Editorials ajog.

org

Is an episode of suspected preterm labor that

subsequently leads to a term delivery benign?
Roberto Romero, MD, DMedSci; Offer Erez, MD; Eli Maymon, MD; Percy Pacora, MD

T he most common cause for admission to the hospital of

pregnant women is an episode of suspected preterm
labor,1-4 with a frequency ranging from 9% (234 of 2534) in a
evidence reported in recent years and published in this issue
of the Journal suggests that this conclusion may not be cor-
rect and requires scrutiny.30-32
prospective cohort study of patients with this diagnosis3 to 24% The first evidence that an episode of preterm labor leading
(884 of 3619) based on the database of a large managed care to term delivery may not be entirely benign came from a
organization in the United States (administrative database).5 study by Espinoza et al,31 who reported that the prevalence of
Of patients with suspected preterm labor, approximately small-for-gestational-age (SGA; defined as <10th percentile
one-half deliver at term.3 This information is derived from of birthweight) neonates was significantly higher for those
observational studies,6-9 randomized clinical trials,10-20 and who experienced an episode of suspected preterm labor and
meta-analysis of such trials16,20-26 in which patients were were born at term than for those who were delivered preterm
allocated to placebo or acute intravenous tocolysis. The (21.5% [64 of 298] vs 12.7% [60 of 474]; P ¼ .001; odds ratio,
management of women with suspected preterm labor and the 2.2; 95% confidence interval [CI], 1.3-3.9 after controlling for
decision about the need for hospitalization affect the women confounding variables).31
and their families as well as the health care system. Patients were included in this study if they had an episode
The estimated cost to the US health care system for the of suspected preterm labor (20-36 weeks) defined as increased
treatment of suspected preterm labor exceeded $800 million uterine contractility with intact membranes requiring hos-
in 2005.27,28 It is likely that this cost has increased because pitalization and follow-up until delivery. Two subsequent
there is no evidence that the prevalence of suspected preterm studies confirmed the higher rate of SGA neonates for pa-
labor has decreased,29 and the cost of hospitalization and tients with an episode of preterm labor who subsequently
medical care has increased in the last decade. delivered at term.30,32
There is a widespread belief that if an episode of preterm In a large retrospective study including deliveries occurring
labor resolves spontaneously or after treatment with acute over a period of 20 years (between 1989 and 2009) at the
tocolysis, the major risk is recurrence of an episode of sus- Soroka Medical Center, Ben Gurion University (Beer-Sheva,
pected preterm labor24 and preterm delivery. In contrast, if Israel), the frequency of SGA birth at term in patients who
the patient delivers at term, it is thought that the episode of delivered after an episode of suspected preterm labor was also
preterm labor was benign and sometimes labeled as false higher than in patients who delivered preterm (10.1% [191 of
preterm labor, a designation that appears inappropriate for 1897] vs 5.6% [22 of 393]; P ¼ .005; crude odds ratio, 1.88,
many reasons to be discussed herein. 95% CI, 1.19-2.98).32
It is also thought that there are no long-term effects for the Further confirmation derives from a prospective cohort
fetus, neonate, or infant if birth occurs at term. Accumulating study conducted in Canada, in which patients with an episode
of suspected preterm labor had an odds ratio of 3.9 (95% CI,
1.3e11.4) to deliver an SGA neonate at term.30 Collectively, the
From the Perinatology Research Branch, Program for Perinatal Research
and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver
clinical epidemiological evidence is consistent, indicating that a
National Institute of Child Health and Human Development, National patient with an episode of suspected preterm labor who sub-
Institutes of Health, Bethesda, MD, and Detroit, MI (all authors); the sequently delivers a neonate at term (with or without tocolysis)
Department of Obstetrics and Gynecology, University of Michigan, Ann is at increased risk for delivering an SGA neonate. Why?
Arbor, MI (Dr Romero); the Department of Epidemiology and Biostatistics,
Michigan State University, East Lansing, MI (Dr Romero); the Center for
Molecular Medicine and Genetics, Wayne State University, Detroit, MI Placental vascular lesions in patients with preterm labor
(Dr Romero); and the Department of Obstetrics and Gynecology, Wayne who deliver an SGA neonate at term
State University School of Medicine, Detroit, MI (Drs Erez, Maymon, and To address the mechanisms whereby an episode of preterm
Pacora). labor may be associated with the delivery of an SGA neonate at
Received Dec. 17, 2016; accepted Dec. 19, 2016. term, Espinoza et al examined the frequency of placental his-
The authors report no conflict of interest. tological findings for women with an episode of preterm labor
Corresponding author: Roberto Romero, MD, DMedSci. rr.ajoged@ who delivered an SGA vs an appropriate-for-gestational-age
gmail.com neonate at term: patients who delivered at term had a higher
0002-9378/free frequency of maternal vascular lesions of underperfusion or
Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.ajog.2016.12.030
fetal thrombotic lesions than those who delivered preterm
(29.1% [43 of 148] vs 18.9% [65 of 344]; P ¼ .02).31
Related article, page 157. These results were novel and contrary to expectation
(indeed, placentas are normally not examined in patients who
FEBRUARY 2017 American Journal of Obstetrics & Gynecology 89
Editorials ajog.org

had an episode of preterm delivery and subsequently deliv- neonates delivered at term were relatively smaller than their
ered at term). What was known at the time was that patients peers at birth, compared to the end of the second trimester
who delivered preterm after spontaneous preterm labor or (after stratification by sex, internal z-scores, and birth stan-
preterm premature rupture of the membranes (PROM) had dard scores).56 Moreover, Lampl et al56 were able to show a
an excess rate of vascular lesions of the placenta.33,34 How- significant downward crossing in the percentile of growth,
ever, this was interpreted as a potential etiology for sponta- indicating a disturbance of individual growth trajectories,
neous preterm delivery. The specific lesions, found in excess meaning that the proportion of fetuses experiencing down-
in placentas delivered after spontaneous preterm labor, were ward centile crossing was greatest among those who experi-
diagnosed as maternal decidual vasculopathy (defined as the enced an episode of preterm labor (P ¼ .05).56
presence of failure of physiological transformation of the In a separate study, Lampl et al57 called attention to the
decidual portion of the spiral arteries and organized thrombi complexity of the relationship between fetal growth and
and multiple placental infarcts).35-38 preterm labor. The authors reported that, in early pregnancy,
The proposed operative mechanism of disease responsible acceleration of fetal growth predisposes to an episode of
for preterm labor in these cases is utero-placental ischemia.39 preterm labor.57 This could be interpreted as a mismatch
There are multiple lines of evidence in support of this view, between nutrient supply and fetal demands for growth.58
but perhaps the most compelling is that clamping the uterine These findings were consistent with an earlier work by our
arteries in nonhuman primates to generate an animal model team in which fetal growth acceleration was associated with
of preeclampsia often failed because the animals went into preterm labor and delivery in a subset of patients.59 Collec-
preterm labor.40 tively, this suggests that there is relationship between fetal
Further evidence that vascular lesions are implicated in growth and the initiation of parturition at term60 as well as
preterm labor was strengthened by studies of the placental preterm.
bed (to detect disorders of deep placentation and failure of
physiological transformation of the spiral arteries). Kim Is a fetus exposed to an episode of suspected preterm
et al38 showed that failure of physiological transformation of labor at risk for neurodevelopmental disorders in
the myometrial segment of the spiral arteries is more com- childhood?
mon in patients with an episode of preterm labor or with In this issue of the Journal, Paules et al61 from the Uni-
preterm PROM who delivered preterm than in patients who versity of Zaragoza and Johns Hopkins University report the
delivered at term. results of a prospective cohort study in which the in-
Although originally thought to be typical of preeclampsia vestigators examined the outcome at 2 years of age of infants
and SGA,41-48 it is now well-established that a disorder of who experienced an episode of preterm labor during gesta-
deep placentation with failure of physiological transformation tion but were delivered at or near term. The cohort included
of the spiral arteries (and even atherosis) occurs in the “great 3 groups: (1) women without an episode of preterm labor
obstetrical syndromes,” including preterm labor and preterm who delivered at term (37 weeks; control group) (n ¼ 42);
PROM.49 The reader is referred to reference 34 for a dis- (2) women with an episode of preterm labor who delivered
cussion of why similar vascular lesions may present differ- late preterm (32e36 weeks) (n ¼ 22); and (3) women
ently among the great obstetrical syndromes. who had an episode of preterm labor and delivered at term
Issues of time, severity, widespread involvement, timing, and (n ¼ 23).
additional insults/pathological processes all may play a role.50 The key finding was that infants at the age of 2 years who
Altogether, it seems that the most severe vascular lesions had been born at term after an episode of suspected preterm
would be associated with preterm labor progressing to preterm labor scored lower in the global cognitive index, cognition,
delivery, while less severe lesions may predispose to under- fine and gross motor skills, memory, receptive language,
perfusion of the uterus with increased uterine contractility, speed of processing, and visual motor coordination than
which can be compatible with the continuation of pregnancy, children who were born at term who had not experienced an
but this may come at a price, namely the deceleration of fetal episode of preterm labor (after adjustment for gestational
growth predisposing to the birth of an SGA neonate. age at delivery, birthweight, neonatal sex, cesarean delivery,
and maternal education) (see Table 3 from the article by
Deceleration of fetal growth following an episode of Paules et al61).
preterm labor
The evidence that SGA was more common in patients who What other factors may explain the changes in
delivered after spontaneous preterm labor originally came neurodevelopmental outcomes in babies born at term
from cross-sectional studies.51-55 However, the most after an episode of suspected preterm labor reported by
compelling evidence derives from longitudinal studies in Paules et al?
which fetuses experiencing an episode of suspected preterm One possibility is that the association between an episode
labor were followed with fetal biometry. Lampl et al56,57 re- of suspected preterm labor and adverse outcome is due to
ported a series of seminal observations indicating that, in the presence of intraamniotic inflammation. Recent evi-
patients who presented with an episode of preterm labor, dence indicates that increased preterm uterine contractility,

90 American Journal of Obstetrics & Gynecology FEBRUARY 2017

ajog.org Editorials

even in the absence of the cervical changes (which does not potentially important, and interesting for the understanding
mean the traditional definition of preterm labor62), is of the most common complication requiring admission of
associated with an increased frequency of intraamniotic pregnant women to the hospital. The authors are correct in
inflammation determined by amniocentesis and an elevation calling for replication and further research, given the poten-
in amniotic fluid matrix metalloproteinase-8 concentrations tial clinical implications.
(23 ng/mL). The investigators point out that a larger sample size is
In that cohort study by Kim et al,62 of 132 patients with an desirable and that infants should be evaluated at more than
increased frequency of premature contractions without cervical one single time because this may limit the ability to determine
changes who underwent amniocentesis to rule out the presence the full capabilities of a child examined in a professional
of intraamniotic infection and/or inflammation, 12.1% (16 of setting rather than at home. Also, careful consideration
132) had proven intraamniotic inflammation. Interestingly, should be given to comorbidities and the potential effect of
only 32.8% of these patients (38 of 116) delivered preterm interventions such as tocolysis and steroids.
(P < .001), indicating that not all patients with intraamniotic It is noteworthy that 100% of the children born at term
inflammation progress to spontaneous preterm delivery and after a suspected episode of preterm labor and only 55% of
that some may experience chronic intraamniotic inflammation, those who experienced an episode of preterm labor and were
a condition that has not been recognized until recently and may delivered late preterm received antenatal glucocorticosteroids.
represent a hostile intrauterine environment for the fetus. Recent experimental and observational studies in human
necropsies on preterm babies who died after receiving glu-
Is there evidence that chronic intrauterine inflammation cocorticosteroids in utero showed that these powerful agents
without preterm delivery may be associated with induce dramatic apoptosis in the hippocampal neurons in
neurodevelopmental disorders? animals as well as human fetuses, an effect that is dramatic,
The consequences of chronic exposure to subclinical and its impact is not understood.76,77 This effect is potentially
intraamniotic inflammation have only begun to be recog- important, given the inclination to repeat steroid adminis-
nized. First, in women undergoing midtrimester amniocen- tration during fetal life at the time of rapid neuronal/glial
tesis and who have intraamniotic inflammation determined development.
by matrix metalloproteinase-8 or interleukin-6, a fraction Another factor that may be important is the potential effect
delivered at term.63 Although these processes have been of tocolytic agents. For example, the administration of ter-
largely overlooked, there is now evidence that these infants butaline has been implicated in the genesis of autism in
are at increased risk for motor and cognitive disabilities.62,64. infants exposed because of an episode of preterm labor.78
The association between intraamniotic inflammation and Although this has been a controversial subject that has not
possibly neonatal brain injury has been demonstrated in an gained popularity, it is prudent to remember that birth is
animal model in which intrauterine inflammation was induced associated with a dramatic change in the g-aminobutyric acid
by injection of low-dose lipopolysaccharides. At this dose, secretion neurotransmitters, and that this process may be
preterm labor did not occur and the animals delivered at term. susceptible to endocrine and paracrine regulation during
However, the neonates exposed to endotoxin in utero had parturition.79,80
severe neuroinflammation detected with positron emission
tomography and microglial activation, which was proven by Should the findings lead to a change in clinical
histological examination of the brain after euthanasia. More- management?
over, the neonates showed evidence of severe motor disorder.65 The report of Paules et al61 is important and hence has
Similar observations have been made by Elovitz et al.66 been highlighted in the pages of the Journal. However, we
The totality of the evidence suggests the following: (1) agree with the authors that no change in the clinical
patients with an episode of suspected preterm labor may have management is required other than being prudent in the
subclinical intraamniotic inflammation of unknown etiology, way we counsel patients about long-term prognosis after
which has recently been attributed to danger signals67-69; (2) an episode of suspected preterm labor and delivery at
some of these patients do not progress to preterm delivery term. We believe that it is appropriate to counsel patients
and may enter a state of chronic intraamniotic inflammation that they may be at risk for delivering an SGA neonate
to which the fetus may be exposed; (3) experimental evidence based on the 3 epidemiological studies30-32 reporting
in animal models shows that this process can lead to fetal consistent results; however, any counseling about the risk
neuroinflammation and damage65; and (4) interestingly, this of neurodevelopmental disorders must await replication of
process can be subject to treatment with targeted nanodevices these findings. It is important to note that the absolute
(ie, dendrimers) if detected early.70-75 magnitude of risk is small and most of the infants would
be unaffected.
Are infants born at term after an episode of preterm labor There is a need to refine the nomenclature for suspected
at risk for neurodevelopmental disorders? preterm labor, threatened preterm labor, and true vs false
The findings of this study published in this issue of the preterm labor, which have been used in the literature, not
Journal by Dr Cristina Paules and her associates61 are novel, always with clarity.

FEBRUARY 2017 American Journal of Obstetrics & Gynecology 91

Editorials ajog.org

Are there biomarkers that identify patients with 3. McPheeters ML, Miller WC, Hartmann KE, et al. The epidemiology of
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syndrome,100 twin-to-twin transfusion syndrome,101 etc. A prospective randomized comparison of oral terbutaline and magnesium
During the course of prospective studies, we observed that oxide for the maintenance of tocolysis. Am J Obstet Gynecol 1990;163:
some patients with a high concentration of endoglin (an anti- 879-82.
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