include cervical length,
presence of a funnel, funnel width or length and the diameter of
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PROBLEM-BASED LEARNING IN OBSTETRICS
in the treatment of the twin transfusion syndromes. Earlier
commencement of screening (e.g. from 14 weeks) may have to be
considered when cervical weakness is a potential cause of very
early premature delivery. Such earlier screening may enable one
to select patients who would be suitable for cervical cerclage. In
the final analysis, it would seem best to base the decision on the
duration of monitoring on individual clinical presentations and
findings. Further research is required to improve the evidence
base for such decisions.
Case 2: diagnosis of preterm birth
A 35-year-old woman in her second pregnancy presents to the
triage area of her local delivery suite at 26 weeks’ gestation with a
history of ‘tightenings’ occurring once every 10 minutes. Her first
pregnancy culminated in PTB at 27 weeks and she is anxious that
she may deliver prematurely again. There are no neonatal
intensive care cots in the local hospital, though a cot has been
identified in a unit 100 miles away. Decisions need to be made
regarding a care plan in the best interests of the mother and her
baby, and taking into account the availability of health-care
resources. How would you manage her pregnancy?
This clinical scenario is not uncommon in the UK, and indeed
in other developed economies. It highlights the pitfalls that attend
the clinical diagnosis of preterm labour and the apparent
limitations in the availability of neonatal intensive care resources
for those at risk of (usually unexpected) PTB. To deal with this
problem, the obstetrician, in cooperation with the neonatal team,
needs to adopt an approach that more accurately identifies
women who are likely to deliver prematurely, while avoiding
unnecessary and often expensive care and treatments for women
who ultimately do not deliver prematurely.
Achieving this goal is hampered by the notorious inaccuracy of
the clinical diagnosis of preterm labour based on the traditional
methods of uterine activity monitoring and digital assessment of
the cervix. In one study that evaluated the clinical diagnostic
criteria of preterm labour, 40% of patients who were diagnosed
as being in preterm labour but were treated with placebo
delivered at term, reflecting a high false-positive rate. In another
study, 18% of women not thought to be in preterm labour by
traditional clinical criteria delivered prematurely, reflecting the
high false-negative rate of clinical assessment. Too many women
receive unnecessary treatment to prevent cervical dilation
beyond 3 cm, when clinical assessment becomes more accurate.
Accurate diagnosis also impacts on the results of clinical studies,
because treatment of women who are not in labour may be
erroneously considered successful.
In symptomatic women such as this case, the best signs of true
labour include cervical dilation greater than 2 cm, a short cervix,
and demonstration of a change in cervical dilation of 2 cm or
more over a short time frame. Diagnosis before the cervix reaches
3 cm is more reliably made by cervical ultrasonography than by
digital assessment. In the setting of early preterm labour, the
cervical canal has a Y-shaped appearance that is more likely to
indicate pressure on the lower uterine segment as a result of true
labour than the flat, ‘T’ configuration of the non-labouring cervix.
FFN assessment is a powerful adjunct as a screening tool in this
clinical scenario. In women such as this case, with symptoms
of preterm labour before advanced cervical dilation, a recent
Figure 1 Antenatal management of a pregnant woman at risk of preterm
birth. fFN, fetal fibronectin.
cervical scanning simultaneously with FFN assessment depends
on local manpower and funding resources. The author’s practice
is to use cervical ultrasonography as the primary tool for
antenatal screening; FFN assessment is incorporated when the
cervical parameters become borderline or ‘abnormal’, or demonstrate more rapid change than is considered normal, or when key
decisions must be made regarding the interval between clinic
visits, the need for hospitalisation or the administration of
corticosteroids.
There is little clinical evidence on how long to screen women
at risk for PTB by cervical ultrasonography and FFN assessment.
Broadly, antenatal screening is best started shortly after 20
weeks, and most practitioners would discontinue it by 32 weeks.
However, there are certain clinical situations in fetal care when
such screening tools may inform management decisions, including the management of multiple gestation, polyhydramnios, and
as an adjunct to fetal invasive procedures such as amnio-drainage
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meta-analysis of trials of FFN summarised that the test is
probably most accurate in predicting spontaneous PTB within
7–10 days of testing. Thus, FFN determination enables clinicians
to avoid over-diagnosis and unnecessary treatment of preterm
labour. The test also improves the sensitivity of diagnosis of
preterm labour by identifying women who may benefit from
further observation or treatment. There are now several reports
suggesting that use of the FFN test in scenarios similar to Case 2
may be cost-beneficial by enabling savings on hospital admissions and therapy.
Cervical length over 30 mm on ultrasonography coupled with a
negative FFN test suggest that true preterm labour is highly
unlikely within 2 weeks. Consideration may therefore be given to
deferring tocolysis and avoiding expensive and often unnecessary
transfer to distant hospitals because of shortages in neonatal
facilities. When uterine activity is not established, discharge from
hospital to outpatient follow-up may be appropriate. Conversely,
a short or dilated cervix on ultrasonography and/or a positive
FFN test may indicate hospitalisation, tocolysis, corticosteroid
therapy or transfer. An important caveat is the need for a strategy
to review the above findings, as dictated by changes in the
mother’s clinical situation.
For other factors that may be relevant to the management of
confirmed or suspected preterm labour, the reader is referred to
the Further Reading. Treatments that are often indicated in the
setting of a high risk of early PTB include corticosteroids,
antibiotic therapy and tocolysis.
assessing the value of maternal antibiotic therapy in preventing
preterm labour or PTB. The ORACLE study, evaluated with other,
smaller trials, led to the conclusion that antibiotic use did not
improve fetal outcome but may have caused a trend towards
increased death rates in the infants of treated women. Maternal
administration of progestogen has now been shown in several
randomised trials to prevent PTB in women with a previous
idiopathic preterm labour or PROM. Weekly injections of 17ahydroxyprogesterone caproate, starting at 16–20 weeks’ gestation, significantly reduced delivery at less than 37, less than 35
and less than 32 weeks’ gestation and led to improved neonatal
outcomes. Similar observations have been made with vaginally
administered progestogen. The dose, route and regimen of
administration of progestogen in this setting remain to be
determined, and the place of progestogen therapy in the
management of multiple pregnancy, positive FFN swabs, cervical
cerclage and a short cervix remains to be clarified. Prophylactic
cerclage for a short cervix as a means of preventing PTB remains
unclear. Bed rest and hydration do not appear to improve the rate
~
of PTB.
FURTHER READING
Ekwo E E, Gosselink C A, Moawad A. Unfavorable outcome in penultimate
pregnancy and premature rupture of membranes in successive
pregnancy. Obstet Gynecol 1992; 80: 166–72.
Heath V C, Daskalakis G, Zagaliki A, Carvalho M, Nicolaides K H.
Cervicovaginal fibronectin and cervical length at 23 weeks of
gestation: relative risk of early preterm delivery. Br J Obstet Gynaecol
2000; 107: 1276–81.
Iams J D, Goldenberg R L, Mercer B M et al. The preterm prediction study:
recurrence risks of spontaneous preterm birth. Am J Obstet Gynecol
1998; 178: 1035–40.
Joffe G M, Jacques D, Bemis-Heys R, Burton R, Skram B, Shelburne P.
Impact of the fetal fibronectin assay on admissions for preterm labor.
Am J Obstet Gynecol 1999; 180: 581–6.
Kenyon S L, Taylor D J, Tarnow-Mordi W. Broad spectrum antibiotics for
spontaneous preterm labor: the ORACLE II randomized trial. ORACLE
Collaborative Group. Lancet 2001; 357: 989–94.
King J F, Grant A, Keirse M J, Chalmers I. Beta-mimetics in preterm labour:
an overview of the randomized controlled trials. Br J Obstet Gynaecol
1988; 95: 211–22.
Liggins G C, Howie R N. A controlled trial of antepartum corticosteroid
treatment for prevention of the respiratory distress syndrome in
premature infants. Pediatrics 1972; 50: 515–25.
Meis P J, Klebanoff M, Thom E et al. Prevention of recurrent preterm labor
by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003; 348:
2379–85.
Resnik R. Issues in the management of preterm labor. J Obstet Gynaecol
Res 2005; 31: 354–8.
Prevention of preterm birth
Of the many agents used to inhibit preterm labour in the acute
setting, the b-adrenergic receptor agonists atosiban and indomethacin have been shown to be effective in prolonging
pregnancy in large, randomised trials. Most clinical trials have
shown that the tocolytic drugs might prevent delivery for 2–7
days, which is enough time for the use of corticosteroids to
induce lung maturation. Neither maintenance treatment with
tocolytic drugs nor repeated acute tocolysis improves perinatal
outcome. Since the early reports of a controlled trial by Liggins
and Howie in 1972, several studies have confirmed the beneficial
effects of corticosteroids in reducing the incidence and severity of
surfactant-deficient respiratory distress syndrome, improving the
survival rates of infants born at 24–34 weeks’ gestation and
decreasing CNS and gastrointestinal complications. Betamethasone or dexamethasone is administered in two doses of 12 mg, 24
hours apart. Repeat doses of corticosteroids weekly or every other
week do not appear to improve composite outcome in terms of
respiratory distress syndrome, survival, bronchopulmonary
dysplasia, necrotising enterocolitis and periventricular leukomalacia. Potential harmful effects of such repeated therapy (risk of
infection and impaired fetal brain development) preclude the
adoption of such a practice.
The potential association of cervical and intrauterine infection
with idiopathic spontaneous preterm labour has led to trials
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