Review

OPEN

Preterm Birth, From the Biological Knowledges to

the Prevention: An Overview
Valentina Tosto1, Irene Giardina1, Valentina Tsibizova2, Gian Carlo Di Renzo1,∗

Abstract
The time of birth is a critical determinant of perinatal and long-term outcomes, and even trans-generational effects. Preterm birth is still
the leading cause of infant mortality and morbidity. Unfortunately, rates of preterm birth remain high worldwide. Preterm parturition is
a complex syndrome, which can be induced by several factors such as infection, cervical pathology, uterine overdistension,
progesterone deficiency, vascular alterations (utero-placental ischemia, decidual hemorrhage), maternal and fetal stress, allograft
reaction, allergic phenomena, and probably other several unknown factors. The mechanisms responsible for early labor activation
have been partially identified and involve receptors, chemokines, and inflammatory cytokines. It is very useful to understand the
cellular and biochemical pathways responsible for preterm labor activation to identify, treat, and prevent negative outcome in a timely
Downloaded from https://journals.lww.com/mfm by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3GqhOzspyl8zx6AjKIxSLITq14QpVKz4yu4RPtwxT9a8= on 08/15/2020

manner. Researchers and clinicians play a key role in improving biochemical knowledge on preterm delivery, identifying risk factors,
and applying multilevel preventive strategies.
Keywords: Premature birth; Biological pathways; Inflammation; Prevention strategies

Introduction In 2012, the Born Too Soon report highlighted the

Preterm birth (PTB) is defined as birth at < 37 weeks of
gestation or at 259 days since the first day of woman’s last
menstrual period. It is classified into extremely preterm
(PT) if <28 weeks, very PT if 28 to <33 weeks, and
moderate PT if 34 to <37 completed weeks of gestation.
The last class is further categorized as early PTB (EPTB)
and late PTB depending on whether the birth occur: <34
weeks or between 34 and <37 weeks of gestation,
respectively.1
PTB is still the leading cause of neonatal mortality and
infant morbidity worldwide. PT rates remain high in both
high and low-resource countries, ranging from 5% to
18%, with the highest burden in low-income areas.1
Moreover, rates appear to increase in countries as data
systems improve.1,2 Complications of PTB result in
significant risks for developmental disability in survivors
and high costs for long-term complex health care needs.1
1
Department of Obstetrics and Gynecology and Center for Perinatal
and Reproductive Medicine, University of Perugia, Santa Maria della
Misericordia University Hospital, Perugia 06132, Italy; 2 Department of
Obstetrics and Gynecology, Almazov National Medical Research
Center, St. Petersburg 191014, Russia.
∗ of public health worldwide.
Corresponding author: Prof. Gian Carlo Di Renzo, Department of
Obstetrics and Gynecology, Center for Perinatal and Reproductive
Medicine, University of Perugia, Santa Maria della Misericordia
University Hospital, Perugia 06132, Italy.
E-mail: giancarlo.direnzo@unipg.it
Copyright © 2020 The Chinese Medical Association, published by
Wolters Kluwer Health, Inc.
This is an open access article distributed under the terms of the
Creative Commons Attribution-Non Commercial-No Derivatives License
4.0 (CCBY-NC-ND), where it is permissible to download and share the
work provided it is properly cited. The work cannot be changed in any
way or used commercially without permission from the journal.
Maternal-Fetal Medicine (2020) 2:3
Received: 20 January 2020
http://dx.doi.org/10.1097/FM9.0000000000000054
problem by publishing country-specific rates of PTB and
calling for implementation of simple interventions that
decreased PTB complications in high-income countries
before the influence of neonatal intensive care.3 A further
complication is that the causes of PTB are multifactorial, and
classification of a phenotype of PTB is imprecise because of
heterogeneous clinical presentations and confounding
factors such as maternal malnutrition and infections.4–6
At this regard, in 2015 the World Health Organization
(WHO) published recommendations for interventions to
improve preterm outcomes.7 A mathematical model
Maternal and Neonatal Directed Assessment of Technol-
ogy (MANDATE) of the potential reduction of preterm
mortality in Sub-Saharan Africa was tested to assess its
useful to prioritize implementation strategies.8 This model
showed that WHO-recommended interventions could
have saved the lives of nearly 300 000 infants born
preterm in Sub-Saharan Africa and that combined
interventions are necessary to maximize these improved
results.
Considering the newborn and infant mortality rates, the
short and long-term adverse health outcomes of premature
and the socio-economic impact, the interest in PTB
increased in the last decades and now is a crucial topic
Preterm parturition is a complex syndrome9 that can be
induced by various factors that might trigger myometrial
contractions, premature rupture of membranes, and
cervical maturation, thus resulting in preterm delivery.
Most cases are of unknown cause. Although the mecha-
nisms triggering PTB remain in part unclear, it seems
reasonable from the recent scientific evidences, that an
inappropriate imbalance in net inflammatory load, due to
several underlined factors, could be key.10,11
PTB is difficult to predict. Prediction means to identify
women at risk for preterm delivery within relatively short
time interval (usually within 48 hours, 7–14 days). A test
with high negative predictive value and a high positive

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Tosto et al., Maternal-Fetal Medicine (2020) 2:3
predictive value would offer the best result. The available
predictors have usually a low positive predictive value and
a good negative predictive value profile, and; therefore, are
still not ideal for identifying all patients at risk. There has
been considerable interest in means of identifying women
at risk of delivering prematurely by clinical signs and
symptoms, biochemical markers (cervicovaginal fluid,
blood, urine, salive, amniotic fluid), and cervical length
(CL) by digital examination and/or ultrasound scan.12,13
In particular, transvaginal ultrasound CL and detection of
some biomarkers in cervico-vaginal fluid (fetal fibronec-
tion (fFN), placental alpha macroglobulin-1 (PAMG-1),
and phosphorylated insulin-like growth factor binding
protein 1 (phIGFBP-1)) represent the most useful available
tests for the prediction of PTB.12 Nikolova et al. compared
the PAMG-1 and the phIGFBP-1 alone and in combination
with CL measurement for the prediction of imminent risk
of PTB in symptomatic women. PAMG-1 resulted the best
Figure 1. Pathways of preterm delivery syndrome. CRH: Corticotropin releasing hormone; CSF: Colony stimulating factor; E1-E3: Enzyme 1 and 3; FasL:
Fas ligand; Gap jct: Gap junction; HPA: Hypothalamic-pituitary-adrenal axis; IL-1: Interleukin 1; IL-3: Interleukin 3; IL-6: Interleukin 6; IL-8: Interleukin 8; OT:
Oxytocin; Thrombin Rc: Thrombin receptor; TNF: Tumor necrosis factor.
163
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predictor: it seems significantly more specific than
phIGFBP-1 for PTB prediction within 7 days, whereas
both tests had comparable sensitivity.14
Recently, Darghahi et al. proposed the cell-free fetal
DNA detection for prediction of spontaneous preterm
labor (PTL): the study showed that the cumulative
frequency of PTL for women with positive cell-free fetal
DNA was significantly higher.15
To date, many interventions able to contribute to reduce
the risk of PTB were identified. Most of them are effective
only in specific population groups, thus demonstrating the
great heterogeneity of the PTB etiopathogenesis and the
subsequent complexity in its management. Figure 1 briefly
explains the proposed pathways of PTB syndrome.
A primary prevention is greatly needed and worldwide
experts are focusing their attention on this aspect, carrying
out complex biologic and molecular studies on the specific
trigger mechanisms involved in the PT genesis. At this
Tosto et al., Maternal-Fetal Medicine (2020) 2:3
regard, bioactive and nutritional solutions represent a
promising strategies as well as an accurate detection and
treatment of infection/inflammation status.
Considering the public health relevance of PTB and its
negative related consequences, innovative interventions
should be studied and analyzed in large and well-designed
clinical trials. The current essay briefly treat the main clues
for PTB syndrome, focusing on current preventive
strategies available to try to limit the adverse outcomes.
PTB biological basis
Despite intensive research, the molecular mechanisms
responsible for the onset of labor both at term and
especially preterm remain still unclear. It is likely that a
“parturition complex cascade” triggers labor at term; PTL
results from mechanisms that either prematurely stimulate
or short-circuit this cascade, and these mechanisms involve
the activation of pro-inflammatory pathways within the
uterus triggered by events like intrauterine infection,
hemorrhage, excessive uterine stretch (multiple pregnancy,
polyhydramnios, macrosomia), and/or maternal or fetal
stress.16–22
Authors suggested that a “decidual clock” could be
involved in the time of birth: the endometrium/decidua is
identified as the organ primarily involved.23 The switch of
the myometrium from a quiescent to a contractile state is
accompanied by a shift in signaling between anti-
inflammatory and pro-inflammatory pathways, including
chemokine (interleukin (IL)-8), cytokine (IL-1 and IL-6),
and contraction-associated protein (expression of oxyto-
cin receptors, connexin 43, prostaglandin receptors)
production. Progesterone maintains uterine quiescence
by repressing the expression of these genes. Increased
expression of the miR-200 family near term can derepress
contractile genes and; therefore, promote progesterone
catabolism and thus the activation of labor. Cervical
ripening in preparation for dilatation is mediated by
changes in extracellular matrix proteins, which include a
loss in collagen cross-linking and an increase in glyco-
saminoglycans, as well as changes in epithelial barrier and
immune surveillance properties. This decreases the tensile
strength of the cervix, key for cervical dilatation. Decidual/
membrane activation refers to the anatomical and
biochemical events involved in the withdrawal of decidual
support for pregnancy, separation of the chorioamniotic
membranes from the decidua, and, eventually, membrane
rupture.10
Increased expression of inflammatory cytokines (tumor
necrosis factor-a and IL-1) and chemokines, increased
activity of proteases (matrix metalloproteinase (MMP)-8
and MMP-9), dissolution of cellular cements such as
fibronectin (this event explains the positivity for the
fFN test), and apoptosis have been implicated in this
process.
Inflammation/infection role
Infection is a well-described pro-inflammatory event able
to trigger the PTL. Approximately 50% of PTBs and 70%
of preterm premature rupture of membranes (p-PROMs)
are associated with intra-amniotic infection (IAI) and
inflammation. Histological and microbiological findings
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indicate that focal infection and inflammation may play a
key role in the pathogenesis of PTB and p-PROMs.
Inflammatory changes that precede PTB are leukocyte
activation, increased inflammatory cytokines and chemo-
kines, and collagenolysis of the extracellular MMPs,
resulting in a loss of membrane structural integrity,
myometrial activation, and cervical ripening.24–26 Recent
studies have supported that the heterogeneity in the
inflammatory response (cytokines, chemokines, and toll-
like receptors) is associated with the IAI and PTB risk
factors.27–30 Moreover, a “sterile intrauterine inflamma-
tion” is also described as a possible trigger for PTB and p-
PROMs.31 An Italian multicentric, observational, retro-
spective, cross-sectional study, which included 7 631
women, revealed and confirmed the involvement of
inflammation/infection in pathogenetic mechanisms lead-
ing to early preterm delivery in the Italian pregnant
population. These evidences were supported by a higher
incidence of both clinical and pathological parameters of
inflammation/infection, such as p-PROMs, genitourinary
tract infections, placenta histopathological inflammation,
increased levels of white blood cells and C-reactive
protein.32
The dogma of “sterile womb” has been challenged in a
study published in Science in 2014, which suggested that
the placenta is not sterile and has a bacterial flora more
similar to the oral cavity than to the vagina.33 Researchers
described that human b-defensin-3 is a physiological
constituent of amniotic fluid and increases during the
process of labor at term. Amniotic fluid concentrations of
human b-defensin-3 resulted increased in women with
spontaneous PTL with intact membranes or p-PROMs
with intra-amniotic inflammation or intra-amniotic infec-
tion, indicating that this defensin participates in the host
defense mechanisms in the amniotic cavity against micro-
organisms or danger signals. These findings provide
insight into the soluble host defense mechanisms against
intra-amniotic inflammation and IAI.34
In recent years, it has been documented that women who
used oral probiotic products had reduced risk of preterm
delivery35 and pre-eclampsia.36 Interestingly, the superna-
tant of the probiotic organism Lactobacillus rhamnosus
has been found to reduce the lipopolysaccharide inflam-
matory response in placenta trophoblast cells.37
A really interesting new etiopathogenetic PTBs hypoth-
esis consists in the fetal immune system involvement.
Gomez-Lopez et al. provided evidence showing that the
fetal immune system undergoes premature activation in
women with PTL without intra-amniotic inflammation,
providing a potential new mechanism of disease for some
cases of idiopathic PTL. They showed that fetal T cells are
a predominant leukocyte population in amniotic fluid
during preterm gestations. Interestingly, only fetal CD4+ T
cells were increased in amniotic fluid of women who
underwent idiopathic PTL and PTB. This increase in fetal
CD4+ T cells was accompanied by elevated amniotic fluid
concentrations of T cell cytokines such as IL-2, IL-4, and
IL-13, which are produced by these cells upon in vitro
stimulation, but was not associated with the prototypical
cytokine profile observed in women with intra-amniotic
inflammation. Also, the found that cord blood T cells,
mainly CD4+ T cells, obtained from women with
idiopathic PTL and PTB displayed enhanced ex vivo
Tosto et al., Maternal-Fetal Medicine (2020) 2:3
activation, which is similar to that observed in women with
intra-amniotic inflammation.38
Genetic predisposition
A substantial body of evidence has been demonstrated the
contribution of genetic factors in gestational length and
PTB risk.10 For example, twin and family studies suggest
that 30%–40% of the variation in birth timing, or risk for
PTB, largely arises from genetic factors but not exclusively
from the maternal genome.39–44 Zhang et al. identified
maternal genetic variants that are robustly associated with
gestational duration: four loci (early B-cell factor 1,
selenocysteinyl-tRNA-specific eukaryotic elongation fac-
tor, angiotensin type 2 receptor gene), and wingless-type
MMTV integration site family member 4) achieved
genomewide significance.45 Wingless-type MMTV inte-
gration site family member 4 is critical for decidualization
of the endometrium and subsequent implantation and
establishment of pregnancy. Other researchers studied the
associations between spontaneous PTB and single or
combined polymorphisms associated with the apoptotic
pathways triggered by oxidative stress.46 Tarquini et al.
suggested that, independently of other maternal factors,
pregnant women carrying the TT/GA genotype of Jun N
terminal kinase/Caspasi 3 were more susceptible to PTB
than women bearing the GT/GA genotype.46
Microbiome
Many studies showed that the human indigenous
microbial communities (microbiota) play critical roles
in health and may be especially important for the mother
and fetus during pregnancy, also in the PTB syndrome.
Microbiome composition is determined largely by body
site, host genetics, environmental exposures, and time.
Growing scientific evidence suggests that the immune
regulation of the maternal-fetal interface is the result of
the coordinated interaction among maternal microbiome,
trophoblast, and maternal cellular components. From this
view, we understand PTL as a result of dysregulation of
this equilibrium.47 In the case of a human host, the
microbiome occupies several specific anatomic niches, for
example, the vagina, gastrointestinal tract, urogenital
tract, skin, nasal and paranasal sinuses, and oral
cavity.48–54 Under the best conditions, each of these
microbiome niches represents a species-balanced com-
munity, which is important for the establishment and
maintenance of human health.48 Significant evidence is
available to consider that the majority of PTBs due to
infection result from an ascendancy of bacterial patho-
gens from the vaginal microbiome to infect the clinically
sterile intrauterine cavity consisting of the placenta,
amniotic fluid, and fetus. This does not preclude the
possibility of a hematogenous spread (bacteremia) of
pathogenic microorganisms and inflammatory mediators
originating from other sources, including untreated
periodontal disease, and their contributions to an
adverse pregnancy outcome, such as pre-eclampsia,
PTB and low birth weight, fetal growth restriction,
and fetal loss.10 Although bacterial species that are
present in preterm pregnancies may not be pathogenic
necessarily, a relatively altered microbial community
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structure (dysbiosis) may convey an environment of
localized inflammation that results in PTB.
Clues for PTB prevention
Basically, three levels of interactions (genetics, environ-
ment, and human behaviors) are recognized crucial for
PTB syndrome and thus are identified as useful targets
for prevention strategies. Current scientific evidences
show that a PTB prevention is feasible. Interventions
available can be classified as primary, secondary, and
tertiary prevention. The most relevant interventions are
the primary prevention directed at all women, and the
secondary level of prevention, directed at a sub-group of
women with known or identified risk factors.
Currently, screening, while imperfect, is done based on
pregnant history and on measuring the CL (the strongest
clinical predictor of PTB in asymptomatic women), as well
as fFN levels and CL assessment, the latter in singleton
pregnancies with acute PTL symptoms. These approaches
still remain to be proven in multiple pregnancies.55
Recently, a review of systematic reviews on PTB
prevention was published.56 In total 112 reviews were
included in the analysis: sixty papers assessed the effect of
primary prevention interventions on risk of PTB. Positive
effects were reported for lifestyle and behavioral changes
(including diet and exercise); nutritional supplements
(including calcium and zinc supplementation); nutritional
education; screening for lower genital tract infections.
Eighty-three systematic reviews were identified relating to
secondary PTB prevention interventions. Positive effects
were found for low dose aspirin (LDASA) among women
at risk of pre-eclampsia; clindamycin treatment for
bacterial vaginosis (BV); treatment of vaginal candidiasis;
progesterone in women with prior spontaneous PTB and
in those with short mid-trimester CL; L-arginine in women
at risk for preeclampsia; levothyroxine among women
with thyroid disease; calcium supplementation in women
at risk of hypertensive disorders; smoking cessation; CL
screening in women with history of PTB with placement of
cerclage in those with short cervix; cervical pessary in
singleton gestations with short cervix; and treatment of
periodontal disease. The overview serves as a guide to
current evidence relevant to PTB prevention. Only few
interventions have been demonstrated to be effective,
including cerclage, progesterone, LDASA, and lifestyle and
behavioral changes. For several of the interventions
analyzed, there was insufficient evidence to assess whether
they were really effective or not.56
Interestingly, a cross-country individual participant
analysis of 4.1 million singleton births in five worldwide
countries with very high human development index (Czech
Republic, New Zealand, Slovenia, Sweden, and U.S.
California) confirmed already known associations with
PTB, but provided no biologic explanation for 2/3 of all
PTBs.57
Primary prevention strategies
The primary prevention for PTB consists in the early
identification of risk factors and education. Several risk
factors are non-modifiable, such as history of PTB,
extremes maternal ages (<18 years and >35 years),58–60
Tosto et al., Maternal-Fetal Medicine (2020) 2:3 Maternal-Fetal Medicine

multiple pregnancies,61 short CL,62 previous uterine Table 2

surgeries,63 male sex and nulliparity,57 ethnicity and family Risk factors, level of association with PTB, available
history,64 and genetic factors.10,65 In addition, others interventions (Adapted from Goffinet, 2005).55–68
factors are modifiable, such as nutrition, low socioeconomic
status, extremes body mass index (BMI), poor pregnancy Associations
weight gain, smoking, substance abuse, short inter- Risk factors with PTBs Interventions
pregnancy interval, periodontal disease, genital infections, Ethnicity (black) x No
late or no prenatal care, untreated antenatal depression, and Maternal age (young age <15–19 years) x Yes
use of assisted reproductive technologies.66 For these Lives alone x No
variables clinicians can act an effective prevention, also in Domestic violence xx Yes
the pre-conceptional period, “a critical window” during Low socioeconomic status xx ?
which health-care professionals can help women to prepare Stress, despression, negative life events xx Yes
as well as possible for the pregnancy. In the last years, Hard work xx Yes
country-based population analysis deepened the maternal No or poor prenatal care xx Yes
risk factors for PTB, providing a global overview of that Smoking, substance abuse (cocaine) x Yes
specific population situation. For example, Di Renzo et al. Alcohol, caffeine x Yes
provided an overview of the Italian situation underlying a Low maternal weight before pregnancy x No
significant association between PTB and previous repro- Weight gain in pregnancy x ?
ductive history, in particular previous preterm delivery (P = Maternal short stature x No
0.0099), previous abortions (P = 0.0116), and previous Previous preterm delivery or second xxx Yes
cesarean section (P = 0.0371). From this analysis also trimester pregnancy loss
factors as maternal BMI (BMI >25 kg/m2, P = 0.0365) Previous cone biospy xx ?
and employment (heavy work, P = 0.0089) resulted associ- Previous cesarean section x Yes
ated with an higher PTB risk.67 At this regard, Table 1 Mullerian abnormalities x No or ?
resumes the main risk factors related to PTB condition. Parity – –
Table 2 gives an overview about PTB risk factors, their level Short inter-pregnancy interval x ?
of association with PTB and presence/absence of available Family history - genetics x No
interventions.68 IVF x Yes
A growing body of scientific evidences described a Multiple pregnancy xxx Yes
clearly links between diet, lifestyle, behaviors, and high Bleeding x No
PTB risk. Cervico-vaginal infections xx Yes
There are increasing knowledge that specific diet Uterine contractions x Yes
patterns and nutritional/bioactive interventions are able Short cervix/cervical modification xx Yes
to modulate inflammation/infection pathways and reduce (during antenatal surveillance)
the risk of PTB.69 Observational studies indicate that poor Risk scores xx Yes
maternal pre-conceptional nutrition and also during early
IVF: In vitro fertilization; PTB: Preterm birth.
pregnancy may influence PTB risk.69,70 Pregnant women –: Not applicable; ?: Not still identified intervention; x: Demonstrated correlation.
should be encouraged on increasing high-quality foods
and beverages, thus appropriate vitamin and mineral
supplementation, avoidance of alcohol, tobacco, and other harmful substances. Several mechanisms are postulated
through which a prudent diet may reduce PTB risk,
including an anti-stressor effect of a low fat diet on the
Table 1 hypothalamic-pituitary-adrenal axis or an anti-inflamma-
Preterm birth risk factors.56–65 tory effect due to an increased antioxidant intake or
Risk factors OR 95% CI attributable to a diet low in saturated fat. Assessment of
dietary patterns found that high scores on a “prudent”
History for spontaneous preterm birth 3.6 3.2–4.0 dietary pattern (higher intakes of vegetables, salad, onion/
History for medically preterm birth 1.6 1.3–2.1 leek/garlic, fruit and berries, nuts, vegetable oils, water as
History for cervix surgery 1.7 1.24–2.35 beverage, whole grain cereals, poultry, and fiber rich
Inter-pregnancy interval <12 months 4.2 3.0–6.0 bread, as well as low intake of processed meat products,
Maternal age <18 years 1.7 1.02–3.08 sugar-sweetened beverages, white bread, and pizza) was
Poor socio-economic level 1.75 1.65–1.86 associated with significant reductions in the risk of PTB.11
Single mother 1.61 1.26–2.07 In addition, adherence to a Mediterranean diet has been
Bacterial vaginosis 1.4 1.1–1.8 linked with a reduced PTB risk. Among Danish women,
Asymptomatic bacteriuria 1.5 1.2–1.9 intake of a Mediterranean diet (fish bi-weekly or more,
Vaginal bleeding in early pregnancy 2.0 1.7–2.3 using olive or rape seed oil, >5 portions of fruit and
Vaginal bleeding in late pregnancy 5.9 5.1–6.9 vegetables/day, meat other than poultry and fish at most
Twin pregnancy 6.0 – twice a week, and at most 2 cups of coffee/day) lowered the
Smoking 1.7 1.3–2.2 risk of EPTB by 72%, although PTB risk was not
Periodontitis 2.0 1.2–3.2 significantly reduced.70 Adherence to a dietary pattern
Anemia 1.5 1.1–2.2 similar to Mediterranean diet was associated with a 30%
CI: Confidence interval; OR: Odds ratio. decreased risk of PTB specifically in overweight and obese
–: Not applicable. patients.71

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Tosto et al., Maternal-Fetal Medicine (2020) 2:3
Diet regimens, such as vegetarian diet or predominantly
plant-based diet, both low in vitamin B12, vitamin D, zinc,
eicosaphentaenoic acid and docosahexanoic acid (DHA),
as well as marginal intakes or low status of these nutrients
have been associated with increased PTB risk.11 It is
recommended to obtain eicosaphentaenoic acid and DHA
preformed from additional dietary sources including fish/
seafood and oils from marine animals, such as fish oil
and cod liver oil. DHA intake across the world is variable.
It could be hypothesized that DHA supplementation
reduces the inflammation responsible for both cervical
ripening and spontaneous EPTB.72 Omega 3 fatty acids are
also thought to have an “antiarrhythmic” effect on the
myometrium that may delay the initiation of labor.73
About other macro- and micronutrients, zinc supplemen-
tation has been proposed to reduce the incidence or the
severity of maternal infections, and thereby lower the risk
of PTB.11 Vitamin D deficiency in reproductive-age
women is widespread and low maternal vitamin D status
during pregnancy is a risk factor for various adverse birth
outcomes including PTB. Two recent meta-analyses of
observational studies have shown that vitamin D deficien-
cy as indicated by serum 25 hydroxyvitamin D levels <50
nmol/L is associated with an increased risk of PTB (by an
odds of 1.25–1.29 times).74,75 Table 3 briefly resumes the
main nutrients with known efficacy to reduce the risk of
PTB. Observational studies showed that both anemia and
iron deficiency are associated with increased risk of PTB.11
Recently, a large prospective cohort study performed
in India and Pakistan was published: severe maternal
anemia (according to WHO definition criteria) was
associated with PTB.76 Iron supplementation was evalu-
ated in several reviews. Daily iron supplementation with
iron alone or in combination with folic acid or others
vitamins was found to reduce PTB <34 weeks when
compared to placebo or no treatment.56 It is important
to consider maternal anemia and its related risks of
poor maternal, fetal, and neonatal outcomes, especially in
low/middle-income countries where this condition repre-
sent a crucial health problem. Nutritional counseling, pre-
pregnancy and pregnancy weight control, and weight gain,
nutrients supplementation are important and helpful
primary interventions to reduce the risk of preterm onset
of labor. Obviously, a regular physical activity (especially
aerobic activities) could be associated with a healthy diet,
Table 3
Overview of nutrients with known efficacy to reduce PTB risk.11
Nutrients Evidence for efficacy
n-3 LC-PUFA (combination 26%–61% reduction
of EPA and DHA) in PTB risk
DHA 51.6%–87.5% reduction in
PTB risk before 34 weeks
Zinc 14% PTB risk reduction
Vitamin D 64% PTB risk reduction
25(OH)D: 25-hydroxyvitamin D; DHA: Docosahexanoic acid; EPA: Eicosaphentaenoic acid; LC-PUFA: Long-chain polyunsaturated fatty acids; PTB: Preterm birth.
www.maternal-fetalmedicine.org
in order to reinforce its immunomodulatory and anti-
inflammmatory properties. Risk of PTB was lower in
women who received nutritional education.56
Another goal in the primary PTB prevention strategies is
reducing the risk of infection, especially vaginal infections
and dysbiosis. At this regard, the use of probiotics could
represent a useful tool. It is universally accepted that a certain
proportion of PTB is caused by ascending infections from
vagina underlying the importance of vaginal health.
Moreover, it has been suggested that vaginal dysbiosis
(BV) could trigger an inflammatory cascade leading to PTB
even in the absence of ascending infection. Vaginosis is
characterized by the absence of lactobacilli in addition to the
presence of specific pathogenic organisms, and antibiotics
cannot restore the depleted lactobacilli. Thus, lactobacillus
probiotics could fulfill this role through the production of
lactic acid, lowering vaginal pH, and helping to prevent the
growth of potentially pathogenic microorganisms through.77
In addition, and independently of maintenance of vaginal
health, oral probiotics may act directly in the gut, down-
modulating local and systemic inflammation.78 Data of
scientific literature are not unanimous on recognize the real
positive impact of probiotics for PTB prevention and the
overall conclusion is that there is insufficient evidence and
more research is needed.11
Primary prevention includes also lifestyle changes, stop
smoking, and substance abuse and offer social support in
poor and disadvantages socio-economic situations.56
Recent papers reported evidences that exposure to
environmental contaminants might be a significant
contributing factors for PTB. At this regard, Ferguson
et al. analyzed the association between urinary phthalate
metabolite concentrations measured at 20, 24, and 28
weeks of gestation in Puerto Rico: among pregnant women
in the Puerto Rico Testsite for Exploring Contamination
Threats cohort group, specific phthalate metabolites were
associated with increased odds of PTB.79
Secondary prevention strategies
PTB secondary prevention includes lifestyle and behavior-
al changes, anticoagulant and anti-platelets agents,
progesterone administration, antibiotics, devices.
Accumulating evidences suggests that utero-placental
ischemia plays an important role in the etiology of
Dose Duration
DHA 133–2 199 mg/day Supplementation between 12
EPA 100–3 000 mg/day and 30 weeks
DHA 600–800 mg/day Supplementation started before
20 weeks
5–44 mg/day Supplementation started from as
early as possible (even before
conception)
400–1 000 IU/day (two trials), Supplementation started between
or 6 000–12 000 IU/day 20 and 30 weeks of gestation
(depending on serum
25 (OH)D)(one trial)
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Tosto et al., Maternal-Fetal Medicine (2020) 2:3
spontaneous PTB, comparable to its role in pre-eclampsia.
Thus, studies reported that LDASA alone or in combina-
tion with dipyridamole was found to reduce the risk of
PTB among women at high risk for pre-eclampsia through
its antithrombotic and anti-inflammatory properties.56
LDASA is a promising agent for the PTB prevention, but at
this moment there insufficient evidence to implement low-
dose aspirin in clinical practice. New trials are needed to
confirm the effectiveness of this therapy.80 No advantages
seems derived to low molecular weight heparin and
aspirin, compared to aspirin alone.56
Several clinical studies have found an association
between preterm delivery and BV. It seems to increase
the risk of PTB by more than two times (odds ratio (OR):
2.19, 95% confidence interval (CI): 1.54–3.12); this risk
can increase more than four times when it is identified
before 20 weeks of gestation (OR: 4.20, 95% CI: 2.11–
8.39) and seven times when it is diagnosed before 16 weeks
of pregnancy (OR: 7.55, 95% CI: 1.80–31.65).81 The
exact pathophysiological mechanisms through which BV
could be involved remain unclear. It has been hypothesized
that early antibiotic treatment might prevent some preterm
deliveries. Scientific literature on this topic is not
unanimous. Clindamycin for BV and vaginal candidiasis
therapy were associated with a reduction of PTB.56
Prevention of very preterm delivery by testing for and
treatment of bacterial vaginosis, a double-blind random-
ized controlled trial done in 40 French centers, investigated
whether early clindamycin treatment for BV in pregnancy
decreases spontaneous very PTB. This trial showed that a
systematic screening and subsequent treatment for BV in
pregnant women with low-risk profile had no evidence of
risk reduction of spontaneous very PTB.82
About progesterone use, in contemporary practice its
role in PTB prevention is important. Progesterone is an
essential hormone in the process of reproduction: it has
been largely studied in the treatment of several gynecolog-
ical and obstetrics conditions (contraceptions, abnormal
uterine bleeding, assisted reproductive technologies).
However, its pathophysiology of pregnancy remains
debated. Progesterone, oral or intramuscular, is recog-
nized as an effective prevention strategy in women with
singleton gestations and with previous PTB.83 One review
reported that daily vaginal progesterone is a better
alternative to weekly intramuscular 17-alpha-hydroxy-
progesterone caproate(17-OHPC or 17P) in preventing
PTB <34 weeks (three trials, 680 women, relative risks:
0.71, 95% CI: 0.53–0.95) and PTB <32 weeks (relative
risks: 0.62, 95% CI: 0.40–0.94, low quality evidence).56,84
Recently, Patki et al. proposed a novel noninvasive
approach for PTB prevention using 17P molecule: they
prepared and evaluated a self-nanoemulsifying vaginal
tablet of 17P, with specific characteristics in emulsification
time, particle size, solid state properties, and drugs release.
Vaginal use of 17P (preferable for patient compliance,
fewer side effects and no need for hospitalization than
intramuscular administration) showed significant differ-
ences in PTB rates in pregnant mice population; these
results may have a significant clinical relevance in the
future.85
A 2019 systematic review and meta-analysis on oral
progesterone use for the prevention of recurrent PTB in
singleton pregnancies was performed: it appears to be
168
Maternal-Fetal Medicine
effective for the recurrent PTB prevention and a reduction
in perinatal morbidity and mortality. Further randomized
study on oral progesterone use compared with other better
established therapies for the prevention of reccurrent
preterm delivery are warranted.86
Progesterone supplementation, neither vaginal nor
intramuscular, for women with multiple pregnancies
seems to not reduce PTB risk.56 Herbert et al. described
a possible role of aminophylline (a nonspecific phospho-
diesterase inhibitor that increases intracellular cyclic
adenosine monophosphate levels) and progesterone com-
bined use for the preterm parturition prevention in the
mouse: data obtained on the mouse model suggest that the
combination of these two molecules has a significant
potent anti-inflammatory effect and may be an effective
strategy in women at high risk for PTL, but further
investigations are needed.87
Cerclage and pessary were proposed as other possible
strategies for PTB prevention. Several studies support the
benefit of cerclage for women with singleton pregnancies,
history of PTB, and short mid-trimester cervix <25 mm.
Conde-Agudelo et al. recently compared the efficacy of
vaginal progesterone and cerclage in preventing PTB and
adverse perinatal outcomes in women with a singleton
gestation, previous spontaneous PTB, and a mid-trimester
sonographic short cervix: vaginal progesterone and
cerclage resulted equally effective for preventing PTB
and improving perinatal outcomes in women with a
singleton gestation, previous spontaneous PTB, and a mid-
trimester sonographic short cervix. Thus, the choice of
treatment will depend on adverse events and cost-
effectiveness of interventions and patient/physician’s
preferences.88 Cerclage for multiple pregnancies showed
non-significant effect on PTB.56
Cervical pessary has been tried as a simple, non-invasive
alternative that might replace the cerclage (an invasive
procedure that needs anesthesia) to prevent PTB.
One Cochrane review assessed cervical pessary vs.
expectant management in singleton pregnancies with short
CL and found a reduction in PTB risk.89 Goya et al.
showed that cervical pessary use could prevent PTB in a
population of appropriately selected at-risk women
previously screened for CL assessment at the mid-trimester
scan. Spontaneous delivery before 34 weeks of gestation
resulted significantly less frequent in the pessary group
than in the expectant management group (6% vs. 27%,
respectively, OR: 0.18, 95% CI: 0.08–0.37; P < 0.0001)
and no serious adverse effects associated with the use of a
cervical pessary was reported.90
In 2018 a randomized controlled trial demonstrated that
the cervical pessary was not non-inferior to vaginal
progesterone for preventing spontaneous birth before 34
weeks of gestation in pregnant women with short cervixes
(rate of PTB before 34 weeks of gestation was 14% in the
pessary group and 14% in the progesterone group). The
incidence of increased vaginal discharge (87% vs. 71%,
P = 0.002) and discomfort (27% vs. 3%, P < 0.001) was
significantly higher in the pessary group.91
Later, Barinov et al. analyzed risk factors and predictors
of pregnancy loss and compared the efficacy of Arabin
pessary with cervical cerclage in women at a high risk of
PTB: the two-center retrospective case-control study
demonstrated that the use of the Arabin pessary reduced
Tosto et al., Maternal-Fetal Medicine (2020) 2:3
the rate of PTB by 1.7 fold. Moreover, women with a high
risk treated with Arabin pessary or cerclage plus vaginal
progesterone (200 mg/day until and including 34 weeks of
gestation) had a term delivery rate of 70.4%, demonstrat-
ing that the combined strategy of management allowed to
markedly reduce the PTB cases.92
No conclusive interventions have proved effective to
date in reducing the spontaneous PTB rate in twin
pregnancies. Recently, Merced et al. presented the results
of a randomized controlled trial designed to ascertain
whether cervical pessary could be useful in preventing PTB
in twin pregnancies: significant differences were observed
in PT rate before 34 weeks between the pessary group
(16.4%) vs. the control group (32.3%) after a threatened
PTL episode.93
Conclusions
The multifactorial pathophysiologic pathways that result
in PTB, where biological and social drivers intersect in
unique ways for different women, make difficult to
propose an universal way for the management. At the
moment there are some essential fixed points on PTL:
(1) PTB is “one syndrome, with many causes”.
(2) Early inflammatory activation pathways are the
common denominator of all etiologies, consisting in a
premature shift in signaling between anti-inflammatory to
pro-inflammatory response (increased/decreased expression
of specific chemokines, cytokines, and contraction-associated
proteins).
(3) Well-known risk factors related to this condition may
greatly contribute in the early prediction and prevention
processes.
Thanks to all the previous reported scientific evidences,
it is now possible to improve the primary prevention of
PTL activation and PTB short- and long-term outcomes.
Combined early interventions, often already in the pre-
conceptional period, can have a great clinical and socio-
economic impact. Clearly, complex and eterogeneous
relationships exist between quality of care and subsequent
outcomes worldwide and further researches are needed for
the implementation of the available preventive strategies.
For several of the interventions proposed and evaluated
in the last years, there was insufficient evidence to assess
whether the intervention was really effective or not.
Relevant focal points for the future researches are:
(1) It is recognized that a focus on epidemiology is required
to continue the quest to identify new risk conditions
associated with PTB.
(2) Further research studies are required to identify new
potential biomarkers related to pathways associated
mechanisms leading to PTB.
(3) The identification of the most important risk factors
associated with PTB may have a high priority.
(4) The concept of interventions to prevent PTB would
require the identification of new pathways.
Funding
None.
169
www.maternal-fetalmedicine.org
Conflicts of Interest
None.
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Edited By Yang Pan and Dan-Dan Shi