In total, 378 pregnant women before 28 weeks of gestation at risk of SPTB were hospitalized at Toyama University Hospital between April 2000 and March 2008. We excluded patients with multiple pregnancies, fetal growth restriction (less than −1.5 S.D.), congenital fetal anomalies, an abnormal fetal karyotype, preeclampsia, gestational diabetes mellitus, a history of cervical surgery, uterine anomalies, and steroid users. We also excluded patients with PTL and pPROM.

Cases in which bag formation of visible bulging membranes was detected in a digital speculum (Cuzco) examination were also excluded. In the present study, cervical insufficiency was defined as visible bulging fetal membranes from the cervix in asymptomatic pregnant women with or without a previous history of SPTB [2]. And “asymptomatic” was defined as a pregnant woman who visited hospital for routine pregnancy check-up. Therefore, the study population was considered to be normal pregnant women without an evaluation by a sonographic examination.

Cervical length was routinely measured every 2 weeks between 20 and 28 weeks of gestation with or without clinical symptoms, such as genital bleeding. The length between the internal and external os was assessed by transvaginal ultrasonography.

When asymptomatic pregnant women with a sonographic short cervix were identified in the outpatient clinic, hospitalization for physical rest was recommended. Generally, hospitalization is an exaggerated management (overtreatment), however, our treatment policy was to perform cervical cerclage immediately, when the cervix is suddenly shorter. After hospitalization, we evaluated cervical length every day for first week, and one or two times per week after the first week. Cardiotocogram (CTG) monitoring was also performed one or two times per day. Management strategies, such as therapeutic cerclage (McDonald’s cerclage), and maintenance tocolysis [29] [30] were carried out in each case at the discretion of the attending obstetricians. Vaginal progesterone was not administered because it was not covered by the national health insurance system of Japan. Patients were hospitalized from admission to 28 - 30 weeks of gestation. Cases without clinical symptoms, such as regular uterine contractions, were discharged from the hospital and managed in the outpatient clinic.

Transabdominal amniocentesis for research purpose was performed within 2 days of admission after informed written consent had been obtained. The Ethics Committee (No.187) of Toyama University Hospital approved amniocentesis for patients at risk of SPTB to evaluate the AF-IL-8 and infection. Intra-amniotic microbes were evaluated by culture system. Approximately 5 - 10 mL of amniotic fluid (AF) was obtained. Amniocentesis was only performed on asymptomatic pregnant women with a sonographic short cervix until March 2008 because of the rarity of asymptomatic cases with severe intra-amniotic inflammation and/or infection.

Demographic and clinical data [maternal age, nullipara, a history of SPTB, pre-pregnancy body mass index (BMI), smoking during pregnancy, gestational weeks on admission, maternal body temperature, WBC, CRP, cervical length, Nugent score, fFN in vaginal secretions, CM-IL-8, AF-IL-8, AF-glucose, AF-WBC, AF-microbes, tocolysis, cerclage, gestational weeks at birth, neonatal birth weight, still birth, Apgar scores, and admission to the NICU] were collected and compared between delivery at <34 weeks and ≥34 weeks [31].

Risk factors associated with preterm delivery at <34 weeks of gestation (PTD at <34 weeks) were assessed using a univariate analysis, which was performed using the χ²-test or Mann-Whitney U test, where appropriate. Cut-off values for risk factors were analyzed using a receiver operating characteristics (ROC) curve, and independent risk factors were investigated using a multiple regression logistic analysis. All analyses were performed using statistical analysis software (JMP, version 11.2.0; SAS Institute Inc., Tokyo, Japan). A p-value < 0.05 was considered to be significant.

We also discussed the pathology and management strategy for asymptomatic pregnant women with a short cervix based on the results of this retrospective study.

We generally examine cervical length using ultrasonography in the outpatient clinic between 22 to 24 weeks of gestation because a short cervix is a pre-sign of SPTB. The early detection of this pre-sign before the appearance of clinical symptoms, such as cervical insufficiency (visible bag formation), PTL, or pPROM, looks to be beneficial.

Management strategies for asymptomatic pregnant women with a short cervix include the administration of progesterone [32] [33] [34], therapeutic cerclage [35] [36] [37], a vaginal pessary [38] [39] [40]. However, these treatment strategies had not been administered according to each etiology. The strategy based on the pathological condition may improve the prognosis. On the other hand, previous studies pointed out that the pregnant women with a short cervix had delivered at term without treatment in most cases [41] [42] [43]. Therefore, observation without treatment would be better choice in some cases.

In the present study, the following 5 risk factors for PTD at <34 weeks were identified in the univariable analysis; a history of SPTB, gestational weeks on admission ≤23 weeks, AF-IL-8 ≥2.4 ng/mL, CM-IL-8 ≥803.5 ng/mL, and cervical length ≤15 mm. Therefore, management strategies according to each risk factor are possible. In particular, CM-IL-8 and cervical length were identified as independent risk factors.

Although there was a significant difference in amniotic inflammation by univariable analysis, the level of inflammation was extremely low [24]. It is clinically important that the intra-uterine environment is still maintained in asymptomatic pregnant women with short cervix.

Based on our previous findings, CM-IL-8 ≥803.5 ng/mL indicates severe cervical inflammation (cervicitis >360 ng/mL) [44], which may be strongly associated with SPTB. In the pathology of asymptomatic short cervical cases, cervical inflammation may play a crucial role in shortening mechanisms.

Progesterone exerts anti-inflammatory effects [45] [46], and natural progesterone is often used in the treatment of asymptomatic short cervical cases to prevent SPTB [8] [34] [47]. Therefore, the present results may indicate its efficacy against local severe inflammation in the cervix.

Decreases in cervical length may increase the risk of SPTB [48]. In the present study, cervical length ≤15 mm was identified as an independent risk factor for PTD at <34 weeks with or without a history of SPTB. Previous studies reported a correlation between a short cervix ≤15 mm and SPTB [49] [50], which is consistent with the present results.

The efficacy of therapeutic cerclage has been suggested for patients with a short cervix ≤15 mm [51] [52] [53]. Therapeutic cerclage was recently shown to significantly reduce PTD at <35 weeks of gestation in patients with a short cervix <10 mm and no history of SPTB, who are at a high risk of SPTB [37]. Considering these reports and our results, the therapeutic cerclage is not necessary for cases with cervical length more than 16 mm.

The present study had the following strengths: 1) Although the etiology of or risk factors for SPTB in asymptomatic short cervical pregnant women have been extensively examined, there is no report that which factors associated with SPTB is more important by a multiple regression analysis. 2) This is the first study to clarify whether cervical or intra-amniotic inflammation is more important using inflammatory markers, such as IL-8. 3) The present results advocate the clinical concept that manages patients with a short cervix according to each individual cause. Therefore, the present results may lead to be a new logical and novel management strategy. For example, hospitalization, progesterone, and cerclage may not be necessary in asymptomatic short cervical cases at a low risk of SPTD. We previously reported that elevated CM-IL-8 in cerclage cases was an indicator of SPTD [35].

The present study had the following limitations: 1) The number of patients examined was small (73 cases), the 95% confidence interval (CI) was larger, and clinical data were gathered from a single hospital; however, further studies with a large number of patients will increase its significance. 2) Although severe cervicitis is significant risk factor for PTD at <34 weeks, the cause of cervicitis was not identified in the present study. Vaginal microbes, such as bacteria and/or Ureaplasma/Mycoplasma [54], which have recently been reported to correlate with SPTB [55] [56], may contribute to severe cervicitis; however, the Nugent score was not related in this study. 3) Although the rate of therapeutic cerclage for a short cervix was high, a significant difference was not observed between the two groups (PTD at <34 weeks vs. Delivery at ≥34 weeks).

In the management of asymptomatic pregnant woman with a short cervix, we propose the selection of suitable strategies based on each etiology. Therefore, the mechanisms contributing to cervical shortening without clinical symptoms need to be elucidated. Furthermore, large clinical studies, such as randomized controlled trials, are needed to clarify the ascending mechanisms of vaginal, cervical, and intra-amniotic inflammation and/or infection.