CONTEMPORARY
January 2008
OB/GYN
䊛
Translating science into sound clinical practice
The Delivery
Probability
Profile:
A new tool to
predict PTD?
By James Kurtzman, MD
Vol. 53, No. 1
Tina Clark
The Delivery Probability Profile:
A new tool to predict PTD?
By James Kurtzman, MD
N
o one questions the fact that preterm
delivery (PTD) and the resulting
prematurity contribute to perinatal
complications and mortality, raising health-care costs
along the way.1 Unfortunately, despite technologic
advances in our field, we have yet to decrease the
frequency of this life-threatening problem, as the
statistics bear out: The incidence of preterm birth has
increased 14.4% over the past 12 years in the United
States and is now the leading cause of infant death.2,3
Using traditional risk factors to screen for PTD is
clearly inadequate. In fact, such screening fails to identify up to 70% of patients who delivered at less than 37
weeks’ gestation.4 Similarly, screening for demographic, social, and medical risk factors for PTD has
had limited effectiveness.5,6 Complicating matters even
further, in approximately 80% of cases in which signs
and symptoms of preterm labor are present, PTD does
not occur.4
On a more positive note, newer biologic markers for
PTD, including fetal fibronectin (fFN) in cervicovaginal secretions and shortened cervical length (CL),
as determined by ultrasound, have been more closely
DR. KURTZMAN is Associate Professor, Department of Obstetrics
and Gynecology, Division of Maternal-Fetal Medicine, University of
California, Irvine Medical Center, Irvine, CA.
linked to PTD.7 With that in mind, our goal here is to
introduce the concept of a multifactorial delivery
probability profile (DPP) that has the potential to
predict PTD using these newer markers.
The DPP incorporates data on fFN, CL, and a
history of PTD to generate standard pregnancy
survival curves. Theoretically, when a woman is
screened for these predictors of PTD, she can be
matched with a corresponding DPP curve, providing a
clear illustration and “profile” of the risk of PTD at
different times in her pregnancy. This information
might also help in developing patient-specific strategies to help prevent prematurity.
Setting the groundwork
for the Delivery Probability Profile
In the landmark Preterm Prediction Study, sponsored
by the National Institute of Child Health and Human
Development (NICHD), almost 3,000 asymptomatic
gravid women were screened at 22 to 24 weeks’ gestation for possible risk factors for PTD. Their pregnancy
outcomes were used to determine the relative risk of
PTD for each risk factor (Table 1).7 Interestingly,
substance abuse, smoking, no prenatal care, maternal
age younger than 17 or older than 35 years, and low
socioeconomic status did not correlate with PTD.
However, a history of PTD, fFN, and shortened CL
Can a “Delivery Probability Profile” help ob/gyns determine who’s most
likely to deliver prematurely? One expert in the field examines the evidence.
were by far the strongest predictors for PTD. Other Alterations in sonographic cervical morphology
risk factors associated with PTD (but less predictive such as funneling and dynamic change (or real-time
than fFN or CL) included vaginal bleeding, bacterial cervical shortening) have also been associated with
vaginosis, body mass index below 19.8, African-Amer- PTD.13,15
ican race, and uterine contractions.7 The combination
of fFN and CL in nulliparous patients and the combi- Generating the DPP
nation of fFN, CL, and obstetric history in multiparous Fetal fibronectin, cervical ultrasound, obstetric
patients presently comprise the strongest basis for history, and pregnancy outcome data from the PrePTD prediction.8
term Prediction Study were used to create the DPP
Fetal fibronectin. Several studies have confirmed
curves presented here. Data on the risk of spontaneous
that the presence of fFN in cervicovaginal secretions PTD at less than 32, 35, and 37 weeks’ gestation in
between 22 and 34 weeks’ gestation is associated with patients with different combinations of risk factors
PTD in symptomatic4,9 and asymptomatic7,10-12 were plotted to create standard pregnancy “survival
women. In the Preterm Prediction Study, patients with curves” (or “DPP curves”) for both nulliparous and
a positive fFN at 24 weeks’ were 59.2 times more likely multiparous women (Figures 1 and 2, respectively).
to deliver within 4 weeks, and
fFN identified nearly two thirds
TABLE 1
of patients destined to deliver in
this time period.10 The relative
Risk factors for preterm birth
risk for spontaneous PTD when
Delivery at
Delivery at
Delivery at
fFN was present was greater than
<
32
weeks
<
35
weeks
<
37 weeks
with any other risk factor at each
RR
RR
RR
point in time during pregnancy
Characteristic
(95% CI)
(95% CI)
(95% CI)
(Table 1).7 Additionally, though
a history of prior PTD was an
Presence of fFN
14.1 (9.3, 21.4)
6.7 (4.9, 9.2)
3.3 (2.5, 4.2)
independent risk factor for
at
22–24
weeks
recurrent PTD, the presence of
fFN was three times more likely
CL by ultrasound at 22–24 weeks
to predict recurring PTD than
11
< 25 mm
7.7 (4.5, 13.4)
6.5 (4.5, 9.3)
3.5 (2.7, 4.6)
history alone.
Cervical ultrasound. Simi26-35 mm
0.9 (0.4, 1.9)
1.2 (0.8, 1.8)
1.3 (2.7, 4.6)
larly, there is now abundant
evidence to show that cervix
History of PTD
7.1 (3.8, 13.2)
6.4 (4.4, 9.2)
2.7 (2.1, 3.4)
shortening increases the risk of
preterm delivery.7,13,14 In the
Vaginal bleeding
2.7 (1.4, 5.1)
1.9 (1.2, 3.0)
1.5 (1.1, 2.1)
Preterm Prediction Study,
cervical shortening (≥ 25 mm)
Bacterial vaginosis
2.7 (1.6, 4.6)
1.4 (0.9, 2.0)
1.3 (0.98, 1.6)
was found to be the second
strongest predictor of PTD
RR—relative risk; CI—confidence interval; CL—cervical length
(Table 1); the shorter the
length, the higher the risk.7,14
PREDICTING PTD
Percent remaining pregnant
FIGURE 1
100
100
Neg. fFN,
nl CL
90
90
Pos. fFN,
nl CL
80
80
Neg. fFN, nl
CL < 25 mm
70
70
60
60
50
50
40
40
Pos. fFN+CL
< 25 mm
30
24
32
35
37
30
40
Weeks
7
*Source: Goldenberg RL, et al.
fFN—fetal fibronection; nl—normal; CL—cervical length
Delivery Probability Profiles for nulliparous women*
FIGURE 2
patients were still pregnant at
35 weeks.
When fFN was positive and
CL was 25 mm or less, the
increase in risk was dramatically more than additive, as is
readily apparent from the
DPP curves generated from
this population (Figure 1). As
early as 32 weeks’ gestation,
approximately one third of
these patients had already
delivered. At 35 weeks, about
50% fewer women remained
pregnant compared to those
with a single positive factor,
and nearly two thirds of these
women delivered before 37
weeks’ gestation.
DPPs for
patients.
multiparous
Percent remaining pregnant
Outcome data
based on pregnancy history
All 3 negative
90
90
along with fFN status and CL at
CL < 25 mm
Hx PTD
24 weeks’ gestation from the
80
80
Pos. fFN
Preterm Prediction Study7
70
70
were again plotted to generate
CL <25 mm
+Hx PTD
pregnancy survival curves for
60
60
Pos. fFN+CL
each risk factor alone and in
< 25 mm
50
50
combination (Figure 2). When
Pos. fFN+Hx
PTD
all three factors were reassuring
40
40
All 3 positive
(negative fFN, CL >35 mm, no
30
30
prior PTD), over 95% of multi24
32
35
37
40
parous women remained
Weeks
pregnant at 32 and 35 weeks’
*Source: Goldenberg RL, et al. 7
gestation, and approximately
fFN—fetal fibronectin; CL—cervical length; Hx PTD—history of preterm delivery
92% of women were still pregnant at 37 weeks’ gestation.
Delivery Probability Profiles for multiparous women*
As
with
nulliparous
women, the presence of
DPPs for nulliparous patients. Outcome data
multiple risk factors resulted in more than additive
based on fFN status and CL at 24 weeks’ gestation risk. When two risk factors were present, the curves
from the Preterm Prediction Study7 were plotted to diverged sharply beginning at 32 weeks’ gestation
generate DPPs for each risk factor alone and in combi- compared with curves showing PTD risk from any
nation (Figure 1). The risk for delivery before 37 single factor. This significantly increased risk of
weeks’ gestation was very low when fFN was negative PTD is again readily apparent in the DPP curves
and CL was above 35 mm at 24 weeks’ gestation, with derived from multiparous patients shown here.
approximately 95% of these women remaining preg- When all three risk factors were present, the risk for
nant at 37 weeks’ gestation. When only one factor was PTD was exponentially greater than with any single
present, a slightly higher percentage of women deliv- risk factor alone or any two risk factors together,
ered prematurely (between 32 and 37 weeks’ with slightly over half of women delivering by 32
gestation); however, about 90% (or more) of these weeks’ gestation (Figure 2).
100
100
PREDICTING PTD
In the final analysis
The DPP graphically depicts the estimated probability
of delivery at several points during pregnancy based
on key predisposing risk factors including fFN, sonographic cervical shortening, and history of PTD.
Although the profiles of risk for PTD presented here
were created using data published in the Preterm
Prediction Study,7 these profiles can be potentially
generated from any given outcome study in which
uniform assessment was performed at a uniform
gestational age. A unique profile exists for each
different combination of risk factors. These profiles
may also be generated from outcome studies in symptomatic patients.
THEORETICALLY, when a woman is assessed at 24
weeks’ gestation for PTD risk factors (fFN, CL, and
delivery history), she can be matched with a corresponding DPP. Her comparative risk for PTD over
time can be illustrated, and a specific example of this is
shown in Figure 3. These DPP curves may thus be used
to visually assist both clinicians and patients to understand the risk of PTD throughout gestation and
facilitate patient profile-specific plans of care.
Dr. Iams and colleagues conducted a study using
data from the Preterm Prediction Study to retrospectively evaluate the value of fFN and short CL in
predicting PTD.16 They included in their analysis
both nulliparous and multiparous patients without a
history of PTD. The sensitivities for predicting PTD
for a single risk factor of a positive fFN or CL of 25
mm or less alone were relatively low (23.4% and
39.1%, respectively), although the negative predictive
values were high for each factor alone (98%). When
both risk factors were present, the sensitivity for
predicting PTD remained low, however, the positive
predictive value for birth at 35 weeks’ or less gestation
was 50%, consistent with the DPP curves generated
here based on the Preterm Prediction Study.
Although the authors point out that many low-risk
patients who delivered preterm could not be identified, one of two women with both risk factors
nonetheless delivered preterm, and most had at least
one positive risk factor.
OBVIOUSLY, additional prospective studies are
needed to validate the DPP model for predicting
PTD. Using raw data from the Preterm Prediction
Study,7 more precise probability profiles could be
generated to more accurately estimate the risk of PTD
at each week of gestation following screening. The
generation of DPP curves using studies in symptomatic patients is also needed. In both asymptomatic
and symptomatic patients, these DPP curves may be
used to help delineate when patients are at highest
risk for PTD across gestation, identifying optimal
candidates for studies assessing the efficacy of
prophylactic therapy (e.g., 17OH-progesterone,
bedrest) and treatment interventions (e.g., tocolysis).
The inclusion of patients who are, in fact, at minimal
risk for PTD may, in part, explain why previous
studies involving tocolytic therapy for treatment of
preterm labor have not shown any significant
improvement in outcomes. Accordingly, when
patient selection is optimized using the newer predictive markers of PTD, it may be determined that
certain prophylactic measures and therapeutic interventions are more effective in preventing PTD than
previously demonstrated. 䊴
REFERENCES
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Institute of Child Health and Human Development Maternal-Fetal
Case study
Percent remaining pregnant
A patient with a prior PTD at 32
weeks’ gesta tion under goes fFN
and CL screening at 24 weeks’
gestation. Her CL is reassuring at
34 mm but her fFN is positive. Her
baseline risk for PTD, presuming
her fFN and CL screens had been
negative, is shown in the top
curve. In this case, her curve has
shifted down ward significantly
due to the positive fFN, despite
having a reassuring CL
(specifically, > 25 mm). Her risk of
PTD at < 32 weeks’ gestation is
nearly 25%, and her risk of PTD
< 35 weeks’ ges tation is
approximately 40% (over four
times her baseline risk).
FIGURE 3
100
100
90
90
Prior PTD
only
80
80
70
70
60
60
Prior PTD+
positive fFn+
CL > 25 mm
50
50
40
40
30
30
24
32
35
37
40
Weeks
7
Source: Goldenberg RL, et al.
PTD—preterm delivery; fFN—fetal fibronectin; CL—cervical length
Delivery Probability Profile
Medicine Units Network. Am J Obstet Gynecol. 1998;178:1035-1040.
Network. N Engl J Med. 1996;334:567-572.
12. Nageotte MP, Casal D, Senyei AE. Fetal fibronectin in patients at
15. Kurtzman JT, Jenkins SM, Brewster WR. Dynamic cervical change
increased risk for premature birth. Am J Obstet Gynecol. 1994;170(1
during real-time ultrasound: prospective characterization and
Pt 1):20-25.
comparison in patients with and without symptoms of preterm labor.
13. Guzman ER, Walters C, Ananth CV, et al. A comparison of sono-
Ultrasound Obstet Gynecol. 2004;23:574-578.
graphic cervical parameters in predicting spontaneous preterm birth
16. Iams JD, Goldenberg RL, Mercer BM, et al. The preterm prediction
in high-risk singleton gestations. Ultrasound Obstet Gynecol.
study: can low-risk women destined for spontaneous preterm birth be
2001;18:204-210.
identified? Am J Obstet Gynecol. 2001;184:652-655.
14. Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix
and the risk of spontaneous premature delivery. National Institute of
Dr. Kurtzman is on the Speakers Bureau for Cytyc
Biomedical.
Child Health and Human Development Maternal Fetal Medicine Unit
© Reprinted from CONTEMPORARY OB/GYN, January 2008
Printed in U.S.A.