Editorials
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
prospective cohort study of patients with this diagnosis3 to 24%
(884 of 3619) based on the database of a large managed care
organization in the United States (administrative database).5
Of patients with suspected preterm labor, approximately
one-half deliver at term.3 This information is derived from
observational studies,6-9 randomized clinical trials,10-20 and
meta-analysis of such trials16,20-26 in which patients were
allocated to placebo or acute intravenous tocolysis. The
management of women with suspected preterm labor and the
decision about the need for hospitalization affect the women
and their families as well as the health care system.
The estimated cost to the US health care system for the
treatment of suspected preterm labor exceeded $800 million
in 2005.27,28 It is likely that this cost has increased because
there is no evidence that the prevalence of suspected preterm
labor has decreased,29 and the cost of hospitalization and
medical care has increased in the last decade.
There is a widespread belief that if an episode of preterm
labor resolves spontaneously or after treatment with acute
tocolysis, the major risk is recurrence of an episode of sus-
pected preterm labor24 and preterm delivery. In contrast, if
the patient delivers at term, it is thought that the episode of
preterm labor was benign and sometimes labeled as false
preterm labor, a designation that appears inappropriate for
many reasons to be discussed herein.
It is also thought that there are no long-term effects for the
fetus, neonate, or infant if birth occurs at term. Accumulating
From the Perinatology Research Branch, Program for Perinatal Research
and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver
National Institute of Child Health and Human Development, National
Institutes of Health, Bethesda, MD, and Detroit, MI (all authors); the
Department of Obstetrics and Gynecology, University of Michigan, Ann
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
(Dr Romero); and the Department of Obstetrics and Gynecology, Wayne
State University School of Medicine, Detroit, MI (Drs Erez, Maymon, and
Pacora).
Received Dec. 17, 2016; accepted Dec. 19, 2016.
The authors report no conflict of interest.
Corresponding author: Roberto Romero, MD, DMedSci. rr.ajoged@
gmail.com
0002-9378/free
Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.ajog.2016.12.030
Related article, page 157.
ajog.
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
The first evidence that an episode of preterm labor leading
to term delivery may not be entirely benign came from a
study by Espinoza et al,31 who reported that the prevalence of
small-for-gestational-age (SGA; defined as <10th percentile
of birthweight) neonates was significantly higher for those
who experienced an episode of suspected preterm labor and
were born at term than for those who were delivered preterm
(21.5% [64 of 298] vs 12.7% [60 of 474]; P ¼ .001; odds ratio,
2.2; 95% confidence interval [CI], 1.3-3.9 after controlling for
confounding variables).31
Patients were included in this study if they had an episode
of suspected preterm labor (20-36 weeks) defined as increased
uterine contractility with intact membranes requiring hos-
pitalization and follow-up until delivery. Two subsequent
studies confirmed the higher rate of SGA neonates for pa-
tients with an episode of preterm labor who subsequently
delivered at term.30,32
In a large retrospective study including deliveries occurring
over a period of 20 years (between 1989 and 2009) at the
Soroka Medical Center, Ben Gurion University (Beer-Sheva,
Israel), the frequency of SGA birth at term in patients who
delivered after an episode of suspected preterm labor was also
higher than in patients who delivered preterm (10.1% [191 of
1897] vs 5.6% [22 of 393]; P ¼ .005; crude odds ratio, 1.88,
95% CI, 1.19-2.98).32
Further confirmation derives from a prospective cohort
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
clinical epidemiological evidence is consistent, indicating that a
patient with an episode of suspected preterm labor who sub-
sequently delivers a neonate at term (with or without tocolysis)
is at increased risk for delivering an SGA neonate. Why?
Placental vascular lesions in patients with preterm labor
who deliver an SGA neonate at term
To address the mechanisms whereby an episode of preterm
labor may be associated with the delivery of an SGA neonate at
term, Espinoza et al examined the frequency of placental his-
tological findings for women with an episode of preterm labor
who delivered an SGA vs an appropriate-for-gestational-age
neonate at term: patients who delivered at term had a higher
frequency of maternal vascular lesions of underperfusion or
fetal thrombotic lesions than those who delivered preterm
(29.1% [43 of 148] vs 18.9% [65 of 344]; P ¼ .02).31
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
had an episode of preterm delivery and subsequently deliv-
ered at term). What was known at the time was that patients
who delivered preterm after spontaneous preterm labor or
preterm premature rupture of the membranes (PROM) had
an excess rate of vascular lesions of the placenta.33,34 How-
ever, this was interpreted as a potential etiology for sponta-
neous preterm delivery. The specific lesions, found in excess
in placentas delivered after spontaneous preterm labor, were
diagnosed as maternal decidual vasculopathy (defined as the
presence of failure of physiological transformation of the
decidual portion of the spiral arteries and organized thrombi
and multiple placental infarcts).35-38
The proposed operative mechanism of disease responsible
for preterm labor in these cases is utero-placental ischemia.39
There are multiple lines of evidence in support of this view,
but perhaps the most compelling is that clamping the uterine
arteries in nonhuman primates to generate an animal model
of preeclampsia often failed because the animals went into
preterm labor.40
Further evidence that vascular lesions are implicated in
preterm labor was strengthened by studies of the placental
bed (to detect disorders of deep placentation and failure of
physiological transformation of the spiral arteries). Kim
et al38 showed that failure of physiological transformation of
the myometrial segment of the spiral arteries is more com-
mon in patients with an episode of preterm labor or with
preterm PROM who delivered preterm than in patients who
delivered at term.
Although originally thought to be typical of preeclampsia
and SGA,41-48 it is now well-established that a disorder of
deep placentation with failure of physiological transformation
of the spiral arteries (and even atherosis) occurs in the “great
obstetrical syndromes,” including preterm labor and preterm
PROM.49 The reader is referred to reference 34 for a dis-
cussion of why similar vascular lesions may present differ-
ently among the great obstetrical syndromes.
Issues of time, severity, widespread involvement, timing, and
additional insults/pathological processes all may play a role.50
Altogether, it seems that the most severe vascular lesions
would be associated with preterm labor progressing to preterm
delivery, while less severe lesions may predispose to under-
perfusion of the uterus with increased uterine contractility,
which can be compatible with the continuation of pregnancy,
but this may come at a price, namely the deceleration of fetal
growth predisposing to the birth of an SGA neonate.
Deceleration of fetal growth following an episode of
preterm labor
The evidence that SGA was more common in patients who
delivered after spontaneous preterm labor originally came
from cross-sectional studies.51-55 However, the most
compelling evidence derives from longitudinal studies in
which fetuses experiencing an episode of suspected preterm
labor were followed with fetal biometry. Lampl et al56,57 re-
ported a series of seminal observations indicating that, in
patients who presented with an episode of preterm labor,
90 American Journal of Obstetrics & Gynecology FEBRUARY 2017
ajog.org
neonates delivered at term were relatively smaller than their
peers at birth, compared to the end of the second trimester
(after stratification by sex, internal z-scores, and birth stan-
dard scores).56 Moreover, Lampl et al56 were able to show a
significant downward crossing in the percentile of growth,
indicating a disturbance of individual growth trajectories,
meaning that the proportion of fetuses experiencing down-
ward centile crossing was greatest among those who experi-
enced an episode of preterm labor (P ¼ .05).56
In a separate study, Lampl et al57 called attention to the
complexity of the relationship between fetal growth and
preterm labor. The authors reported that, in early pregnancy,
acceleration of fetal growth predisposes to an episode of
preterm labor.57 This could be interpreted as a mismatch
between nutrient supply and fetal demands for growth.58
These findings were consistent with an earlier work by our
team in which fetal growth acceleration was associated with
preterm labor and delivery in a subset of patients.59 Collec-
tively, this suggests that there is relationship between fetal
growth and the initiation of parturition at term60 as well as
preterm.
Is a fetus exposed to an episode of suspected preterm
labor at risk for neurodevelopmental disorders in
childhood?
In this issue of the Journal, Paules et al61 from the Uni-
versity of Zaragoza and Johns Hopkins University report the
results of a prospective cohort study in which the in-
vestigators examined the outcome at 2 years of age of infants
who experienced an episode of preterm labor during gesta-
tion but were delivered at or near term. The cohort included
3 groups: (1) women without an episode of preterm labor
who delivered at term (37 weeks; control group) (n ¼ 42);
(2) women with an episode of preterm labor who delivered
late preterm (32e36 weeks) (n ¼ 22); and (3) women
who had an episode of preterm labor and delivered at term
(n ¼ 23).
The key finding was that infants at the age of 2 years who
had been born at term after an episode of suspected preterm
labor scored lower in the global cognitive index, cognition,
fine and gross motor skills, memory, receptive language,
speed of processing, and visual motor coordination than
children who were born at term who had not experienced an
episode of preterm labor (after adjustment for gestational
age at delivery, birthweight, neonatal sex, cesarean delivery,
and maternal education) (see Table 3 from the article by
Paules et al61).
What other factors may explain the changes in
neurodevelopmental outcomes in babies born at term
after an episode of suspected preterm labor reported by
Paules et al?
One possibility is that the association between an episode
of suspected preterm labor and adverse outcome is due to
the presence of intraamniotic inflammation. Recent evi-
dence indicates that increased preterm uterine contractility,
ajog.org
even in the absence of the cervical changes (which does not
mean the traditional definition of preterm labor62), is
associated with an increased frequency of intraamniotic
inflammation determined by amniocentesis and an elevation
in amniotic fluid matrix metalloproteinase-8 concentrations
(23 ng/mL).
In that cohort study by Kim et al,62 of 132 patients with an
increased frequency of premature contractions without cervical
changes who underwent amniocentesis to rule out the presence
of intraamniotic infection and/or inflammation, 12.1% (16 of
132) had proven intraamniotic inflammation. Interestingly,
only 32.8% of these patients (38 of 116) delivered preterm
(P < .001), indicating that not all patients with intraamniotic
inflammation progress to spontaneous preterm delivery and
that some may experience chronic intraamniotic inflammation,
a condition that has not been recognized until recently and may
represent a hostile intrauterine environment for the fetus.
Is there evidence that chronic intrauterine inflammation
without preterm delivery may be associated with
neurodevelopmental disorders?
The consequences of chronic exposure to subclinical
intraamniotic inflammation have only begun to be recog-
nized. First, in women undergoing midtrimester amniocen-
tesis and who have intraamniotic inflammation determined
by matrix metalloproteinase-8 or interleukin-6, a fraction
delivered at term.63 Although these processes have been
largely overlooked, there is now evidence that these infants
are at increased risk for motor and cognitive disabilities.62,64.
The association between intraamniotic inflammation and
possibly neonatal brain injury has been demonstrated in an
animal model in which intrauterine inflammation was induced
by injection of low-dose lipopolysaccharides. At this dose,
preterm labor did not occur and the animals delivered at term.
However, the neonates exposed to endotoxin in utero had
severe neuroinflammation detected with positron emission
tomography and microglial activation, which was proven by
histological examination of the brain after euthanasia. More-
over, the neonates showed evidence of severe motor disorder.65
Similar observations have been made by Elovitz et al.66
The totality of the evidence suggests the following: (1)
patients with an episode of suspected preterm labor may have
subclinical intraamniotic inflammation of unknown etiology,
which has recently been attributed to danger signals67-69; (2)
some of these patients do not progress to preterm delivery
and may enter a state of chronic intraamniotic inflammation
to which the fetus may be exposed; (3) experimental evidence
in animal models shows that this process can lead to fetal
neuroinflammation and damage65; and (4) interestingly, this
process can be subject to treatment with targeted nanodevices
(ie, dendrimers) if detected early.70-75
Are infants born at term after an episode of preterm labor
at risk for neurodevelopmental disorders?
The findings of this study published in this issue of the
Journal by Dr Cristina Paules and her associates61 are novel,
Editorials
potentially important, and interesting for the understanding
of the most common complication requiring admission of
pregnant women to the hospital. The authors are correct in
calling for replication and further research, given the poten-
tial clinical implications.
The investigators point out that a larger sample size is
desirable and that infants should be evaluated at more than
one single time because this may limit the ability to determine
the full capabilities of a child examined in a professional
setting rather than at home. Also, careful consideration
should be given to comorbidities and the potential effect of
interventions such as tocolysis and steroids.
It is noteworthy that 100% of the children born at term
after a suspected episode of preterm labor and only 55% of
those who experienced an episode of preterm labor and were
delivered late preterm received antenatal glucocorticosteroids.
Recent experimental and observational studies in human
necropsies on preterm babies who died after receiving glu-
cocorticosteroids in utero showed that these powerful agents
induce dramatic apoptosis in the hippocampal neurons in
animals as well as human fetuses, an effect that is dramatic,
and its impact is not understood.76,77 This effect is potentially
important, given the inclination to repeat steroid adminis-
tration during fetal life at the time of rapid neuronal/glial
development.
Another factor that may be important is the potential effect
of tocolytic agents. For example, the administration of ter-
butaline has been implicated in the genesis of autism in
infants exposed because of an episode of preterm labor.78
Although this has been a controversial subject that has not
gained popularity, it is prudent to remember that birth is
associated with a dramatic change in the g-aminobutyric acid
secretion neurotransmitters, and that this process may be
susceptible to endocrine and paracrine regulation during
parturition.79,80
Should the findings lead to a change in clinical
management?
The report of Paules et al61 is important and hence has
been highlighted in the pages of the Journal. However, we
agree with the authors that no change in the clinical
management is required other than being prudent in the
way we counsel patients about long-term prognosis after
an episode of suspected preterm labor and delivery at
term. We believe that it is appropriate to counsel patients
that they may be at risk for delivering an SGA neonate
based on the 3 epidemiological studies30-32 reporting
consistent results; however, any counseling about the risk
of neurodevelopmental disorders must await replication of
these findings. It is important to note that the absolute
magnitude of risk is small and most of the infants would
be unaffected.
There is a need to refine the nomenclature for suspected
preterm labor, threatened preterm labor, and true vs false
preterm labor, which have been used in the literature, not
always with clarity.
FEBRUARY 2017 American Journal of Obstetrics & Gynecology 91
Editorials
Are there biomarkers that identify patients with
suspected preterm labor and maternal vascular lesions
who subsequently deliver SGA neonates?
The fundamental mechanism of disease responsible for the
excess rate of vascular lesions in the placenta of patients with
spontaneous preterm labor has been unknown. However, hints
have begun to emerge. The balance of angiogenic and anti-
angiogenic factors appears to be key in the establishment of a
successful and functional utero-placental circulation.81-86
A deficiency in angiogenic factors was first implicated in
the pathogenesis of preeclampsia87-95 and subsequently
discovered to play a role in SGA/fetal growth restriction,93,96
fetal death,97,98 spontaneous preterm labor,99 Ballantyne
syndrome,100 twin-to-twin transfusion syndrome,101 etc.
During the course of prospective studies, we observed that
some patients with a high concentration of endoglin (an anti-
angiogenic factor) had spontaneous preterm delivery.99 This
anti-angiogenic factor is higher in patients destined to deliver
an SGA neonate.93 Moreover, among women with preterm
labor who delivered preterm, those with placental maternal
vascular lesions of underperfusion, but not inflammatory
lesions, had a higher median maternal plasma endoglin
concentration 5-10 weeks prior to the clinical presentation of
preterm labor that led to preterm birth.99
Recently, a case-cohort study identified that the ratio of
placental growth factor to soluble vascular endothelial growth
factor receptor-1 below the 2.5 centile is a biomarker for
maternal vascular lesions of underperfusion, and that this
biomarker is abnormal not only in women who subsequently
develop preeclampsia and an SGA neonate, but also in those
who subsequently develop preterm labor with maternal
vascular lesions of underperfusion.85 Therefore, this ratio
could be used as a biomarker in patients admitted with an
episode of suspected preterm labor.
Whether this biomarker can identify women with sus-
pected preterm labor who develop an SGA neonate remains
to be determined. If this proves to be the case, then thera-
peutic interventions and intense surveillance may be war-
ranted to prevent adverse pregnancy outcomes, even at term.
The emerging picture is that biomarkers and improved un-
derstanding of the mechanisms of disease responsible for the
great obstetrical syndromes are beginning to yield benefits in
the prevention of obstetrical disorders.
ACKNOWLEDGMENT
We acknowledge Agustin Conde-Agudelo, MD, PhD, and Bogdan
Panaitescu, MD, PhD. - 20. van Vliet EO, Nijman TA, Schuit E, et al. Nifedipine versus atosiban for
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60. Deter RL, Lee W, Sangi-Haghpeykar H, Tarca AL, Yeo L, Romero R.
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61. Paules C, Pueyo V, Martí E, et al. Threatened preterm labor is a risk
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62. Kim SM, Romero R, Lee J, et al. The frequency and clinical significance
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63. Bujold E, Laforest G, Vachon-Marceau C, Duperron L, Hassan S,
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64. Soucy-Giguere L, Vachon-Marceau C, Tétu A, Giguère Y, Marc I,
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in the midtrimester and the subsequent development of abnormal
gross motor skills in infants born either term or preterm. Abstract 115.
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FEBRUARY 2017 American Journal of Obstetrics & Gynecology 93
Editorials
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66. Elovitz MA, Brown AG, Breen K, Anton L, Maubert M, Burd I. Intra-
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67. Gomez-Lopez N, Romero R, Xu Y, et al. A role for the inflammasome
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68. Plazyo O, Romero R, Unkel R, et al. HMGB1 induces an inflammatory
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69. Romero R, Xu Y, Plazyo O, et al. A role for the inflammasome in
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70. Bosnjakovic A, Mishra MK, Han HJ, Romero R, Kannan RM.
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71. Dai H, Navath RS, Balakrishnan B, et al. Intrinsic targeting of inflam-
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72. Kannan S, Dai H, Navath RS, et al. Dendrimer-based postnatal
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73. Lesniak WG, Mishra MK, Jyoti A, et al. Biodistribution of fluorescently
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74. Menjoge AR, Rinderknecht AL, Navath RS, et al. Transfer of PAMAM
dendrimers across human placenta: prospects of its use as drug carrier
during pregnancy. J Control Release 2011;150:326-38.
75. Navath RS, Menjoge AR, Dai H, Romero R, Kannan S, Kannan RM.
Injectable PAMAM dendrimer-PEG hydrogels for the treatment of genital
infections: formulation and in vitro and in vivo evaluation. Mol Pharmaceut
2011;8:1209-23.
76. Noorlander CW, Tijsseling D, Hessel EV, et al. Antenatal glucocorti-
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77. Tijsseling D, Wijnberger LD, Derks JB, et al. Effects of antenatal
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78. Elliott JP, Morrison JC, Chauhan SP. A critical appraisal of the po-
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79. Ben-Ari Y. Is birth a critical period in the pathogenesis of autism
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80. Tyzio R, Nardou R, Ferrari DC, et al. Oxytocin-mediated GABA in-
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81. Crispi F, Llurba E, Dominguez C, Martin-Gallan P, Cabero L,
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82. Petzold K, Jank A, Faber R, Stepan H. Relation between maternal
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83. Redman CW, Staff AC. Preeclampsia, biomarkers, syncytiotropho-
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84. Woelkers DA, Ghashghaei R, Klisser K, Archer T. PP143. Relation-
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85. Kim YM, Chaemsaithong P, Romero R, S, et al. Placental lesions
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86. Korzeniewski SJ, Romero R, Chaiworapongsa T, et al. Maternal
plasma angiogenic index-1 (placental growth factor/soluble vascular
endothelial growth factor receptor-1) is a biomarker for the burden of
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87. Bujold E, Romero R, Chaiworapongsa T, et al. Evidence supporting
that the excess of the sVEGFR-1 concentration in maternal plasma in
preeclampsia has a uterine origin. J Matern Fetal Neonat Med 2005;18:
9-16.
88. Chaiworapongsa T, Chaemsaithong P, Korzeniewski SJ, Yeo L,
Romero R. Pre-eclampsia part 2: prediction, prevention and manage-
ment. Nat Rev Nephrol 2014;10:531-40.
89. Chaiworapongsa T, Chaemsaithong P, Yeo L, Romero R. Pre-
eclampsia part 1: current understanding of its pathophysiology. Nat Rev
Nephrol 2014;10:466-80.
90. Erez O, Romero R, Espinoza J, F, et al. The change in concentrations
of angiogenic and anti-angiogenic factors in maternal plasma between
the first and second trimesters in risk assessment for the subsequent
development of preeclampsia and small-for-gestational age. J Matern
Fetal Neonat Med 2008;21:279-87.
91. Kusanovic JP, Romero R, Chaiworapongsa T, et al. A prospective
cohort study of the value of maternal plasma concentrations of angio-
genic and anti-angiogenic factors in early pregnancy and midtrimester in
the identification of patients destined to develop preeclampsia. J Matern
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92. Powers RW, Jeyabalan A, Clifton RG, et al. Soluble fmslLike tyrosine
kinase 1 (sFlt1), endoglin and placental growth factor (PlGF) in pre-
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93. Romero R, Nien JK, Espinoza J, et al. A longitudinal study of
angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin
and soluble vascular endothelial growth factor receptor-1) factors in
normal pregnancy and patients destined to develop preeclampsia and
deliver a small for gestational age neonate. J Matern Fetal Neonat Med
2008;21:9-23.
94. Soto E, Romero R, Kusanovic JP, et al. Late-onset preeclampsia is
associated with an imbalance of angiogenic and anti-angiogenic factors
in patients with and without placental lesions consistent with maternal
underperfusion. J Matern Fetal Neonat Med 2012;25:498-507.
95. Vaisbuch E, Whitty JE, Hassan SS, et al. Circulating angiogenic and
antiangiogenic factors in women with eclampsia. Am J Obstet Gynecol
2011;204:152.e1-9.
96. Chaiworapongsa T, Romero R, Whitten AE, et al. The use of
angiogenic biomarkers in maternal blood to identify which SGA fetuses
will require a preterm delivery and mothers who will develop pre-
eclampsia. J Matern Fetal Neonat Med 2015 Aug 14:1-15 [Epub ahead of
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97. Chaiworapongsa T, Romero R, Kusanovic JP, et al. Unexplained
fetal death is associated with increased concentrations of anti-
angiogenic factors in amniotic fluid. J Matern Fetal Neonat Med
2010;23:794-805.
98. Espinoza J, Chaiworapongsa T, Romero R, et al. Unexplained fetal
death: another anti-angiogenic state. J Matern Fetal Neonat Med
2007;20:495-507.
99. Chaiworapongsa T, Romero R, Tarca A, et al. A subset of patients
destined to develop spontaneous preterm labor has an abnormal
angiogenic/anti-angiogenic profile in maternal plasma: evidence in
support of pathophysiologic heterogeneity of preterm labor derived
from a longitudinal study. J Matern Fetal Neonat Med 2009;22:
1122-39.
100. Espinoza J, Romero R, Nien JK, et al. A role of the anti-angiogenic
factor sVEGFR-1 in the ‘mirror syndrome’ (Ballantyne’s syndrome).
J Matern Fetal Neonat Med 2006;19:607-13.
101. Kusanovic JP, Romero R, Espinoza J, et al. Twin-to-twin trans-
fusion syndrome: an antiangiogenic state? Am J Obstet Gynecol
2008;198:382.e1-8.