The Journal of Maternal-Fetal & Neonatal Medicine

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Association between maternal/newborn genetic

variants, placental pathology and spontaneous
preterm birth risk: a Romanian population-based
study

Andreia Preda, Gabriela Caracostea, Dan Ona, Gabriela Zaharie & Florin
Stamatian

To cite this article: Andreia Preda, Gabriela Caracostea, Dan Ona, Gabriela Zaharie & Florin
Stamatian (2018): Association between maternal/newborn genetic variants, placental pathology and
spontaneous preterm birth risk: a Romanian population-based study, The Journal of Maternal-Fetal
& Neonatal Medicine, DOI: 10.1080/14767058.2018.1517311

To link to this article: https://doi.org/10.1080/14767058.2018.1517311

Published online: 25 Sep 2018.

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THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE
https://doi.org/10.1080/14767058.2018.1517311

ORIGINAL ARTICLE

Association between maternal/newborn genetic variants, placental pathology

and spontaneous preterm birth risk: a Romanian population-based study
Andreia Predaa, Gabriela Caracosteaa, Dan Onaa, Gabriela Zaharieb and Florin Stamatiana,c
a
1st Department of Obstetrics and Gynaecology, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania;
b
Department of Neonatology, Iuliu Haţieganu, University of Medicine and Pharmacy, Cluj-Napoca, Romania; cImogen Research
Center, Cluj County Emergency Hospital, Cluj-Napoca, Romania

ABSTRACT ARTICLE HISTORY

Objective: The objective of this study was to determine the association between maternal/new- Received 16 April 2018
born single-nucleotide polymorphisms (SNPs) in three candidate genes, placental pathology and Revised 26 July 2018
the risk of spontaneous preterm birth (SPTB) in a Romanian population. Accepted 26 August 2018
Methods: We performed a prospective case-control study in a tertiary maternity in Romania,
KEYWORDS
including 79 mother-newborn pairs with SPTB and 81 mother-newborn pairs with term delivery. Multilocus genetic analyses;
Using real-time Polymerase Chain Reaction (PCR), three SNPs rs8192282 A > G, rs2277698 C > T placental lesions; single
and rs34003 A > C located on interleukin 6 receptor (IL6R), tissue inhibitor of matrix metallopro- nucleotide polymorphisms;
teinase-2 (TIMP2) and fibroblast growth factor 1 (FGF1) genes were assessed. The minor allele spontaneous preterm birth
and genotype frequencies were compared between groups. Multilocus genetic association anal-
yses were performed. From pathology reports, the morphological and histopathological examin-
ation of the placentas were extracted.
Results: The rs34003 C/C genotype frequency in newborns FGF1 gene was significantly higher in
the spontaneous preterm birth (SPTB) group compared to the control group (p ¼ .045). In single-
locus analyses, C/C genotype was associated with an increased risk of spontaneous preterm birth
(OR ¼ 2.59, 95%CI: 1.02–6.58). Additionally, this homozygote genotype was correlated with the
presence of placental pathology, especially with the inflammatory and vascular lesions (p < .01).
The prediction model based on rs34003 C/C genotype – placental pathology joint influence had a
statistically significant regression coefficient (p < .01, OR ¼ 7.76, 95%CI: 4.03–14.93). Single nucleo-
tide polymorphisms related to IL6R gene in maternal samples and FGF1 gene in newborns were
associated with spontaneous preterm delivery in multilocus genetic association analyses (p ¼ .028,
OR of 2.375).
Conclusions: Our results indicate that rs34003 C/C genotype in newborns FGF1gene is corre-
lated with the occurrence of placental pathological lesions and with an increased SPTB risk. The
association of two SNPs in maternal and fetal genes doubled the risk of spontaneous preterm
birth in our population.

Introduction premature birth [5]. The amount of fetal and maternal

Prematurity remains a real and actual problem of pub-
lic health worldwide [1]. Despite the great interest for
ongoing research and the advancement of health-care
systems, the rate of spontaneous premature birth
(SPTB) remains unchanged [2]. Considering the fact
that in about half of cases the etiology is unknown,
the number of presumed risk factors in its determin-
ism is continuously increasing [3]. Genetic predispos-
ition to SPTB was highlighted in previous studies, by
segregation analysis showing a 27–36% variation in
birth timing due to genetic factors [4] and by high
rates of recurrence in women with a history of
genetic contribution is not fully understood, varying
between populations [6] and could not be separated
from environmental influence [7].
Although an exact mechanism has not been estab-
lished, infection/inflammation and the consecutive
changes in the extracellular matrix, are thought to be
primary contributors of SPTB [8]. Some studies
reported the vascular lesions as a potential mechanism
[9,10], possibly because defective angiogenesis may
play a role in some cases of preterm birth [11]. The
presence of a genetic component underlying these
processes, that made single nucleotide polymorphisms

CONTACT Gabriela Caracostea caracostea1@yahoo.com 1st Department of Obstetrics and Gynaecology, Iuliu Hațieganu University of Medicine
and Pharmacy, Clinicilor Str. No.3–5 400006, Cluj-Napoca, Romania
ß 2018 Informa UK Limited, trading as Taylor & Francis Group
2 A. PREDA ET AL.
(SNPs) in candidate genes, to be the most investigated
genetic markers in relation with SPTB [12,13].
An important number of genetic variants in pro and
anti-inflammatory cytokine genes [14,15], their receptors
[16] and the matrix-degrading metalloproteinase genes
and their tissue inhibitors [17], have been significantly
associated with SPTB in previous reports. Because the
maternal and fetal genetic variation may influence the
time of birth, incorporating data on morphological and
functional placental development can lead to the dis-
covery of genetic associations with SPTB.
The objective of this study was to evaluate whether
specific maternal/newborn SNPs, located on genes
implicated in the most incriminated mechanisms
(inflammation/infection, extracellular matrix metabol-
ism, and angiogenesis) and placental histology charac-
teristics are associated with SPTB, in a Romanian
population. In a multilocus genetic approach, we also
aimed to determine if the interaction between the
analyzed maternal/newborn SNPs has an impact in the
initiation of the premature labor.
Materials and methods
Study design
We performed a prospective case-control study during
a 24-month period. We included women with single-
ton gestation and live birth, admitted in Obstetrics-
Gynecology I Clinic Cluj Napoca, a tertiary maternity
to which are referred high-risk pregnancies and pre-
term neonates from central and western region of
Romania. The study was approved by the Ethical
Committee of the Iuliu Haţieganu University of
Medicine and Pharmacy Cluj Napoca (number 739).
Delivery between 24 weeks 0 days and 36 weeks
6 days (inclusive) following the spontaneous onset of
labor or indicated for >48 h of premature and prelabor
rupture of membranes (PPROM) for cases and delivery
between 37 weeks 0 days and 41 weeks 6 days (inclu-
sive) for controls and live birth with a child free of con-
genital abnormalities, represented the inclusion criteria.
Women with known aneuploidy or lethal fetal anoma-
lies and with maternal or fetal conditions known to be
associated with preterm delivery or often requiring early
delivery of the baby (placenta praevia, placental abrup-
tion, hydramnios, isoimmunization, placental insuffi-
ciency, preeclampsia/eclampsia, etc.) were excluded.
Baseline characteristics
Patients epidemiological and clinical characteristics
were registered. Demographic and social information
(maternal age, education level, weight gain, tobacco
use) and obstetrical history features (the outcome of
all prior pregnancies and dates of termination, infor-
mation about current pregnancy and its complica-
tions) were included. Data about labor (type,
membrane status at the onset of labor, gestational
age at delivery), route of delivery and neonatal out-
come (gender, birth weight, perinatal morbidity, and
mortality) were collected from medical records.
Genetic analyses and SNPs selection
DNA samples from maternal peripheral blood and
newborn cord blood were extracted for mother-new-
born pairs in the study group and in controls. Three
single-nucleotide polymorphisms related to interleukin
6 receptor (IL6R) rs8192282 A > G, tissue inhibitor of
matrix metalloproteinase-2 (TIMP2) rs2277698 C > T
and fibroblast growth factor 1 (FGF1) rs34003 A > C
were analyzed for both mothers and newborns genes.
These candidate genes and their specific SNPs were
chosen based on literature evidence for a potential
role in SPTB determinism [14,17,18]. By Real-Time PCR,
a custom 3 SNPs array was used (TaqMan probes) and
the minor allele, was designated as the risk allele for
each polymorphism. Genotype-based analyses
were performed.
Placental pathological examination
Macropathologic and histologic examination of the
placentas, membranes, and umbilical cord was per-
formed. Pathological abnormalities, consisted of infec-
tious/inflammatory lesions, with maternal or/and fetal
inflammatory response, maternal vascular malperfu-
sion lesions and other modifications (true knots, vela-
mentous umbilical cord insertion, old infarction, etc.)
were recorded. The anomalies observed at the level of
the villi and of the vascular wall including accentuated
villous maturation, distal villous hypoplasia, fibrin
deposits and syncytial knotting, were considered vas-
cular malperfusion lesions.
Statistical analysis
The statistical analysis was performed using the SPSS
24 statistical software. The comparisons between the
study group and the control group regarding epi-
demiological variables, obstetrical background, labor,
delivery and placental pathology, were based on the
v2 test, Somer’s d and Kendall in the tau-b form
(ordinal variables), using the Bonferroni p value
 THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 3

Table 1. Baseline characteristics of women who had a SPTB and women who delivered at term.
Characteristic Spontaneous PTB (N ¼ 79) Term birth (N ¼ 81) p value
Maternal age, ya 29.58 ± 4.71 30.09 ± 4.2 .486
Education > High school, n 33 (46.5%) 55 (72.4%) <.01
Smoking, n 16 (20.5%) 14 (17.6%) .609
Weight gain, kga 10.71 ± 4.53 15.29 ± 5.24 <.01
No. of previous pregnancies, nb 1 (7) 1 (4) <.01
History of SPTB, n 15 (21.1%) 1 (1.4%) <.01
Gestational age at delivery, wkb 32.8 (5) 40 (1) <.01
Preterm premature rupture of the membranes, n 7 (8.9%) 0 (0%) <.01
Route of delivery, n <.01
vaginal birth 63 (88.7%) 76 (100%)
C-section 8 (11.3%) 0 (0%)
Neonatal gender .513
Birthweight, ga 2142.04 ± 692.9 3541.45 ± 447.84 <.01
Composite neonatal morbidity, n 39 (54.9%) 0 (0%) <.01
Prenatal mortality, n 0 0 –
Placental pathology (inflammatory/infectious and vascular malperfusion lesions), n 38 (52.8%) 1 (1.3%) <.01
a
Mean and standard deviation; bMedian (interquartile range)
PTB: preterm birth.

adjustment option. Given that some of the quantita-
tive variables were not normally distributed, the
median values (interquartile range- IQR) were ren-
dered as descriptive parameters. Comparisons
between the two groups were made using Student’s t
test (t) in the case of normally distributed variables
and nonparametric tests (Mann–Whitney and
Wilcoxon) for the others.
The intensity of the correlation between the varia-
bles was evaluated by the Kendall and Spearman coef-
ficients for ordinal variables and through the Pearson’s
one for scale variables. In the case of variables with
significant differences between the two groups, the
odds ratio and the confidence interval were calculated.
Significance was considered at a value of p < .05.
Logistic regression was used to test the association
between maternal/newborn SNPs and the presence of
placental lesions. By factorial analysis, a prediction
model for SPTB was developed based on the presence
of a tag SNP on FGF1gene and changes in histopatho-
logical examination of the placenta.
In order to determine the interactions among
maternal and fetal SNPs, multilocus genetic association
analyses were performed. We used Multifactor
Dimensionality Reduction (MDR) software, a genetic
association analysis program, developed by the
Computational Genetics Laboratory (CGL) at the
Perelman School of Medicine of the University of
Pennsylvania and publicly available at www.epista-
sis.org.
Results
We analyzed 79 mother-newborn pairs with spontan-
eous preterm delivery and 81 pairs with term delivery.
Baseline characteristics of women who had a spontan-
eous preterm delivery and women who delivered at
term were similar regarding maternal age, smoking
status, and neonatal gender. The risk of SPTB was in
an inversely proportional relationship with the educa-
tion level and weight gain during pregnancy. Women
who delivered preterm were more likely to have a
higher number of previous pregnancies, especially a
history of previous preterm birth, regardless of the
time interval between pregnancies. Significant differ-
ences between cases and controls were also identified
for route of delivery, perinatal morbidity and placental
pathology (Table 1). Placental modifications, consisting
of inflammatory/infectious and vascular malperfusion
lesions, were more common in SPTB cases compared
with term deliveries (52.8 versus 1.3%, p < .01).
However, we have not obtained statistical difference
between these types of lesions in relation with SPTB.
In a simple analysis, of the three single nucleotide
polymorphisms tested for mother-newborn pairs, a
single significant association was observed for the
rs34003 C/C polymorphism in FGF1 gene in newborns
(Table 2). This homozygous genotype was also associ-
ated with an increased risk of placental pathological
lesions (p ¼ .002). Considering that the presence of
rs34003 C/C polymorphism in FGF1 gene and the
histopathological changes observed in placental exam-
ination influence the gestational age at birth, we com-
bined them into a prediction model. Based on their
joint influence, the regression coefficient was statistic-
ally significant (p value ¼ .000, OR ¼ 7.76, 95%
CI: 4.03–14.93).
The multilocus genetic association was performed
by exploratory MDR analyses. Maternal and newborn
homozygote genotypes for selected SNPs were com-
bined. In all used algorithms, the model with a prob-
ability value of <.05 was the one that included
rs8192282 G/G _maternal and rs34003 C/C_ newborn
4 A. PREDA ET AL.

Table 2. SNPs genotype-based analyses comparing women with SPTB with women who delivered
at term.
Minor Genotype
allele frequency frequency
Gene SNP Minor allele Preterm Term Genotype Preterm Term p value OR (95%CI)
Maternal
FGF1 rs34003 C 0.39 0.38 CC 0.12 0.11 .762
CA 0.53 0.53
AA 0.34 0.35
IL6R rs8192282 G 0.27 0.23 GG 0.12 0.04 .083
GA 0.27 0.37
AA 0.59 0.58
TIMP2 rs2277698 T 0.12 0.1 TT 0.01 0 .314
TC 0.21 0.21
CC 0.77 0.79
Fetal
FGF1 rs34003 C 0.34 0.39 CC 0.2 0.09 .045 2.59 (1.02–6.58)
CA 0.26 0.58
AA 0.53 0.32
IL6R rs8192282 G 0.22 0.22 GG 0.07 0.07 .314
GA 0.27 0.28
AA 0.64 0.64
TIMP2 rs2277698 T 0.11 0.12 TT 0 0.01 .322
TC 0.22 0.22
CC 0.77 0.76
SNP: single nucleotide polymorphism; OR: odds ratio; CI: confidence interval

genotypes (p ¼ .028, OR ¼ 2.375). This model, with stat-
istically significant effect after MDR analyze, had a
good cross-validation consistency (10/10) and a tested
balanced accuracy of 0.57.
Discussion
Within this prospective study, conducted in a third-
level facility unit in Romania, we identified a number
of potential risk factors that can influence a woman’s
risk for premature birth in a given population.
After primary analysis, out of the single nucleotide
polymorphisms considered, an individual polymorph-
ism, rs34003 on FGF1 gene, was found to be associ-
ated with SPTB. Our results showed that C/C
homozygote genotype in newborns was associated
with an approximately two and a half higher risk of
SPTB. Supported by the recent evidence [19], this
highlights the potential role that fetus is playing in
the onset of premature labor.
The FGF-1gene encodes a protein that promotes
blood vessel branching, induce lymphangiogenesis,
extracellular matrix degradation and can function as a
modifier of endothelial cell migration and proliferation
[20,21]. Despite the fact that we found no evidence in
the literature regarding the relationship between this
specific SNP and the risk of premature birth, a strong
association of a maternal haplotype for FGF1 with the
risk of SPTB was reported [14]. This data indicates that
the genetic variation of FGF1 gene, implicated in the
angiogenic mechanism, may have a role in the patho-
genesis of SPTB.
Because the infectious/inflammatory mechanism is
routinely incriminated in premature birth pathogenesis
[22], we choose a polymorphism located on IL6R
gene. IL6 is one of the most studied cytokines in pre-
term labor [23] and genetic variants of IL6 and IL6R
genes may play an important role in regulation of
maternal and fetal immune response [24]. There is evi-
dence of a possible relationship between some SNPs
found on IL6R gene and SPTB risk in different ethnic
populations, but their predictive value has not yet
been established [16]. In our single-locus analysis, the
selected rs8192282 polymorphism was not associated
with the risk of preterm delivery.
TIMP2 regulates the activity of matrix proteolytic
enzymes and its aberrant expression at the local level
can lead to degradation of the extracellular matrix [25]
and premature labor [26]. Although strongly related to
PTB in other studies [17], the chosen polymorphism
on the TIMP2 gene was not associated with SPTB risk
in our cohort.
The multitude of existing studies on single nucleo-
tide polymorphisms could not yet give us completely
reproducible results [18,27]. The lack of statistical sig-
nificance obtained in our population for rs8192282
and rs2277698 polymorphisms comes to reinforce the
above. Because SNPs alone are not strong determi-
nants of preterm birth [28], we also tried the multilo-
cus genetic approach. We found a model with a good
cross-validation consistency, based on maternal and

newborn genetic variants. In cases in which
rs8192282 G/G polymorphism in maternal IL6R gene
and rs34003 C/C polymorphism in FGF1 newborn
gene were present, an 2.3 higher risk of SPTB was
recorded. Without statistical significance in the primary
analysis, the SNP located on IL6R maternal gene seems
to have an influence on the SPTB risk in the presence
of gene-gene interaction. This results confirms the
assumption of a multilocus genetic susceptibility for
premature initiation of labor [29] and the importance
of genetic mother-fetus interaction in modifying the
women risk of preterm delivery [30].
Increasingly more attention was shifted to the
study of morpho-functional characteristics of the pla-
centa. The mechanisms presumed to be involved in
the initiation of preterm labor can be reflected in
pathophysiological changes present at histological
evaluation [31]. Recent research on the placental fea-
tures incriminates the vascular lesions, consisting of
villous abnormalities and decidual vasculopathy (accel-
erated villous maturation, syncytial knotting, fibrinoid
necrosis of vessel wall, perivillous fibrin deposition,
mural hypertrophy of decidual arterioles) as a primary
mechanism of spontaneous preterm birth [32].
Although these lesions were thought to be the cause
of indicated prematurity [33], newly evidence prove
their implication in about one-third of SPTB
cases [34,35].
The coexistence of inflammatory/infection and vas-
cular malperfusion lesions was associated with SPTB in
our study. Even though inflammation/infection is
linked to an earlier gestational age [22], in cases of
extreme prematurity, we observed the presence in the
same extent of both types of lesions. These lesions
can act simultaneously or sequentially [33], leading to
spontaneous preterm delivery and to a neonatal
unfavorable prognosis [36].
Furthermore, we identified a homozygous genotype
in newborns FGF1gene associated with a higher rate
of placental pathological lesions. This gene is impli-
cated in angiogenic process and it is possible that
angiogenesis may be involved in the occurrence of
typical malperfusion lesions [37,38] and in preterm
parturition [39]. Our prediction model based on the
significant joint influence of rs34003 C/C genotype
and placental pathology supports this assumption.
Therefore we suggest a sequential course of action
starting with genetic variance of FGF1 gene, continu-
ing with placental anomalies and leading to pre-
term delivery.
Selecting variants for the genes involved in infec-
tious/inflammatory mechanism and in angiogenesis
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 5
may lead to the identification of a predictive method
for SPTB, especially for our population segment. The
SNPs interaction with specific environmental factors
can lead to very different clinical results [40], so their
association with placental pathological changes may
be a feasible approach.
The strengths of this study are represented by the
evaluation of SNPs in newborn genome and their cor-
relation with maternal ones. The limitations consists of
a small sample size and in the evaluation of only three
single nucleotide polymorphisms on genes previously
incriminated for association with SPTB. However, the
analysis of these SNPs in maternal and newborn gen-
ome allowed us to demonstrate the mother-fetus pos-
sible genetic interaction and a prediction model for
SPTB risk.
In conclusion, our results suggest that a tag poly-
morphism on newborn FGF1 gene, not previously
investigated individually, may be involved in the
occurrence of placental pathological abnormalities and
in rising SPTB risk. The joint influence of rs34003 C/C
polymorphism and placental pathology seems to be
an important contributor to SPTB susceptibility. The
association of SNPs in a model with maternal and fetal
contribution pointed out the potential interplay
among maternal and fetal genome for a specific popu-
lation and may serve as genetic markers for spontan-
eous premature delivery risk.
Acknowledgements
We acknowledge the clinical team for their help on patient
recruitment and on genetic analysis.
Disclosure statement
No potential conflict of interest was reported by the authors.
References
[1] Blencowe H, Cousens S, Chou D, et al. Born too soon:
the global epidemiology of 15 million preterm births.
Reprod Health. 2013 Nov;10(1):S2.
[2] Hug L. ES et al. YD. Global, regional, and national lev-
els and trends in under-5 mortality between 1990
and 2015, with scenario-based projections to 2030: a
systematic analysis by the UN Inter-Agency Group for
Child Mortality Estimation (vol 386, pg 2275, 2015).
Lancet. 2015;386(1001 0):2256.
[3] Iams JD. Clinical practice. Prevention of preterm par-
turition. N Engl J Med. 2014;370(3):254–261.
[4] Parets SE, Knight AK, Smith AK. Insights into genetic
susceptibility in the etiology of spontaneous preterm
birth. Appl Clin Genet. 2015;8:283–290.
6 A. PREDA ET AL.
[5] Esplin MS, O’Brien E, Fraser A, et al. Estimating recur-
rence of spontaneous preterm delivery. Obstet
Gynecol. 2008;112(3):516–523.
[6] Manuck TA. Racial and ethnic differences in preterm
birth: a complex, multifactorial problem. Semin
Perinatol. 2017;41(8):511–518.
[7] York TP, Eaves LJ, Lichtenstein P, et al. Fetal and
maternal genes’ influence on gestational age in a
quantitative genetic analysis of 244,000 Swedish
births. Am J Epidemiol. 2013;178(4):543–550.
[8] Romero R, Dey SK, Fisher SJ. Preterm labor: one syn-
drome, many causes. Science. 2014;345(6198):
760–765.
[9] Kelly R, Holzman C, Senagore P, et al. Placental vascu-
lar pathology findings and pathways to preterm deliv-
ery. Am J Epidemiol. 2009;170(2):148–158.
[10] Arias F, Rodriquez L, Rayne SC, et al. Maternal placen-
tal vasculopathy and infection: two distinct subgroups
among patients with preterm labor and preterm rup-
tured membranes. Am J Obstet Gynecol. 1993;168(2):
585–591.
[11] 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
Neonatal Med. 2009;22(12):1122–1139.
[12] Dolan SM, Hollegaard MV, Merialdi M, et al. Synopsis
of preterm birth genetic association studies: the pre-
term birth genetics knowledge base (PTBGene).
Public Health Genom. 2010;13(7–8):514–523.
[13] Plunkett J, Muglia LJ. Genetic contributions to pre-
term birth: implications from epidemiological and
genetic association studies. Ann Med. 2008;40(3):
167–195.
[14] Romero R, Velez Edwards DR, Kusanovic JP, et al..
Identification of fetal and maternal single nucleotide
polymorphisms in candidate genes that predispose to
spontaneous preterm labor with intact membranes.
Am J Obstet Gynecol. 2010;202(5):431.e1–431.34.
[15] Harper M, Zheng SL, Thom E, et al. Cytokine gene
polymorphisms and length of gestation. Obstet
Gynecol. 2011;117(1):125–130.
[16] Wu W, Clark EAS, Stoddard GJ, et al. Effect of interleu-
kin-6 polymorphism on risk of preterm birth within
population strata: a meta-analysis. BMC Genet. 2013;
14:30.
[17] Frey HA, Stout MJ, Pearson LN, et al. Genetic variation
associated with preterm birth in African-American
women. Am J Obstet Gynecol. 2016;215(2):
235.e1–235.e8.
[18] Uzun A, Dewan AT, Istrail S, et al. Pathway-based gen-
etic analysis of preterm birth. Genomics. 2013;101(3):
163–170.
[19] York TP, Strauss JF, Neale MC, et al. Racial differences
in genetic and environmental risk to preterm birth.
PLoS ONE. 2010;5(8):e12391.
[20] Auguste P, Javerzat S, Bikfalvi A. Regulation of vascu-
lar development by fibroblast growth factors. Cell
Tissue Res. 2003;314(1):157–166.
[21] Lee SH, Schloss DJ, Swain JL. Maintenance of vascular
integrity in the embryo requires signaling through
the fibroblast growth factor receptor. J Biol Chem.
2000;275(43):33679–33687.
[22] Romero R, Espinoza J, Gonçalves LF, et al. The role of
inflammation and infection in preterm birth. Semin
Reprod Med. 2007;25(1):21–39.
[23] Chaemsaithong P, Romero R, Korzeniewski SJ, et al. A
rapid interleukin-6 bedside test for the identification
of intra-amniotic inflammation in preterm labor with
intact membranes. J Matern Fetal Neonatal Med.
2016;29(3):349–359.
[24] Velez DR, Fortunato SJ, Williams SM, et al. Interleukin-
6 (IL-6) and receptor (IL6-R) gene haplotypes associate
with amniotic fluid protein concentrations in preterm
birth. Hum Mol Genet. 2008;17(11):1619–1630.
[25] Tency I, Verstraelen H, Kroes I, et al. Imbalances
between matrix metalloproteinases (MMPs) and tissue
inhibitor of metalloproteinases (TIMPs) in maternal
serum during preterm labor. PLoS ONE. 2012;7(11):
e49042.
[26] Maymon E, Romero R, Pacora P, et al. A role for the
72 kDa gelatinase (MMP-2) and its inhibitor (TIMP-2)
in human parturition, premature rupture of mem-
branes and intraamniotic infection. J Perinat Med.
2001;29(4):308–316.
[27] Rood KM, Buhimschi CS. Genetics, hormonal influen-
ces, and preterm birth. Semin Perinatol. 2017;41(7):
401–408.
[28] Glover AV, Manuck TA. Screening for spontaneous
preterm birth and resultant therapies to reduce neo-
natal morbidity and mortality: a review. Semin Fetal
Neonat Med. 2018;23(2):126–132.
[29] Orsi NM, Gopichandran N, Simpson NAB. Genetics of
preterm labour. Best Pract Res Clin Obstet Gynaecol.
2007;21(5):757–772.
[30] York TP, Eaves LJ, Neale MC, et al. The contribution of
genetic and environmental factors to the duration of
pregnancy. Am J Obstet Gynecol. 2014;210(5):
398–405.
[31] Sebire NJ. Implications of placental pathology for dis-
ease mechanisms; methods, issues and future
approaches. Placenta. 2017;52:122–126.
[32] Morgan TK, Tolosa JE, Mele L, et al. Placental villous
hypermaturation is associated with idiopathic preterm
birth. J Matern Fetal Neonatal Med. 2013;26(7):
647–653.
[33] Redline RW. The clinical implications of placental
diagnoses. Semin Perinatol. 2015;39(1):2–8.
[34] Parks WT. Placental hypoxia: the lesions of maternal
malperfusion. Semin Perinatol. 2015;39(1):9–19.
[35] Hendler I, Goldenberg RL, Mercer BM, et al. The pre-
term prediction study: association between maternal
body mass index and spontaneous and indicated pre-
term birth. Am J Obstet Gynecol. 2005;192(3):
882–886.
[36] Catov JM, Scifres CM, Caritis SN, et al. Neonatal out-
comes following preterm birth classified according to
placental features. Am J Obstet Gynecol. 2017;216(4):
411.e1–411.e14.
 THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 7

[37] Brosens I, Pijnenborg R, Vercruysse L, et al. The “great [39] Savasan ZA, Romero R, Chaiworapongsa T, et al.
obstetrical syndromes” are associated with disorders Evidence in support of a role for anti-angiogenic
of deep placentation. Am J Obstet Gynecol. 2011; factors in preterm prelabor rupture of
204(3):193–201. membranes. J Matern Fetal Neonatal Med. 2010;23(8):
[38] Taylor RN, Grimwood J, Taylor RS, et al. Longitudinal 828–841.
serum concentrations of placental growth factor: evi- [40] Manuck TA, Esplin MS, Biggio J, et al. The phenotype
dence for abnormal placental angiogenesis in patho- of spontaneous preterm birth: application of a clinical
logic pregnancies. Am J Obstet Gynecol. 2003;188(1): phenotyping tool. Am J Obstet Gynecol. 2015;212(4):
177–182. 487.e1–487.e11.