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Preterm Birth, From the Biological Knowledges to the Prevention: An Overview

Tosto, Valentina1; Giardina, Irene1; Tsibizova, Valentina2; Di Renzo, Gian Carlo1,∗

Editor(s): Pan, YangShi, Dan-Dan

Author Information
doi: 10.1097/FM9.0000000000000054
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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

In 2012, the Born Too Soon report highlighted the 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 Technology (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 of public health worldwide.

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 mechanisms 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 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 fibronection (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 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.

Figure 1
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.

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 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 oxytocin 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 glycosaminoglycans, 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-α 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 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 chemokines, 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 inflammation” is also described as a possible trigger for PTB and p-PROMs.31 An Italian multicentric, observational, retrospective, cross-sectional study, which included 7 631 women, revealed and confirmed the involvement of inflammation/infection in pathogenetic mechanisms leading 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 β-defensin-3 is a physiological constituent of amniotic fluid and increases during the process of labor at term. Amniotic fluid concentrations of human β-defensin-3 resulted increased in women with spontaneous PTL with intact membranes or p-PROMs with intra-amniotic inflammation or intra-amniotic infection, indicating that this defensin participates in the host defense mechanisms in the amniotic cavity against microorganisms 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 supernatant of the probiotic organism Lactobacillus rhamnosus has been found to reduce the lipopolysaccharide inflammatory response in placenta trophoblast cells.37

A really interesting new etiopathogenetic PTBs hypothesis 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 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 factor, angiotensin type 2 receptor gene), and wingless-type MMTV integration site family member 4) achieved genomewide significance.45 Wingless-type MMTV integration 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


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 community, 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 pathogens 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 structure (dysbiosis) may convey an environment of localized inflammation that results in PTB.

Clues for PTB prevention

Basically, three levels of interactions (genetics, environment, 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 multiple pregnancies,61 short CL,62 previous uterine surgeries,63 male sex and nulliparity,57 ethnicity and family history,64 and genetic factors.10,65 In addition, others factors are modifiable, such as nutrition, low socioeconomic status, extremes body mass index (BMI), poor pregnancy weight gain, smoking, substance abuse, short inter-pregnancy interval, periodontal disease, genital infections, late or no prenatal care, untreated antenatal depression, and use of assisted reproductive technologies.66 For these variables clinicians can act an effective prevention, also in the pre-conceptional period, “a critical window” during which health-care professionals can help women to prepare as well as possible for the pregnancy. In the last years, country-based population analysis deepened the maternal risk factors for PTB, providing a global overview of that specific population situation. For example, Di Renzo et al. provided an overview of the Italian situation underlying a significant association between PTB and previous reproductive history, in particular previous preterm delivery (P = 0.0099), previous abortions (P = 0.0116), and previous cesarean section (P = 0.0371). From this analysis also factors as maternal BMI (BMI >25 kg/m2, P = 0.0365) and employment (heavy work, P = 0.0089) resulted associated with an higher PTB risk.67 At this regard, Table 1 resumes the main risk factors related to PTB condition. Table 2 gives an overview about PTB risk factors, their level of association with PTB and presence/absence of available interventions.68

Table 1
Table 1:
Preterm birth risk factors.56–65
Table 2
Table 2:
Risk factors, level of association with PTB, available interventions (Adapted from Goffinet, 2005).55–68

A growing body of scientific evidences described a clearly links between diet, lifestyle, behaviors, and high PTB risk.

There are increasing knowledge that specific diet patterns and nutritional/bioactive interventions are able to modulate inflammation/infection pathways and reduce the risk of PTB.69 Observational studies indicate that poor maternal pre-conceptional nutrition and also during early pregnancy may influence PTB risk.69,70 Pregnant women 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 hypothalamic-pituitary-adrenal axis or an anti-inflammatory effect due to an increased antioxidant intake or attributable to a diet low in saturated fat. Assessment of dietary patterns found that high scores on a “prudent” dietary pattern (higher intakes of vegetables, salad, onion/leek/garlic, fruit and berries, nuts, vegetable oils, water as beverage, whole grain cereals, poultry, and fiber rich bread, as well as low intake of processed meat products, sugar-sweetened beverages, white bread, and pizza) was associated with significant reductions in the risk of PTB.11 In addition, adherence to a Mediterranean diet has been linked with a reduced PTB risk. Among Danish women, intake of a Mediterranean diet (fish bi-weekly or more, using olive or rape seed oil, >5 portions of fruit and vegetables/day, meat other than poultry and fish at most twice a week, and at most 2 cups of coffee/day) lowered the risk of EPTB by 72%, although PTB risk was not significantly reduced.70 Adherence to a dietary pattern similar to Mediterranean diet was associated with a 30% decreased risk of PTB specifically in overweight and obese patients.71

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 supplementation 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 deficiency 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).74,75Table 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 evaluated 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 represent 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, in order to reinforce its immunomodulatory and anti-inflammmatory properties. Risk of PTB was lower in women who received nutritional education.56

Table 3
Table 3:
Overview of nutrients with known efficacy to reduce PTB risk.11

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 behavioral 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 spontaneous PTB, comparable to its role in pre-eclampsia. Thus, studies reported that LDASA alone or in combination 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 randomized 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 gynecological and obstetrics conditions (contraceptions, abnormal uterine bleeding, assisted reproductive technologies). However, its pathophysiology of pregnancy remains debated. Progesterone, oral or intramuscular, is recognized 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-hydroxyprogesterone 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 differences 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 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 phosphodiesterase inhibitor that increases intracellular cyclic adenosine monophosphate levels) and progesterone combined 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 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%, demonstrating 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


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.



Conflicts of Interest



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Premature birth; Biological pathways; Inflammation; Prevention strategies

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