**9. Combination of therapeutic approaches**

In a systematic review and statistical meta-analysis that included both randomized and non-randomized studies, it was found that only seven studies could be included in the review, which only involved singleton pregnancies, and there was no data on twin pregnancies.

This review found that there was no difference in reducing the risk of preterm delivery before 34 weeks gestation when the combination therapy including vaginal pessary and progesterone was compared with pessary monotherapy (RR 1.3, 95% CI 0.7, 2.42) or administration of progesterone (RR 1.16, 95% CI 0.79, 1.72). In addition, there was no difference in the reduction of preterm birth before 37 weeks gestation when the combined treatment of cervical banding and progesterone administration was compared with cervical banding alone (RR 1.04, 95% CI 0.56, 1.93) or progesterone administration. (RR 0.82, 95% CI 0.57, 1.19) [48, 51–54].

However, as mentioned above, these data are limited and related to singleton pregnancies, while there is no data on twin pregnancies.

Since the 22nd week of gestation and every 2 weeks, there was a steady gradual decrease in the cervical length of the study population. The pattern of this decrease was even present in women who did not eventually give birth before 32 weeks of gestation, and this finding was consistent with existing literature data [48, 51–54]. Ramin observed that this decline became apparent after the 20th week of pregnancy, while Hiersch observed a faster rate of cervical length reduction in triplet pregnancies compared to that noted in twin pregnancies. However, a sharp decrease in cervical length from the 22nd to the 24th week of gestation appeared to be specific to triplet pregnancies that are at increased risk for preterm delivery between 24 and 32 weeks of gestation.

Although in many studies in triplet pregnancies, a short cervix is characterized the one that is less than 25 mm, with a cervical length of 34–35 mm, with sensitivity and specificity of 60–80% and 70–90% respectively, considered as critical in this study. A study conducted by Mheen is one of the few in which the cervical length limit has been set to 30 mm. By applying this limit, however, a predictive accuracy of 87.4% has been achieved. Ideally, this accuracy would reach 100%, something previously attempted through the acceptance of the 20 mm threshold between 25 and 28 weeks of gestation, a limit, though, inconsistent with the findings of the current study. Wherever the "critically short" cervical threshold is set in the various studies, it is advisable to keep in mind that women with shorter cervical lengths may have already been led to miscarriages in the second trimester of pregnancy or to preterm birth and therefore not being included in the sample of the study population. However, all described cervical length limits appear to be relevant in clinical practice, and none of them should be considered more accurate and significant than others [48, 51–54].

Concerning the chorionity of the triplet pregnancies, no significant difference was found in cervical lengths. Thus, chorionity was excluded from the prognostic parameters for preterm birth below 32 weeks of gestation in this study, which is not in the AMPHIA study, and the study of Perdigao and colleagues. Therefore, as far as the chorionicity in multiple pregnancies is concerned, it is important to deduct more studies with larger numbers of samples to draw safer conclusions [48, 51–54].

The usefulness of measuring the cervical length at different stages of pregnancy has been investigated in addition to doing so during the second trimester of pregnancy using transvaginal ultrasonography. There is a relatively small number of studies evaluating the sensitivity of the cervical length measured before the 16th week of pregnancy in predicting preterm birth, with the results being controversial [54–58].

Studies by Naim, Berghella, and Andrews found a strong association between short cervical length and preterm labor. A study by Hassan found that a "short" cervix at 14–19 weeks is a weaker predictor of preterm birth than an ultrasound assessment of cervical length in mid-pregnancy. Contradictory results were presented by Hasegawa, as well as by Zorzoli, who found in their studies no association between "early" cervical ultrasound assessment and preterm birth [54–58].

Conoscenti in a study with a sample of 2469 women with singleton pregnancies measured cervical length at 13–15 weeks of pregnancy aiming to calculate the risk of preterm birth. It was found that the average gestational age at birth was 40 weeks, with the incidence of preterm birth being 1.7%. In this study, early risk factors, such as previous history of preterm birth, were found to be consistent with those of other studies, and the main finding of this study was the inability to predict women who would eventually be led to premature birth since cervical length was similar to women who gave birth at term compared to the ones who gave birth prematurely, regardless of the presence of risk factors. In other words, the cervical length measured at 14 weeks of gestation appeared in this study, similar between women at high risk of preterm birth and women at low risk [54–58].

This finding is also not in accordance with other studies that show a strong relationship between cervical length's shortening in mid-pregnancy and a history of previous second-trimester miscarriages or preterm births. A possible explanation for this may be the association of a history of previous preterm birth with the risk of preterm birth, a finding presented also by Heath, who recorded apparent cervical lengthening alterations, after mid-pregnancy in the second trimester of pregnancy. A study conducted by Greco, with a sample of 9974 singleton pregnancies and with ultrasonographic cervical length assessment at 11–13 weeks of gestation to assess the risk of preterm birth, found that labor before 34 weeks of gestation, concerning 1% of the study population, could be predicted at 54.8% (95% CI 44.7–64.6) and with false negative rates of 10%, by combining cervical length with various features of the pregnant woman.

A similar study conducted by Sananes, with a sample of 31,834 pregnancies, seemed to detect at 23.3%, with a 10% false negative rate, preterm birth, which accounted for 3.7% of the study population, by ultrasound assessment of cervical length in the first trimester of pregnancy. In another study by Carvalho, cervical length was estimated in the first (11–14 weeks) and second trimester (22–24 weeks) of pregnancy in a random population of singleton pregnancies. The mean cervical length at 11–14 weeks of gestation was found to be 42.4 mm and 38.6 mm at 22–24 weeks of gestation. These findings of the above-mentioned study are consistent with those of other studies. In a study by Zalar, an ultrasound assessment of cervical length in the first trimester of pregnancy (11.3 ± 1.9 weeks) revealed an average cervical length of 46 mm in a low-risk population of pregnant women. In another study by Kushnir, which included 166 low-risk preterm labor women, cervical length was measured at 8–13 weeks of gestation and found to be 43 mm. Moreover, in a study by Guzman, cervical length assessment was performed in 469 high-risk preterm

labor women with continuous ultrasound measurements between 14 and 24 weeks of gestation. Thus, the cervical length was found to be shorter at 21–24 weeks of gestation than at 15–20 weeks of gestation [54–58].

Cervical length during the first trimester of pregnancy, as shown by the above studies, appears to be even longer than that of non-pregnant premenopausal women. This could probably be explained by understanding the role that the lower part of the uterus plays in the cervical segment in the first trimester of pregnancy.

Carvalho observed that cervical length showed a gradual shortening from the first to the second trimester of pregnancy. This decrease in cervical length, however, was more obvious in the group of women who eventually had preterm birth. Cervical length ranged from 42.7 to 39.3 mm in women who gave birth at term, whereas in women who gave birth prematurely, cervical length decreased from 40.6 mm at 11–14 weeks of gestation to 26.7 mm at 22–24 weeks of pregnancy. Given these data, in the group of the women that will have premature birth, the decrease in cervical length occurs between the first and second trimester of pregnancy, and the degree of cervical shortening is related to the degree of prematurity. Guzman has also described this model of cervical shortening, presenting the weekly rate of cervical shortening between 15 and 24 weeks of gestation in women at high risk of preterm birth. To establish the ultrasonographic diagnosis of cervical insufficiency it was necessary in this study to find a progressive decrease in cervical length below 20 mm before 24 weeks gestation. Sufficient cervices showed a non-significant decrease in cervical length (−0.3 mm/week) compared to "insufficient" cervices (−4.1 mm/week, P < 0.001). In a study presented by Murakawa, which evaluated the cervical length in 32 women with threatened preterm labor and in 177 normal singleton pregnancies between 18 and 37 weeks of gestation, it was found that cervical length in women with threatened preterm labor was even shorter in women who also had history of preterm birth (23.2 mm compared to 31.7 mm in women with a free history of prematurity) [58–62]. In addition to looking at the significance of cervical length during the first trimester of pregnancy, numerous studies also analyze cervical length during the third trimester of pregnancy to evaluate the risk of preterm birth, but mostly to forecast the time of delivery.

Regarding the correlation of cervical length during the third trimester of pregnancy with preterm delivery, in a study of Papastefanou in 1180 low-risk singleton pregnancies cervical length was measured by ultrasound at 24–30 weeks of gestation. It was found that 0.85% of the study population had preterm birth before 34 weeks of gestation and 5.08% had preterm birth before 37 weeks of gestation. Cervical length in the first group of women who had preterm labor before 34 weeks was shorter (mean 11 mm, p < 0.001) than the cervical length of women who gave birth after 34 weeks of gestation (mean cervical length 31 mm). Cervical length was also presented in this study as shorter in the women who had premature birth after 34 but before 37 weeks of gestation (mean cervical length 22 mm, p < 0.001) compared to women who eventually gave birth after 37 weeks of gestation (average 31 mm). Thus, it was found that cervical length could predict preterm labor before 34 weeks with a sensitivity of 70% and labor after 34 weeks but below 37 weeks of pregnancy with a sensitivity of 38.3% [34, 54–60]. In another study by Mahmut Kuntay Kokanali, cervical length was measured using transvaginal ultrasound at 34 weeks of gestation in 318 low-risk for preterm birth primiparous women. It was concluded that there was a statistically significant correlation between cervical length at 34 weeks of gestation with the week of gestation that birth took place (r = 0.614, p < 0.001). After statistical analysis, it was found that cervical length below 25.5 mm predicted preterm labor

over 34 weeks but below 37 weeks with 80% sensitivity, specificity of 93.9%, positive predictive value of 52.6%, and a negative predictive value of 98.2%, while a cervical length above 42.5 mm at 34 weeks of gestation predicted an extension of pregnancy after 41 weeks with 70.4% sensitivity, 93.5% specificity, positive 50% predictive value and 97.1% negative predictive value [58–62]. Regarding the prediction of the successful outcome of labor induction by assessment of cervical length during the third trimester of pregnancy, there are several studies examining this relationship. In one of these studies, Hatfield did not document the use of cervical length as an effective predictor of labor induction success. This review included 20 studies of 3101 women who were about to undergo labor induction and who were subjected to cervical length ultrasonographic assessment before the induction. It was found that cervical length predicted successful labor induction outcome (positive predictive value 1.66, 95% CI 1.20–2.31) as well as failure to induction (negative predictive value 0.51, 95% CI 0.39–0.67) [58–62].

Another systematic review of Saccone's used five 735 singleton pregnancy studies to draw conclusions about the importance of cervical length in predicting the timing of spontaneous birth. It was therefore found that a cervical length of less than 30 mm could predict the automatic start of birth within the following week of the cervical length measurement with 64% sensitivity and 60% specificity. Thus, a woman at term pregnancy and with a cervical length of 30 mm has a less than 50% chance of giving birth within the next 7 days, while a woman with a cervical length of 10 mm has a greater than 85% chance of giving birth within the next 7 days of the measurement. Finally, another systematic review of Verhoeven's used 31 studies of 5029 women to record cervical length and labor outcome. It was found that cervical length predicted cesarean section with sensitivity ranging from 14% to 92% and specificity from 35% to 100%. In particular, cesarean section could be predicted at a cervical length of 20 mm with a sensitivity of 82% and a specificity of 34%, at a cervical length of 30 mm with a sensitivity of 0.64 and a specificity of 0.74%, and at a cervical length of 40 mm with a sensitivity of 13% and specificity of 95% [62–66]. According to the literature, there are many ambiguous and contradictory opinions.

However, in our center, Department of Obstetrics and Gynecology of the Democritus University of Thrace Cervical cerclage is performed at a cervical length shorter than 15 mm. In other cases, at a cervical length greater than 15 mm, pessary is recommended for the pregnant woman. In some cases where, despite the cervix cerclage, a shortening of the cervix is observed, a combination of circumcision and pesso is recommended. In all pregnant women at risk of premature delivery, it is recommended administration of progesterone.

In conclusion, preterm birth continues to complicate 11–12% of all pregnancies with a slightly increasing trend in recent years, which is only partially attributable to the increased number of multiple pregnancies. The impact of preterm birth on public health is very serious as it accounts for 70% of neonatal mortality and 50% of neurodevelopmental problems, and based on the results of this study we conclude that the contribution of transvaginal ultrasound during pregnancy in the early recognition of pregnancies at increased risk for preterm birth is significant.

*Cervical Length and Perinatal Outcome DOI: http://dx.doi.org/10.5772/intechopen.113835*
