Secondary Logo

Journal Logo

Review

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
  • Open

Abstract

Introduction

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

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 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

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.

Conflicts of Interest

None.

References

[1]. Blencowe H, Cousens S, Chou D, et al. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health 2013;10(Suppl 1):S2. doi:10.1186/1742-4755-10-S1-S2.
[2]. Ferrero DM, Larson J, Jacobsson B, et al. Cross-country individual participant analysis of 4.1 million singleton births in 5 countries with very high human development index confirms known associations but provides no biologic explanation for 2/3 of all preterm births. PLoS One 2016;11(9):e0162506. doi:10.1371/journal.pone.0162506.
[3]. World Health Organization (WHO). Born Too Soon: The Global Action Report on Preterm Birth. Geneva WHO; 2012. Available at: https://www.who.int/pmnch/media/news/2012/201204_borntoosoon-report.pdf.
[4]. Goldenberg RL, Gravett MG, Iams J, et al. The preterm birth syndrome: issues to consider in creating a classification system. Am J Obstet Gynecol 2012;206(2):113–118. doi:10.1016/j.ajog.2011.10.865.
[5]. Kramer MS, Papageorghiou A, Culhane J, et al. Challenges in defining and classifying the preterm birth syndrome. Am J Obstet Gynecol 2012;206(2):108–112. doi:10.1016/j.ajog.2011.10.864.
[6]. Villar J, Papageorghiou AT, Knight HE, et al. The preterm birth syndrome: a prototype phenotypic classification. Am J Obstet Gynecol 2012;206(2):119–123. doi:10.1016/j.ajog.2011.10.866.
[7]. World Health Organization (WHO). WHO Recommendations on Interventions to Improve Preterm Birth Outcomes. Geneva WHO; 2015. Available at: https://apps.who.int/iris/bitstream/handle/10665/183037/9789241508988_eng.pdf?sequence=1.
[8]. Griffin JB, Jobe AH, Rouse D, et al. Evaluating WHO-recommended interventions for preterm birth: a mathematical model of the potential reduction of preterm mortality in Sub-Saharan Africa. Glob Health Sci Pract 2019;7(2):215–227. doi:10.9745/GHSP-D-18-00402.
[9]. Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science 2014;345(6198):760–765. doi:10.1126/science.1251816.
[10]. Di Renzo GC, Tosto V, Giardina I. The biological basis and prevention on preterm birth. Best Pract Res Clin Obstet Gynaecol 2018;52:13–22. doi:10.1016/j.bpobgyn.2018.01.022.
[11]. Samuel TM, Sakwinska O, Makinen K, et al. Preterm birth: a narrative review of the current evidence on nutritional and bioactive solutions for risk reduction. Nutrients 2019;11(8):E1811. doi:10.3390/nu11081811.
[12]. FIGO Working Group on Good Clinical Practice in Maternal-Fetal MedicineGood clinical practice advice: prediction of preterm labor and preterm rupture of membranes. Int J Gynaecol Obstet 2019;144(3):340–346. doi:10.1002/ijgo.12744.
[13]. Di Renzo GC, Cabero Roura L, Facchinetti F, et al. Preterm labor and birth management: recommendations form the European Association of Perinatal Medicine. J Matern Fetal Neonatal 2017;30(17):2011–2030. doi:10.1080/14767058.2017.1323860.
[14]. Nikolova T, Uotila J, Nikolova N, et al. Prediction of spontaneous preterm delivery in women presenting with premature labor: a comparison of placenta alpha microglobulin-1, phosphorylated insulin-like growth factor binding protein-1, and cervical length. Am J Obstet Gynecol 2018;219(6):610.e1–610.e9. doi:10.1016/j.ajog.2018.09.016.
[15]. Darghahi R, Mobaraki-Asl N, Ghavami Z, et al. Effect of cell-free fetal DNA on spontaneous preterm labor. J Adv Pharm Technol Res 2019;10(3):117–120. doi:10.4103/japtr.JAPTR_371_18.
[16]. Goncalves LF, Chaiworapongsa T, Romero R. Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev 2002;8(1):3–13. doi:10.1002/mrdd.10008.
[17]. Romero R, Espinoza J, Chaiworaponqsa T, et al. Infection and prematurity and the role of preventive strategies. Semin Neonatol 2002;7(4):259–274. doi:10.1016/s1084-2756(02)90121-1.
[18]. Bruinsma FJ, Quinn MA. The risk of preterm birth following treatment for precancerous changes in the cervix: a systematic review and meta-analysis. BJOG 2011;118(9):1031–1041. doi:10.1111/j.1471-0528.2011.02944.x.
[19]. Norwitz ER, Edusa V, Park JS. Maternal physiology and complications of multiple pregnancy. Semin Perinatol 2005;29(5):338–348. doi:10.1053/j.semperi.2005.08.002.
[20]. Mesiano S. Roles of estrogen and progesterone in human parturition. Front Horm Res 2001;27:86–104. doi:10.1159/000061038.
[21]. Wadhwa PD, Culhane JF, Rauh V, et al. Stress and preterm birth: neuroendocrine, immune/inflammatory and vascular mechanisms. Matern Child Health J 2001;5(2):119–125. doi:10.1023/a:1011353216619.
[22]. Romero R, Kusanovic JP, Muñoz H, et al. Allergy induced preterm labor after the ingestion of shellfish. J Matern Fetal Neonatal Med 2010;23(4):351–359. doi:10.3109/14767050903177193.
[23]. Norwitz ER, Bonney EA, Snegovskikh VV, et al. Molecular regulation of parturition: the role of the decidual clock. Cold Spring Harb Perspect Med 2015;5(11):a023143. doi:10.1101/cshperspect.a023143.
[24]. Romero R, Espinoza J, Goncalves LF, et al. Inflammation in preterm and term labour and delivery. Semin Fetal Neonatal Med 2006;11(5):317–326. doi:10.1016/j.siny.2006.05.001.
[25]. Romero R, Mazor M, Wu YK, et al. Infection in the pathogenesis of preterm labor. Semin Perinatol 1988;12(4):262–279.
[26]. Menon R, Taylor RN, Fortunato SJ. Chorioamnionitis–a complex pathophysiologic syndrome. Placenta 2010;31(2):113–120. doi:10.1016/j.placenta.2009.11.012.
[27]. Abrahams VM, Potter JA, Bhat G, et al. Bacterial modulation of human fetal membrane toll-like receptor expression. Am J Reprod Immunol 2013;69(1):33–40. doi:10.1111/aji.12016.
[28]. Bhat G, Peltier MR, Syed TA, et al. Fetal membrane biomarker network diversity and disease functions induced by intra-amniotic pathogens. Am J Reprod Immunol 2013;69(2):124–133. doi:10.1111/aji.12047.
[29]. Menon R, Peltier MR, Eckardt J, et al. Diversity in cytokine response to bacteria associated with preterm birth by fetal membranes. Am J Obstet Gynecol 2009;201(3):306.e1–306.e6. doi:10.1016/j.ajog.2009.06.027.
[30]. Peltier MR, Drobek CO, Bhat G, et al. Amniotic fluid and maternal race influence responsiveness of fetal membranes to bacteria. J Reprod Immunol 2012;96(1–2):68–78. doi:10.1016/j.jri.2012.07.006.
[31]. Musilova I, Kutova R, Pliskova L, et al. Intramniotic inflammation in women with preterm prelabor rupture of membranes. PLoS One 2015;10(7):e0133929. doi:10.1371/journal.pone.0133929.
[32]. Torricelli M, Conti N, Galeazzi LR, et al. Epidemiology of early pre-term delivery: relationship with clinical and histopathological infective parameters. J Obstet Gynaecol 2013;33(2):140–143. doi:10.3109/01443615.2012.743980.
[33]. Aagaard K, Ma J, Antony KM, et al. The placenta harbors a unique microbiome. Sci Transl Med 2014;6(237):237ra65. doi:10.1126/scitranslmed.3008599.
[34]. Para R, Romero R, Miller D, et al. Human β-defensin-3 participates in intra-amniotic host defense in women with labor at term, spontaneous preterm labor and intact membranes, and preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med 2019;18:1–16. doi:10.1080/14767058.2019.1597047.
[35]. Myhre R, Branstaeter AL, Myking S, et al. Intake of probiotic food and risk of spontaneous preterm delivery. Am J Clin Nutr 2011;93(1):151–157. doi:10.3945/ajcn.110.004085.
[36]. Branstaeter AL, Myhre R, Haugen M, et al. Intake of probiotic food and risk of preeclampsia in primiparous women: the Norwegian Mother and Child Cohort Study. Am J Epidemiol 2011;174(7):807–815. doi:10.1093/aje/kwr168.
[37]. Yeganegi M, Watson CS, Martins A, et al. Effect of lactobacillus rhamnosus GR-1 supernatant and fetal sex on lipopolyssaccharide-induced cytokine and prostaglandin-regulating enzymes in human placental trophoblast cells: implications for treatment of bacterial vaginosis and prevention of preterm labor. Am J Obstet Gynecol 2009;200(5):532.e1–532.e8. doi:10.1016/j.ajog.2008.12.032.
[38]. Gomez-Lopez N, Romero R, Xu Y, et al. Fetal T cell activation in the amniotic cavity during preterm labor: a potential mechanism for a subset of idiopathic preterm birth. J Immunol 2019;203(7):1793–1807. doi:10.4049/jimmunol.1900621.
[39]. Bezold KY, Karjalainen MK, Hallman M, et al. The genomics of preterm birth: from animal models to human studies. Genome Med 2013;5(4):34. doi:10.1186/gm438.
[40]. Clausson B, Lichtenstein P, Cnattingius S. Genetic influence on birthweight and gestational length determined by studies in offspring of twins. BJOG 2000;107(3):375–381. doi:10.1111/j.1471-0528.2000.tb13234.x.
[41]. 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. doi:10.1093/aje/kwt005.
[42]. Plunkett J, Feitosa MF, Trusgnich M, et al. Mother's genome or maternally-inherited genes acting in the fetus influence gestational age in familial preterm birth. Hum Hered 2009;68(3):209–219. doi:10.1159/000224641.
[43]. Kistka ZA, DeFranco EA, Ligthart L, et al. Heritability of parturition timing: an extended twin design analysis. Am J Obstet Gynecol 2008;199(1):43.e1–43.e5. doi:10.1016/j.ajog.2007.12.014.
[44]. Boyd HA, Poulsen G, Wohlfahrt J, et al. Maternal contributions to preterm delivery. Am J Epidemiol 2009;170(11):1358–1364. doi:10.1093/aje/kwp324.
[45]. Zhang G, Feenstra B, Bacelis J, et al. Genetic association with gestational duration and spontaneous preterm birth. N Engl J Med 2017;377(12):1156–1167. doi:10.1056/NEJMoa1612665.
[46]. Tarquini F, Picchiassi E, Coata G, et al. Induction of the apoptotic pathway by oxidative stress in spontaneous preterm birth: single nucleotide polymorphisms, maternal lifestyle factors and health status. Biomed Rep 2018;9(1):81–89. doi:10.3892/br.2018.1103.
[47]. Koucký M, Malíčková K, Hrdý J, et al. The role of maternal imunity and woman's microbiome in the pathogenesis of preterm labor. Ceska Gynekol 2017;82(5):407–410.
[48]. Cho I, Blaser MJ. The human microbiome: at the interface of health and disease. Nat Rev Genet 2012;13(4):260–270. doi:10.1038/nrg3182.
[49]. Cobb CM, Kelly PJ, Williams KB, et al. The oral microbiome and adverse pregnancy outcomes. Int J Womens Health 2017;9:551–559. doi:10.2147/IJWH.S142730.
[50]. Doyle RM, Harris K, Kamiza S, et al. Bacterial communities found in placental tissues are associated with severe chorioamnionitis and adverse birth outcomes. PLoS One 2017;12(7):e0180167. doi:10.1371/journal.pone.0180167.
[51]. Antony KM, Ma J, Mitchell KB, et al. The preterm placental microbiome varies in association with excess maternal gestational weight gain. Am J Obstet Gynecol 2015;212(5):653.e1–653.e16. doi:10.1016/j.ajog.2014.12.041.
[52]. Amabebe E, Reynolds S, Stern V, et al. Cervicovaginal fluid acetate: a metabolite marker of preterm birth in symptomatic pregnant women. Front Med (Lausanne) 2016;3:48. doi:10.3389/fmed.2016.00048.
[53]. Wardwell LH, Huttenhower C, Garrett WS. Current concepts of the intestinal microbiota and pathogenesis of infection. Curr Infect Dis Rep 2011;13(1):28–34. doi:10.1007/s11908-010-0147-7.
[54]. Maymon E, Romero R, Bhatti G, et al. Chronic inflammatory lesions of the placenta are associated with an up-regulation of amniotic fluid CXCR3: a marker of allograft rejection. J Perinat Med 2018;46(2):123–137. doi:10.1515/jpm-2017-0042.
[55]. Son M, Miller ES. Predicting preterm birth: cervical length and fetal fibronectin. Semin Perinatol 2017;41(8):445–451. doi:10.1053/j.semperi.2017.08.002.
[56]. Matei A, Saccone G, Vogel JP, et al. Primary and secondary prevention of preterm birth: a review of systematic reviews and ongoing randomized controlled trials. Eur J Obstet Gynecol Reprod Biol 2019;236:224–239. doi:10.1016/j.ejogrb.2018.12.022.
[57]. Ferrero DM, Larson J, Jacobsson B, et al. Cross-country individual participant analysis of 4.1 million singleton births in 5 countries with very high human development index confirms known associations but provides no biologic explanation for 2/3 of all preterm births. PLos One 2016;11(9):e0162506. doi:10.1371/journal.pone.0162506.
[58]. van Zijl MD, Koullali B, Mol BW, et al. Prevention of preterm delivery: current challenges and future prospects. Int J Womens Health 2016;8:633–645. doi:10.2147/IJWH.S89317.
[59]. Leader J, Bajwa A, Lanes A, et al. The effect of very advanced maternal age on maternal and neonatal outcomes: a systematic review. J Obstet Gynaecol Can 2018;40(9):1208–1218. doi:10.1016/j.jogc.2017.10.027.
[60]. Mayo JA, Shachar BZ, Stevenson DK, et al. Nulliparous teenagers and preterm birth in California. J Perinat Med 2017;45(8):959–967. doi:10.1515/jpm-2016-0313.
[61]. Fuchs F, Senat MV. Multiple gestations and preterm birth. Semin Fetal Neonatal Med 2016;21(2):113–120. doi:10.1016/j.siny.2015.12.010.
[62]. Berghella V. Universal cervical length screening for prediction and prevention of preterm birth. Obstet Gynecol Surv 2012;67(10):653–658. doi:10.1097/OGX.0b013e318270d5b2.
[63]. Lemmers M, Verschoor MA, Hooker AB, et al. Dilatation and curettage increases the risk of subsequent preterm birth: a systematic review and meta-analysis. Hum Reprod 2016;31(1):34–45. doi:10.1093/humrep/dev274.
[64]. Smid MC, Lee JH, Grant JH, et al. Maternal race and intergenerational preterm birth recurrence. Am J Obstet Gynecol 2017;217(4):480.e1–480.e9. doi:10.1016/j.ajog.2017.05.051.
[65]. Manuck TA. The genomics of prematurity in an era of more precise clinical phenotyping: a review. Semin Fetal Neonatal Med 2016;21(2):89–93. doi:10.1016/j.siny.2016.01.001.
[66]. Jarde A, Morais M, Kingston D, et al. Neonatal outcomes in women with untreated antenatal depression compared with women without depression. JAMA Psychiatry 2016;73(8):826–837. doi:10.1001/jamapsychiatry.2016.0934.
[67]. Di Renzo GC, Giardina I, Rosati A, et al. Maternal risk factors for preterm birth: a country-based population analysis. Eur J Obstet Gynecol Reprod Biol 2011;159(2):342–346. doi:10.1016/j.ejogrb.2011.09.024.
[68]. Goffinet F. Primary predictors of preterm labour. BJOG 2005;112(Suppl 1):38–47. doi:10.1111/j.1471-0528.2005.00583.x.
[69]. FIGO Working Group on Good Clinical Practice in Maternal-Fetal MedicineGood clinical practice advice: micronutrients in the periconceptional period and pregnancy. Int J Gynaecol Obstet 2019;144(3):317–321. doi:10.1002/ijgo.12739.
[70]. Mikkelsen TB, Osterdal ML, Knudsen VK, et al. Association between a Mediterranean-type diet and risk of preterm birth among Danish women: a prospective cohort study. Acta Obstet Gynecol Scand 2008;87(3):325–330. doi:10.1080/00016340801899347.
[71]. Saunders L, Guldner L, Costet N, et al. Effect of a Mediterranean diet during pregnancy on fetal growth and preterm delivery: results from a French Caribbean Mother-Child Cohort Study (TIMOUN). Paediatr Perinat Epidemiol 2014;28(3):235–244. doi:10.1111/ppe.12113.
[72]. Moltó-Puigmartí C, Van Dongen MCJM, Dagnelie PC, et al. Maternal but not fetal FADS gene variants modify the association between maternal long-chain PUFA intake in pregnancy and birth weight. J Nutr 2014;144(9):1430–1437. doi:10.3945/jn.114.194035.
[73]. Olsen SF, Secher NJ, Björnsson S, et al. The potential benefits of using fish oil in relation to preterm labor: the case for a randomized controlled trial? Acta Obstet Gynecol Scand 2003;82(11):978–982. doi:10.1034/j.1600-0412.2003.00334.x.
[74]. Zhou SS, Tao YH, Huang K, et al. Vitamin D and risk of preterm birth: up-to-date meta-analysis of randomized controlled trials and observational studies. J Obstet Gynaecol Res 2017;43(2):247–256. doi:10.1111/jog.13239.
[75]. Qin LL, Lu FG, Yang SH, et al. Does maternal vitamin D deficiency increase the risk of preterm birth: a meta-analysis of observational studies. Nutrients 2016;8(5):E301. doi:10.3390/nu8050301.
[76]. Parks S, Hoffman MK, Goudal SS, et al. Maternal anemia and maternal, fetal, and neonatal outcomes in a prospective cohort study in India and Pakistan. BJOG 2019;126(6):737–743. doi:10.1111/1471-0528.15585.
[77]. Al-Ghazzewi FH, Tester RF. Biotherapeutic agents and vaginal health. J Appl Microbiol 2016;121(1):18–27. doi:10.1111/jam.13054.
[78]. Hemarajata P, Versalovic J. Effects of probiotics on gut microbiota: mechanisms of intestinal immunomodulation and neuromodulation. Therap Adv Gastroenterol 2013;6(1):39–51. doi:10.1177/1756283X12459294.
[79]. Ferguson K, Rosen EM, Rosario Z, et al. Environmental phtalate exposure and preterm birth in the PROTECT birth cohort. Environ Int 2019;132:105099. doi:10.1016/j.envint.2019.105099.
[80]. Landman AJEMC, Oudijk MA. Low-dose aspirin as a promising agent for the prevention of spontaneous preterm birth. Evid Based Nurs 2019;22(3):82–83. doi:10.1136/ebnurs-2018-102998.
[81]. Leitich H, Bodner-Adler B, Brunbauer M, et al. Bacterial vaginosis as a risk factor for preterm delivery: a meta-analysis. Am J Obstet Gynecol 2003;189(1):139–147. doi:10.1067/mob.2003.339.
[82]. Subtil D, Brabant G, Tilloy E, et al. Early clindamycin for bacterial vaginosis in pregnancy (PREMEVA): a multicentre, double-blind, randomised controlled trial. Lancet 2018;392(10160):2171–2179. doi:10.1016/S0140-6736(18)31617-9.
[83]. Di Renzo GC, Giardina I, Clerici G, et al. The role of progesterone in maternal and fetal medicine. Gynecol Endocrinol 2012;28(11):925–932. doi:10.3109/09513590.2012.730576.
[84]. Saccone G, Khalifeh A, Elimian A, et al. Vaginal progesterone vs intramuscular 17alfa-hydroxiprogesterone caproate for prevention of recurrent spontaneous preterm birth in singleton gestations: systematic review and meta-analysis of randomized controlled trials. Ultrasound Obstet Gynecol 2017;49(3):315–312. doi:10.1002/uog.17245.
[85]. Patki M, Giusto K, Gorosiya S, et al. 17-Alpha hydroxyprogesterone nanoemulsigying preconcentrate-loaded vaginal tablet: a novel non-invasive approach for the prevention of preterm birth. Pharmaceutics 2019;11(7):E335. doi:10.3390/pharmaceutics11070335.
[86]. Boelig RC, Della Corte L, Ashoush S, et al. Oral progesterone for the prevention of recurrent preterm birth: systematic review and metaanalysis. Am J Obstet Gynecol MFM 2019;1(1):50–62. doi:10.1016/j.ajogmf.2019.03.001.
[87]. Herbert BR, Markovic D, Georgiou E, et al. Aminophylline and progesterone prevent inflammation-induced preterm parturition in the mouse. Biol Reprod 2019;101(4):813–822. doi:10.1093/biolre/ioz112.
[88]. Conde-Agudelo A, Romero R, Da Fonseca E, et al. Vaginal progesterone is as effective as cervical cerclage to prevent preterm birth in women with a singleton gestation, previous spontaneous preterm birth, and a short cervix: updated indirect comparison meta-analysis. Am J Obstet Gynecol 2018;219(1):10–25. doi:10.1016/j.ajog.2018.03.028.
[89]. Abdel-Aleem H, Shaaban OM, Abdel-Aleem MA. Cervical pessary for preventing preterm birth. Cochrane Database Syst Rev 2013;2013(5):CD007873. doi:10.1002/14651858.CD007873.pub3.
[90]. Goya M, Pratcorona L, Merced C, et al. Cervical pessary in pregnant women with a short cervix (PECEP): an open-label randomised controlled trial. Lancet 2012;379(9828):1800–1806. doi:10.1016/S0140-6736(12)60030-0.
[91]. Cruz-Melquizo S, San-Frutos L, Martinez-Payo C, et al. Cervical pessary compared with vaginal progesterone for preventing early preterm birth: a randomized controlled trial. Obstet Gynecol 2018;132(4):907–915. doi:10.1097/AOG.0000000000002884.
[92]. Barinov SV, Artymuk NV, Novikova ON, et al. Analysis of risk factors and predictors of pregnancy loss and strategies for the management of cervical insufficiency in pregnant women at a high risk of preterm birth. J Matern Fetal Neonatal Med 2019;3:1–9. doi:10.1080/14767058.2019.1656195.
[93]. Merced C, Goya M, Pratcorona L, et al. Cervical pessary for preventing preterm birth in twin pregnancies with maternal short cervix after an episode of threatened preterm labor: randomised controlled trial. Am J Obstet Gynecol 2019;221(1):55.e1–55.e14. doi:10.1016/j.ajog.2019.02.035.
Keywords:

Premature birth; Biological pathways; Inflammation; Prevention strategies

Copyright © 2020 The Chinese Medical Association, published by Wolters Kluwer Health, Inc.