Optimising maternal-fetal outcomes in preterm labour: a decision analysis Tại sao trên 36 tuần không nên dùng giảm go

1. BritishJournal of Obstetricsand Gynaecology
May 1998,Vol.105,pp. 541-550
Optimising maternal-fetal outcomesin preterm labour:
a decision analysis
*GeorgeA. Macones,*ThomasJ. Bader, ?DavidA. Asch
*Departments of Obstetrics and Gynaecology, and Biostatistics and Epidemiology, University ofPennsylvania School ofMedicine.
Philadelphia; ?VeteransAffairs Medical Center;Philadelphia, and Division of General Internal Medicine, University of
Pennsylvania SchoolofMedicine, USA
Objective To compare,using decision analytic techniques,maternal and fetal risk and benefits of three
strategies for the management of preterm labour after 32 weeks. These strategies are empiric
tocolysis,no tocolysis,or amniocentesisfor fetalmaturitytesting.
Data Sources Published medical literature provided the probabilities, including those for tocolysis
efficacy,maternalandneonataloutcomes,andsteroidefficacy.
Data SynthesisSeparatedecisiontrees were created for hypotheticalcohorts of patients presentingwith
preterm labour at 32,34, and 36 weeks of gestationto comparestrategies.Theprimaryoutcomewas
the total number of expected adverse maternal and neonatal events for each strategy at each
gestationalage.
ResultsAt 32 weeks tocolysis yielded the lowest total number of adverse maternal and neonatal events.
At 34 weeks, both tocolysis and no tocolysis yielded similar overall outcomes. At 36 weeks most
clinicaloutcomeswere good regardlessof strategy.
Conclusions This analysis supports the empiric use of tocolytics at 32 weeks. At 34 weeks, either
tocolysis or no tocolysis appearto be reasonablealternatives.At 36 weeks no tocolysis is probably
preferred.This analysisalsosuggeststhat amniocentesisshouldnot be employedin the management
ofpreterm labourat these gestationalages.
INTRODUCTION
The management of preterm labour is controversial.At
gestational ages < 32 weeks, when small delays in
deliveryimproveperinatal outcome,the use of tocolytic
agents to arrest labour is common and well accepted'.
At more advanced gestational ages, however, the value
of tocolytics is less clear for several reasons. Although
corticosteroids have been demonstrated to reduce
neonatal complicationsin early preterm labour (ie, <34
completed weeks), no data demonstrate effectiveness
after 34 weeks of gestation2. In these circumstances,
prolonging pregnancy after 34 weeks with tocolytic
agentsmay not appreciablyimprove maternal-fetalout-
come. Secondly,beta-agonist tocolyticagents occasion-
ally cause maternal pulmonary oedema and myocardial
ischaemia3. These adverse maternal events may out-
weigh the limited potential fetal benefits at late gesta-
tional ages. Thirdly, although amniocentesis might be
used to assess fetal lung maturity and to identify those
most likely to benefit from tocolysis, amniocentesishas
its own risks and the tests performed on amniotic fluid
have their own inaccuracies4. Thus, while pretenn
~~
Correspondence: Dr G. A. Macones, Center for Clinical
Epidemiology and Biostatistics, 901 Blockley Hall, 423 Guardian
Drive, Philadelphia, Pennsylvania 19,104-6021, USA.
labour at advanced gestationalages is common,the best
strategyfor managing these pregnancies remains uncer-
tain.
We used decision analysis to determine the optimal
management of preterm labour at advanced gestational
ages (> 32 completed weeks). This research method
is particularly appropriate in this setting, where a
randomised trial may not be feasible (due to the
extremelylarge samplesize that would be needed)5-6.In
this study, we used decision analysis to compare the
three commonly utilised strategies for the management
of preterm labour (tocolysis, no tocolysis, amnio-
centesis) at gestational ages beyond 32 weeks for
singleton gestations, considering both maternal and
fetalrisk and benefit.
METHODS
We constructed a decision tree to compare the three
strategies for the management of preterm labour
in women with intact amniotic membranes and no
contraindications to tocolysis with ritodrine. These
models were constructed and analysed using Data 3.0
for Windows (TreeAge Software, Williamstown
Massachusetts,USA). We constructedseparatetrees for
women presentingat 32,34, and 36 completedweeks of
0 RCOG 1998 British Journal of Obstetrics and Gynaecology 541

2. 542 G. A . M A C O N E S ET A L .
gestation.A condensed version of the decision tree for
women presenting in preterm labour at 34 completed
weeks is shown in Figs. 1 and 2.
By way of explanation, the decision tree is best
followed fiom left to right. The tree begins with a
squarenode, calleda decision node, representinga deci-
sion faced by the obstetrician. In our case, an obstetri-
cian must decide whether to employ tocolysis, or per-
form an amniocentesis when a woman presents with
preterm labour.Thus,the initialbranches fromthe deci-
sionnode are the clinical options availableto the obste-
trician. A circular node is termed a chance node, which
represents an uncertain event. The branches emanating
from a chance node are all the possible outcomes for
that uncertainevent.Theprobabilitiesof theseuncertain
events are usually based on existing medical data. One
example of a chance node and its consequencescan be
seen in the initial section of the amniocentesisstrategy
(Fig. 1). Here, if an amniocentesis is performed in the
setting of preterm labour, there are three possible out-
comes: 1. either complication related to the procedure
that requires immediate delivery; 2. rupture of mem-
branes; 3. or no complications.A triangle represents a
final outcome; in our case the triangles could represent
a major adverse neonatal event, including neonatal
death, or an adversematernalevent (Fig. 2, SubtreeB).
Strategies
1. Tocolysis
We assumed that all women in this arm receive tocoly-
sis with ritodrine at the time of presentation in preterm
labour. This may well result in no maternal adverse
events, a minor adverse event (which is not life-threat-
ening, but requires that the drug be discontinued), or a
major adverse event. We defined major adverse drug
events as pulmonary oedema and myocardial ischaemia,
and either of these events would necessitatea discontin-
uation of tocolysis. We also assumed that women not
experiencing an adverse event, as well as those with a
minor adverse event, receive a full course of steroids if
presenting at or before 34 weeks (if delivery was
delayed for at least 48 hours). We assumedthat women
with a major adversedrug eventwouldnot receive a full
course of antenatal steroid therapy. We also assumed
that in the event of a minor adversedrug event or a drug
failure,no othertocolyticagentsare administered.
We focused on the efficacy and safety data for rito-
drine hydrochloridefor this analysis for several reasons.
Firstly, it has been the most thoroughly researched
tocolytic agent in terms of both efficacy and safety.
Secondly,it is the only agentapprovedby Food and Drug
Administration in the United States for this indication.
Thirdly,it is the most commonlyused agent (and class of
drug) aroundthe world.Althoughmagnesium sulphateis
also a commonly used tocolytic agent in many parts of
the world,no data supportits efficacyin ths context,and
so we chosenotto considerthis agentinourmodel.
2. No tocolysis
Women in this arm receive neither ritodrine nor any
other tocolytic agent; but those 5 34 weeks receive
corticosteroids.
3.Amniocentesis
Women in this armundergo amniocentesisat the time of
initial presentation with preterm labour. We assumed
that amniocentesiscarries a small risk of complications
that require immediate delivery. We also assumed that
there is a small risk of rupture of the membranes with
amniocentesis,which does not require immediatedeliv-
ery, but does affect the use of tocolysis4.If there are no
immediatecomplications,the amnioticfluid is screened
for infection using a Gram stain.Women with evidence
of intrauterine infection are delivered immediately
without steroids or tocolytics, while those without evi-
dence of intrauterineinfection by amniocentesishave a
lecithidsphingomyelin (L:S) ratio performed. Those
with mature ratios (L:S ratio > 2.0) do not receive
tocolyticsor antenatalsteroids.While those with imma-
ture ratios receive tocolysis and, if 5 34 weeks, receive
steroids.The model incorporatesthe inaccuraciesof the
L:S ratio and Gram stain (through estimates of their
sensitivity,specificity, and the prevalence of the condi-
tion), and the impact of these inaccuracies on the ulti-
mate outcome for the strategy. For example, we
assumed that the specificity of a Gram stain for the
diagnosis of intra-amniotic infection was 98% (false
positive rate of 2%). In the amniocentesisstrategyin the
model, this means that approximately 2% of women
withoutan intra-amnioticinfectionwouldbe incorrectly
diagnosed with an intra-amniotic infection, and there-
fore be incorrectly delivered on the basis of this test
result. Similarcalculationswere made to reflect the test
characteristicsof the lungmaturity tests.
Generalcharacteristicsof the model
The ultimate goal when treating a woman in preterm
labour is to maximise the chances for the health of the
newborn infant, while minimising maternal drug-
related adverse events.A principal feature of the tree is
that each strategycan result in adverse maternal events,
adverse neonatal events, or both. Adverse maternal
events in this model occur only with the use of tocoly-
sis. Thus, in the no ‘tocolysisarm’,there are by defini-
tion no adversematernalevents.
0 RCOG 1998 Br J Obstet Gynaecol 105, 541-550

3. O P T I O N S F O R T H E M A N A G E M E N T O F P R E T E R M L A B O U R 543
Pulmonary edema
SubtreeA
Myocardial Ischemia
Subtree A
Tocolysis MinorADE
SubtreeA
I Y
Subtree A
1NoADE
Subtree A
Major Cornp
Subtree B
r--Amino1 4 R O M
Subtree A
1 + Grain stain
ISubtree B
‘-0No Comps
Mature US SubtreeA
Fig. 1. The decision model at 32 weeks of gestation.
An underlying assumption for each strategy in this
model is that a delay in delivery of at least 24 hours
from presentation, either with or without the use of
tocolytics, allows for the use of corticosteroids. We then
assumed that corticosteroids, independent of tocolytic
use, reduce the gestational age-specific risk of neonatal
death, respiratory distress syndrome, necrotising entero-
colitis, and grade I11 and IV intraventricular haemor-
rhage. Thus, potential benefits from tocolysis result
because a greater proportion of women have delivery
delayed long enough for the benefits of steroids use to
accrue. Although the available randomised trials of
beta-agonists for acute tocolysis do not suggest that any
measure of neonatal outcome is improved with tocoly-
sis, a majority of these trials were performed without
the use of antenatal cortico~teroids~.Current thinking
now supports the use of tocolysis in order to allow time
for maximum benefit from steroids8.This is one of the
primary assumptions for this model, and we feel that the
assumption accurately reflects current beliefs and clini-
cal practice with tocolysis.
The benefit of steroids on neonatal outcome was
calculated as follows. Consider a 34 week pregnancy
complicated by preterm labour. The baseline risk for
0 RCOG 1998 Br J Obstet Gynaecol 105, 541-550

4. 544 G . A . M A C O N E S E T A L
Delivery4 4 hours
Subtree B
Subtree B
-9 Delivery 36 weeks
Subtree B
Subtree B
SubtreeA
Sepsis
t-=
Death
Subtree B
Fig. 2. The decision model at 32 weeksof gestation.
respiratorydistress syndrome in a newborn infant born,
not treated with steroids, at this age is approximately
17%.If steroidsare administered,and the infant isborn
24 hours after presentation, the probability of respira-
tory distress syndrome is reduced to 6.8% (a 60%
reduction in risk). Similar calculations are made in the
model to estimatethe impactof steroidson death,Grade
I11and IV intraventricularhaemorrhage,and necrotising
enterocolitis. This method therefore includes both the
baseline gestational age-specific risk of a morbidity
(pre-treatmentprobability),as well as the potentialben-
efit of steroids, if at least 24 hours are gained after
administration.
We assumed that intra-amniotic infection is present
in approximately5% of womenpresentingwith preterm
labour at each gestationalage9-17.We also assumed that
the use ofritodrine in those women with a true intrauter-
ine infection increases the likelihood of maternal pul-
monary oedema, compared with those who do not
receive tocolysis'*. Thus, the correct identification of
intrauterine infection by amniocentesis(where delivery
is expedited without the use of tocolysis) would result
in a lower probability of maternal pulmonary oedema.
We assumed that neonatal outcome is not altered if
intra-amniotic infection is properly diagnosed before
delivery.
Probabilities
Table 1 lists the base line probabilities and plausible
ranges of uncertain e v e n t ~ ~ q ~ , ' ~ ~ .These probabilities
were obtained, when possible, firstly from meta-analy-
ses of randomisedtrials; secondlyfrom randomisedtri-
als not subjected to meta-analysis; thirdly, from obser-
vational studies; and finally, from expert opinion as
necessary. Expert opinion was needed only for the esti-
mation of one variable: the probability of immediate
complicationsof amniocentesis.To obtain this estimate,
seven board-certified obstetricians specialising in
maternal-fetalmedicine all of whom were skilled in the
procedure of amniocentesis,were independentlypolled
about this complication.The base line probability is the
average of their responses, and the plausible range
includes the highest and lowest values of their
responses.Estimatesof major fetal morbidity(eg,respi-
ratory distress syndrome,Grade I11 or IV intraventricu-
lar haemorrhage, necrotising enterocolitis, sepsis) and
mortality in newborn infantsnot treated with steroidsat
the possible gestational ages at delivery were obtained
directly from gestational age-specific morbidity and
mortality c ~ r v e s " ~ ~ ~ ~ .Estimates of pulmonary oedema
and myocardial ischaemiawere based on a comprehen-
sive review of the randomised controlled trials of rito-
drine fortocolysis.
As shown in Fig. 1, a distributionof expected deliv-
ery ages was calculated for each strategy. To estimate
these distributions, we generated survival curves for
women admittedwithpreterm labour at eachgestational
age, based on a recent meta-analysis of the randomised
trials of beta-agonists for tocolysis5. For example,
for those receiving tocolysis (without an adverse
drug event) at 34 weeks, we estimated(basedon tocoly-
sis time-to-delivery curves that we generated) that
approximately 7% of women would deliver within
24 hours; 14%between 24 and 48 hours; 17%between
48 hours and 35 completedweeks; 20%between 35 and
36 completedweeks;and 42%at 3 37 completedweeks.
This expected distribution of birth ages was calculated
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5. O P T I O N S F O R T H E M A N A G E M E N T O F P R E T E R M L A B O U R 545
Table 1. Probability estimates.Values in parentheses are ranges,
~~
Reference
Variable Baseline (Range) no.
LIS sensitivity 0.85 (0.7-0.95) 19-22
LIS specificity 0.85 (0.5-0.99) 19-22
Gram stainsensitivity 0.50 (0.25-0.85) 9,lO
Gram stain specificity 098 (0.95-0.99) 9,lO
Amniocentesis
complicationsnecessitating
delivery 0.001 (0.0001-0.005) Expert
opinion
Rupture of membraneswith
amniocentesis 0.01 (0.005-0.04) 4, 11,12
Delay of delivery* 11
<24h 0.40 (0.20-0.90) 11
2 4 4 8 h 0.50 (0’30-0’50) 11
48 h - 1 week 0.10 (0.05-0.15) 11
lntra-amniotic infection 0.05 (0.01-0.14) 9-17
Tocolytic-relatedadverseevents** 0.01 (0.005-0.03) 2344
Increase in risk of adverse
maternaleventwith tocolysisf 50% (20-70) 18
Minor tocolytic side effects 0.10 (0.05-0.15) 2344
Morbidityreduction
with antenatal steroids 2
Grade 3 or 4 IVH 0.50 (0.20-0.70) 2
Necrotisingenterocolitis 0.65 (0.30-090) 2
Sepsis 0.0 (0.0) 2
RDS 0.60 (0.40-0.80) 2
*Afterrupture of membranes.
**Withoutintra-amnioticinfection.
?With intra-amnioticinfection.
separately for each strategy at each gestational age and
is the basis for the estimates of total expected neonatal
morbidity for each strategy. Best case and worst case
curves were also developed for tocolysis and no tocoly-
sis from the meta-analysis data using a confidence
bandingtechnique(Figs. 3-8)47.
Outcomes
In ourbase line analysisfor each gestationalagewe cal-
culated an expected number of adverse maternal events
and adverse neonatal events per 1000women for each
strategy. The primary outcome for the model was the
total number of adverse events (number of maternal
adverseevents plus number of adverseneonatal events)
per 1000women at each gestationalage. Thus, the most
favourable strategy at a given gestational age is that
which has the lowest combined total number of adverse
maternal and neonatal events.In calculatingthese totals
we considered only major maternal (pulmonary
oedema, cardiac ischaemia) and major neonatal adverse
outcomes (respiratory distress syndrome, Grade I11 or
IV intraventricularhaemorrhage,necrotising enterocol-
itis, sepsis,andneonatal death).
Sensitivity analysis
We performed multiple one- and two-way sensitivity
analyses to test the effect of the probability estimates
andranges on the decisionamong strategiesat each ges-
tational age.As stated earlier,we generated estimatesof
best and worst case time to deliverycurves for both the
tocolysis and no tocolysis curves. To test the impact of
these estimates on our results, we applied the best case
curve for tocolysis with the worst case curve for no
tocolysis to our decisionmodels at the three gestational
ages. In effect, this maximisesthe perceived efficacy of
tocolysis. Similarly, to reflect the minimum plausible
efficacy of tocolysis, we combined our best case esti-
mates for no tocolysis and worst case estimates for
tocolysis.
Using the total number of adverse events as the pri-
mary outcome for the strategies implies that maternal
and fetal wellbeing are considered of equal value.
However, it is likely that there is wide variation among
women on the relative value placed on adversematernal
and adverseneonatalevents.Therefore, we performed a
sensitivity analysis,varying the emphasisthey place on
maternal versus neonatal wellbeing (maternal-fetal
trade-off) to determinethe effect of this trade-off on the
choice among strategies. In the base line analysis,
maternal and fetal events were given equal emphasis
(ratioof 50%maternal wellbeing:50% neonatal wellbe-
ing). In this sensitivity analysis, the weighting system
was varied from 100%placed on maternalwellbeingto
100%placed on neonatal wellbeing.
We alsoperformedsensitivityanalysesto examine of
the other assumptionsin the model:
1. We changed the way lung maturity tests are used. In
the base line analysis we assumed that the results of
these tests would determine whether tocolysis and
steroids would be given. In the sensitivity analysis
we assumedthat steroidswould be given in all cases
-< 34 completed weeks regardless of lung maturity
tests, and that those lung maturity tests would be
used only to determine whether tocolysis would be
given.
2. We changed the assumptionabout neonatal outcome
if true intra-amnioticinfection is documented. In the
base line analysis we assumed no improvement in
outcome if intra-amniotic infection was correctly
identified and the infant delivered.In the sensitivity
analysis we assumed that neonatal morbidity could
be reduced by up to 25% if intra-amniotic infection
was identified, and delivery was expedited. This
probability was based on the expert’s opinion as
previouslyoutlined.
3. We changed the risk of adverse neonatal outcomes
from tocolytic therapy. In the base line model
we assumed that beta-agonist tocolytics do not
0 RCOG 1998 Br J Obstet Gynaecol 105, 541-550

6. 546 G. A . M A C O N E S ET A L .
90
-80
s
2 70
$ 60-
50
40
v
-0
.-9-
3
90
h 80
s
70
z
5 60
3
50
40
v
>
U
c
.-
-
-
-
-
-
30
0
I I I I I I I I
-.......**a ...........
10 20
Time-to-delivery(days)
30 40
Fig. 3. Timc-to-delivery curve for receiving ritodrine at 32 weeks.
-baseline; - - - best case; ._...worst case.
90
80
h
70
D
??
$ 60
50
40
30
.--a,
3
20 I I I I I
0 10 20 30 40
Time-to-delivery (days)
Fig. 4. Time-to-deliverycurve for receiving no tocolysis at 32 weeks.
-baselinc;- --best case; .....worst case.
I
30 ,0 10 20 30 40
Time-to-delivery(days)
Fig. 5. Time-to-delivery curve for receiving ritodrine at 34 weeks.
-baseline; - --best case; .....worst case.
90I
1 1 1 1 1 1 1 1 1 1 1 1
0 2 4 6 8 10 12 14 16 18 20 22 24
Time-to-delivery(days)
Fig. 6. Time-to-deliverycurve for receiving no tocolysis at 34 weeks.
-baseline; - - - best case; .....worst case.
80gOl
4030 t0 1 2 3 4 5 6 7
Time-to-delivery (days)
Fig. 8. Time-to-deliverycurve for receiving no tocolysis at 36 weeks.
-baseline; - --best case; .....worst case.
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7. O P T I O N S FOR T H E M A N A G E M E N T O F P R E T E R M L A B O U R 547
independently increase the risk of any adverse
neonatal outcomes. Since there is some evidence
that tocolyticsmay increasethe risk of intraventricu-
lar haemorrhage, we incorporated this risk in the
sensitivityanalysis4*.
4. We varied the assumptions about the rate of intra-
amnioticinfectionby gestationalage at presentation.
In the base model, we assumed a constant rate of
intra-amniotic infection of 5% across gestational
ages. Since some data suggest that infection rates
may be higher in pregnancies presenting with
pretenn labour at earlier gestational ages, we varied
this in a sensitivityanalysis.
5. We changed the assumption about steroid use in
those with a major adverse drug event associated
with tocolysis. In the base line analysis we assumed
that steroids would not be given in the case of major
adverse drug event’s. In this sensitivityanalysis,we
assumed that steroids were given in cases of mater-
nal pulmonary oedemaand myocardial ischaemia.
6. We altered our assumptions about delivery delay in
women with rupture of the membranesafter amnio-
centesis. Specifically, some data suggest that up to
50% of women receiving antibiotics for premature
rupture of membranes remain undelivered at one
week49. We therefore varied these probabilities
arounda wide range in our sensitivityanalysis.
RESULTS
Table2 lists the expectednumber of maternal,neonatal,
and total events expectedwith each strategyat each ges-
tational age per 1000expectantmotherspresentingwith
preterm labour. An example of the calculation of the
probabilityof various neonatal outcomesfor the tocoly-
sis and no tocolysis strategies for the 32 week tree is
given in Fig. 9. In this example tocolysis is preferred
over no tocolysis since it results in fewer adverse
neonatal events. At all gestational ages tocolysis yields
the highest number of maternal adverse events and the
lowest number of adverse neonatal events. The differ-
ences between the strategies are greatest at 32 weeks
and smallest at 36 weeks at presentation. For example,
at 32 weeks the difference in the total number of
adverse events (per 1000 patients) between the best
strategy (tocolysis) and the second best strategy (no
tocolysis) is 19per 1000patients.At 36 weeks the dif-
ferencebetween the two most favourable strategies (no
tocolysisand amniocentesis)is I eventper 1000women.
Trade-offs between maternal and neonatal outcomes
are also evident in Table 2. At 32 weeks tocolysis with
ritodrine yields the lowest number of total adverse
events. This finding results from a more favourable
neonatal outcome when tocolysis is employed at this
gestational age. The 19fewer expectedadverseneonatal
IMajorADE (0.01)l /-I- No problem(0.911)
NND (0.001)
Morbidity (0.059)
No Droblem (0.940)
”*
NND (0.002)
Morbidity (0.087)
Fig. 9. Exampleof expectedvalue decisionanalysis at 32weeks.
events per 1000 women when tocolysis is compared
with no tocolysis (the second most favourable strategy
at this age) is partially offset by an expected increase in
10 maternal events. Tocolysis remained the most
favourablestrategyat 32 weeks in the multipleone- and
two-way sensitivity analyses performed (eg, tocolytic
delivery delay parameters, steroid effectiveness,Gram
stain and L:S test characteristics,and neonatal morbid-
ity and mortality estimates). The model at 32 weeks is
sensitiveonly to the estimateof major maternal adverse
events associatedwith tocolysis. For this estimate,only
at the highest plausible level for severe maternal mor-
bidity does no tocolysis become the preferred strategy
(threshold value = 3.0%). Under no circumstances in
any of the sensitivity analyses performed did amnio-
centesis ever yield the lowest total number of adverse
events.
Table 2. Expected numbers of adverse events (per 1000patients) for
each strategy (tocolysis,no tocolysis or amniocentesis).
Gestationalage Maternal Neonatal Neonatal
(weeks) event death morbidity TOTAL
32 weeks
Tocolysis
No Tocolysis
Amniocentesis
Tocolysis
No Tocolysis
Amniocentesis
Tocolysis
No Tocolysis
Amniocentesis
34 weeks
36 weeks
10
0
4
10
0
2
10
0
2
1
2
2
0
0
0
0
0
0
59 70
87 89
92 98
16 26
22 22
31 33
5 15
I 7
6 8
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8. 548 G . A . M A C O N E S E T A L .
At 34 weeks no tocolysis results in the fewest total
number of adverse events under baseline probability
estimates. This result is due to a significantly smaller
neonatal benefit achieved with tocolysis at this gesta-
tional age comparedwith that observedat 32 weeks.At
34 weeks only six adverse neonatal events per 1000
women are prevented with tocolysis compared with no
tocolysis.The reduced neonatal benefit at this age fails
to offset maternal risks. Although the differences
between strategies at this age are small, the model
remainsrobust.The model at 34 weeks is sensitiveonly
to theprobabilityof major adversematernalevents
At these earlier gestational ages, amniocentesiscon-
sistentlyis the least favourableof the three strategiesin
terms of the total number of adverse events.
Paradoxically, amniocentesis leads to an increased
probability of adverse neonatal outcome at these ages
compared with tocolysis and no tocolysis,due to a com-
bination of procedure-relatedcomplicationsand inaccu-
racies of the tests performed on the amniotic fluid. As
expected,amniocentesisyields an intermediatenumber
of expectedadversematernal events comparedwith the
other strategies at these ages. The relative disutility of
amniocentesisat these ages was preservedthrough mul-
tiple one- and two- way sensitivity analyses; under no
circumstance does amniocentesis yield the smallest
total numberof adverse events comparedwith tocolysis
orno tocolysis.
All three clinical optionsyield similar outcomesat 36
weeks of gestation with amniocentesis preventing one
adverse event compared with no tocolysis (the second
most favourable strategy). The differences in neonatal
outcomebetween the strategiesarevery smallat this ges-
tational age compared with the others, due to the
low baseline risk at 36 weeks. Because outcomes are so
similarat 36 weeks,this model is sensitiveto many prob-
ability estimates, including fetal morbidity, maternal
morbidity,amniocentesiscomplicationrates,and others.
These results assume equal concern for maternal and
adverse events. Because some women may have differ-
ent priorities, we performed a sensitivity analysis,
adjusting the weight placed on maternal versus fetal
outcomes.At 32 weeks only at the highest weight for
maternal welfare does no tocolysis become the pre-
ferred strategy. At 34 weeks no tocolysis becomes pre-
ferred when slightly > 50% weight is given to maternal
outcome relative to fetal outcome. Under no circum-
stance in this assessmentof the maternal fetal trade-off
did amniocentesiseverbecomethe preferred strategy.
DISCUSSION
This study supports several conclusions. Firstly, for 32
week gestations, tocolysis with ritodrine yields the
greatest probability of overall maternal-fetal health.
This result is sustained over widely varying assump-
tions of clinical probabilities and the value of clinical
outcomes. Secondly,the optimal management of gesta-
tions beyond 32 weeks remains unclear. At these ages,
the choice betweentocolysis with ritodrine or no tocol-
ysis is sensitive to many assumptions, particularly the
priority placed on maternal versus fetal health.
However, an important reason the model is unable to
define a single best strategy at 34 weeks and beyond is
that clinical outcomes at these gestational ages are
already favourable and they remain so regardless of
what managementdecisionsare made.
Thirdly,this study does not supportthe use of amnio-
centesis in the management of preterm labour at 32 or
34 completed weeks of gestation. At both 32 and 34
completed weeks, amniocentesis is dominated by no
tocolysis when consideringmaternal outcome,neonatal
outcome, or combined outcome, and it is dominated by
tocolysis when considering neonatal outcome or com-
bined outcome. These results are largely insensitive to
assumptions of the model. Only at 36 weeks does the
decision to use amniocentesis become comparable to
the other strategies but, as discussed, at 36 weeks most
clinicaloutcomesare favourableanyway.Amniocentesis
became a popular strategy in the management of
preterm labour at a time when little was known about
the protective effect of antenatal corticosteroids.Thus,
at that time, amniocentesis may have been a very
favourable strategy. Now that the benefits of steroids
are well-established, the relative position of the other
strategies(ie, no tocolysisand tocolysis)compared with
amniocentesishave improved, and amniocentesisis no
longer a favourable strategy2.In this setting, the small
risk of procedure-relatedcomplicationsor the inaccura-
cies of lungmaturitytests result in a poorer outcome for
the infant.In the management of preterm labour at these
ages, more informationis not necessarilybetter, and the
use of amniocentesis in the management of preterm
labourat 32 or 34 weeks shouldbe questioned.
An important characteristicof this model is its sepa-
rate considerationof maternal and neonatal welfare.At
34 weeks and beyond, the results obtained depend on
the priority women place on maternal versus fetal
health. If fetal outcome is considered paramount, then
tocolysis should always be chosen, as there is a small
amount of gain in neonatal outcome with tocolysis,
even in advanced gestations. On the other hand, if
maternal outcome is paramount, then no tocolysis will
always yield the most favourableoutcome. Thus, a fur-
ther contribution of this study is that it demonstrates
that at 34 weeks the optimal management of preterm
labour depends largely on the preferences of women.
This suggests that obstetricians should have an under-
standingof these trade-offs, and attemptto elicitprefer-
ences fromcouplesfacedwith this dilemma.
0 RCOG 1998 Br J Obstet Gynaecol 105, 541-550

9. O P T I O N S F O R T H E M A N A G E M E N T O F P R E T E R M L A B O U R 549
Our model assumes that the principal benefit of
tocolysis derives from a higher proportion of women
havingdeliverydelayed sufficientlyfor steroidsto exert
a protective effect. This assumption underlies our
model, but it is controversial.Many of the randomised
trials of tocolysisdid not use steroidsaspart of the man-
agement scheme’. Perhaps for these reasons, these trials
failedto demonstrateimprovementin neonatal outcome
despite showing a benefit in terms of prolongation of
pregnancy for a short time. Nevertheless, the assump-
tion that tocolysis will lead to improved neonatal out-
comes (if steroids are used) is the basis for the manage-
ment of preterm labour at many centers around the
worldR.It was our intention to test the role of tocolysis
in preterm labour at advanced gestational ages under
this commonly held belief. However, for those who
hold that tocolytics may be effective only for delaying
delivery (but not improvingnewborn outcome),tocoly-
sis is clearlynot arationaloption.
Our decision model did not considerthe use of other
tocolytics,such as magnesium sulphate,in the manage-
ment of pretem labour. While magnesium sulphate is
the most commonly used parenteral tocolytic in the
United States (although not worldwide)’, we chose not
to evaluate this agent in our model because of the rela-
tive lack of data on efficacy (in terms of deliverydelay)
compared with the data available for beta-agonists.
Only two placebo controlled trials of magnesium sul-
phate for tocolysis have been published, and neither
(alone or in combination)suggeststhe drugdelaysdeliv-
ery5095’.Nevertheless, many obstetricians believe that
magnesiumis of similarefficacyto beta-agonists,with a
lowerrisk ofboth minor and majoradversedrugevent’s.
If magnesium sulphate is as efficacious as beta-agonists
with an improved minor and major adverse drug event
profile, this model suggests the use of magnesium sul-
phate as a tocolytic would be an even more favourable
strategyat both 32 and 34 completedweeks of gestation,
compared with no tocolysis. Magnesium sulphate will
not alter the relative disutility of amniocentesis com-
pared with the other strategiesat these ages.
Our base line estimate assumed that tocolysis pre-
sents no fetal risk. Although some data suggest an
increase in Grade I11 and IV intraventricular haemor-
rhage associated with beta-agonist toc~lysis~~,this
potential risk does not alterthe results of our study.This
is because Grade I11 and IV intraventricular haemor-
rhage is rare after 32 completed weeks of gestation. In
fact, our neonatal morbidity estimatesare mainly domi-
nated by respiratory distress syndrome, the most com-
mon type of major morbidity in preterm infants. We
must, therefore, caution readers not to generalise these
findingsto earliergestationalages.
In this analysis we estimated that the baseline risk of
a major adversedrug event with ritodrine, with a maxi-
mal risk of 3% (used in the sensitivityanalysis), from a
comprehensivereview of the randomised trials of rito-
drine for tocolysis.Thismay be an underestimateof the
rate of major adverse drug events in actual clinicalprac-
tice for several reasons5*.Firstly, women included in
randomised trials are subject to strict inclusion and
exclusion criteria; therefore, often only the ‘healthiest’
women with the disorder are represented. Secondly,
women in randomisedtrials are treated for well-defined
conditions. In contrast, the diagnosis of preterm labour
is probably much lessrigid in actualpractice, and sothe
differential efficacy of tocolysis compared with no
tocolysis would be diminished.Thirdly, women in ran-
domised trials often undergo intense monitoring for
early signs of adverse events, something which is
unlikely to occur in everyday practice. Although our
estimates of major adverse drug events are low, some
reports suggest that the rate of pulmonary oedema is
3-41 1000, 10-foldless than our estimates53.We recom-
mend that physicians interpret our model using the fie-
quencyof such complicationsat their own institutions.
In summary, this analysis challenges the practice of
performing amniocentesisto assess fetal lung maturity
and infection in premature labour before a gestational
age 34 weeks and supports the empiric use of ritodrine
for tocolysis at 32 weeks. At later gestational ages the
maternal risk of tocolysis offsets the neonatal benefit
(even with the use of steroids) and therefore clinical
decisions should be based on an individual woman’s
trade-off of maternalversusfetalwellbeing.
Acknowledgements
Dr Asch is the recipient of a Department of Veterans
Affairs Health Services Research and Development
ServiceCareerDevelopmentAward.
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Received 7Januaiy 1997
Returnedfor revision 9July 1997
Accepted 7January 1998
0 RCOG 1998 Br J Obstet Gynaecol 105, 541-550