**2.4. Cervical pessary**

Therefore, the Federal University of São Paulo (UNIFESP) has opted for treating the selected cases of preterm birth risk by short cervix, associated to the above-stated risk factors or previous preterm delivery. The standard treatment would be naturally micronized progesterone in the dosage of 200 mg/day, vaginally, or the combination of this therapy associated to cervical pessary AM-Ingamed. As of 2014, all the cases have been treated with pessary plus progesterone in the Department of Screening of Preterm Delivery of the UNIFESP.

This conduct was based on the studies of ProTwin and PECEP-Twins, which identified that twins with short cervix could benefit from the usage of the cervical pessary [29, 30].

Since January 2014 we have obtained 30 cases of dichorionic twin gestations with short cervix (≤25 mm). The gestational age of diagnosis varied between 18 and 27 weeks and 6 days (mean age of 24 weeks and 3 days ± 2.8 weeks). The mean cervical length of these gestations at the time of the pessary placement was 14.9 ± 6.8 mm, which reveals an extremely high risk.

In our series of cases, the mean gestational age of delivery was 34.59 ± 2.72 weeks, and in a group of 32 cases of dichorionic twin gestation, not selected by cervix, the mean delivery time was 35.83 ± 8.7 weeks. It shall be pointed out that between the time of delivery of the group with cervical pessary and the group not selected by cervix there was a small difference of 1.24 weeks—despite a big difference among the groups regarding the risk due to the cervix with statistically no significant difference between the groups (P = 0.11). The mean interval of permanence with cervical pessary was 10.18 ± 3.6 weeks.

A randomized clinical trial published in 2015 [4] with casuistry of about 200 twin pregnancies, not selected by cervix, compared the use of progesterone and expectant management in twin pregnancies and did not find differences between the groups. In another multicenter trial (STOPPIT), 500 twin pregnancies, not selected by cervix also, were randomized, and their perinatal outcomes were statistically not different for none of the evaluated perinatal outcomes [26]. Therefore, according to this author's opinion, we can affirm up to the present moment that isolated progesterone is not efficient in the prevention of preterm birth in not selected twin

Prophylactic cervical cerclage in multiple pregnancies is controversial, since the systematic review of randomized trials was not convincing in proving its efficacy in reducing perinatal death and neonatal morbidity. Even ultrasound-indicated cerclage (i.e., in short cervix) does not seem to show benefit in twin gestations. However, care must be taken in this analysis, once there are few trials and the number of patients included was not so impressive [27]. On the other hand, one author suggested improvement in perinatal outcome when cervical cerclage is indicated in asymptomatic twin pregnant women that present cervical dilatation

ACOG does not recommend cerclage in the incidental short cervix [7], but there is some evidence of benefit of this procedure when short cervix occurs in suspicious but not typical history of cervical insufficiency. The diagnosis can be performed by weekly transvaginal ultrasound since the 16th week. So, cerclage could be performed after shortening of the cervix in these cases, except in exposed membranes, chorioamnionitis, sepsis, and when there is no

Therefore, the Federal University of São Paulo (UNIFESP) has opted for treating the selected cases of preterm birth risk by short cervix, associated to the above-stated risk factors or previous preterm delivery. The standard treatment would be naturally micronized progesterone in the dosage of 200 mg/day, vaginally, or the combination of this therapy associated to cervical pessary AM-Ingamed. As of 2014, all the cases have been treated with pessary plus progester-

This conduct was based on the studies of ProTwin and PECEP-Twins, which identified that

Since January 2014 we have obtained 30 cases of dichorionic twin gestations with short cervix (≤25 mm). The gestational age of diagnosis varied between 18 and 27 weeks and 6 days (mean age of 24 weeks and 3 days ± 2.8 weeks). The mean cervical length of these gestations at the time of the pessary placement was 14.9 ± 6.8 mm, which reveals an extremely high risk.

In our series of cases, the mean gestational age of delivery was 34.59 ± 2.72 weeks, and in a group of 32 cases of dichorionic twin gestation, not selected by cervix, the mean delivery time

twins with short cervix could benefit from the usage of the cervical pessary [29, 30].

one in the Department of Screening of Preterm Delivery of the UNIFESP.

pregnancies; however, in association with short cervix, it can be considered.

(physical examination-indicated cerclage) at 16–24 weeks [28].

**2.3. Cerclage**

192 Multiple Pregnancy - New Challenges

cervical length measurable [16].

**2.4. Cervical pessary**

The result was 79% of the preterm deliveries below 37 weeks, 42% of premature newborns below 34 weeks, 17% below 32 weeks, and 4% below 28 weeks; in comparison, the study published by Fox et al. (2016) with similar case studies (cervix 11.9 ± 4.5 mm with 25.9 ± 2.1 weeks) obtained 44.4% of prematurity below 34 weeks and 28.6% below 32 weeks in patients treated with vaginal progesterone, only [31]. In the group of twins not selected by cervix, preterm birth below 37 weeks is obtained in 50% of the cases, preterm birth below 34 weeks in 19%, below 32 weeks in 9%, and no preterm delivery was registered below 28 weeks, as shown in **Table 1**.

It is important to notice that before 32 weeks (very high risk for adverse neonatal outcome) the group treated by pessary plus progesterone had a better performance if compared to the group treated only by progesterone, regarding cervical length in this group which was 3.0 mm lower.

A recent randomized clinical trial from Egypt (El-refaie's study), compared to the use of progesterone *versus* expectant management in twin pregnancies with short cervix. The number of SPB was considerably lower in progesterone group below 34 and 32 weeks, respectively, 53% (expectant) *versus* 35% (progesterone) and 30% (expectant) *versus* 12% (progesterone group); the mean cervical length was very similar between groups, close to 22 mm [32].

These data from El-refaie's trial are similar to data of twin pregnancy from UNIFESP. In this study pessary plus progesterone group (mean cervical length 14.3 ± 7.1 mm) presents a better performance when compared to El-refaie controls (with short cervix) and also to progesterone group (with short cervix) below 37, 34, 32, and 28 weeks. It is importantly emphasized that UNIFESP controls are not selected by cervix and its performance is better because this group presents lower risk when compared with all other groups. Another important issue is


**Table 1.** Comparison of cervical length, mean gestational age of delivery, and percentage of deliveries according to the gestational age between different groups of treatment: pessary plus progesterone in short cervix twin pregnancy, only progesterone in short cervix twin pregnancy, no selected by cervix, and no treated twin pregnancy.

regarding the mean of cervical length which is lower in UNIFESP pessary plus progesterone group than El-refaie's groups, which cause higher risk to SPB to pessary group; so but the performance is better for pessary, despite high risk mentioned (**Figure 1**).

Considering the birthweight of twins not selected by cervix (n = 32), the mean weight of the biggest twin was 2.492 ± 643 g, and of the smallest twin, it was 2.195 ± 665 g; in comparison, in the twin group with short cervix treated by pessary plus progesterone (n = 24), the weight of the biggest one was 2.148 ± 434 g (p = 0.028), and of the smallest twin, it was 2.037 ± 425 g (p = 0.327), presenting a statistically significant difference between the groups for the biggest newborn, but no statistic difference for the smallest one. This result allows the conclusion that for the most vulnerable newborn (smallest one), the use of the cervical pessary was sufficient to modify the statistic difference expected, by cervical length difference, and in accordance with the difference registered between taller twins.

Furthermore, the use of the cervical pessary did not influence the weight difference between the fetuses. For the group not selected by cervix, the mean difference was 12 ± 6%; for the group of twins with short cervix, the difference was 11 ± 2% (p = 0.375).

This small difference demonstrates clear similarity between treated high-risk cases and cases of habitual twin pregnancy without involvement or diagnosis of complication factors in the prenatal routine (**Table 2**).

This study is according to a prospective, multicenter, randomized clinical trial conducted in Spain (PECEP-Twin). The primary outcome was SPB before 34 weeks of gestation. Neonatal morbidity and mortality were also evaluated. Cervical length was measured in 2287 women.

> Pregnant women (n = 137) with a sonographic cervical length (≤25 mm) were randomly selected to receive an Arabin cervical pessary (**Figure 2**) or expectant management (1:1 ratio). SPB < 34 weeks of pregnancy was significantly less frequent in the pessary group than in the expectant group (16.2% *vs*. 39.4%); relative risk, 0.41. No significant differences were observed in composite neonatal morbidity outcome (5.9% *vs.* 9.1%); relative risk, 0.64. No serious adverse effects associated with the use of a cervical pessary were observed or neonatal

> **Figure 2.** Comparison between the Arabin cervical pessary (blue) and the AM-Ingamed cervical pessary (yellow): They are similar regarding design, size, and texture. The dimensions (largest lower diameter × smallest upper diameter x height) of the most frequently used Arabin pessary are 70 × 32 × 25 mm, and of the Ingamed cervical pessary the

> **Table 2.** Comparison of birthweight and discordance of weight between groups with short cervix/treated by pessary

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plus progesterone twin pregnancy *versus* not selected/not treated twin pregnancy.

So, the insertion of a cervical pessary was associated with a significant reduction in the SPB rate. They propose the use of a cervical pessary for preventing preterm birth in twin pregnan-

When an acute preterm labor is detected, it is possible to use tocolytic drugs to reduce uterine activity, and this is considered part of tertiary prevention. However, the diagnosis of preterm labor is not always simple, being generally defined as painful and regular contractions leading to cervical changes after the 20th week and before the 37th week of pregnancy.

mortality (none) between the groups.

dimensions are 70 × 30 × 25 mm.

cies with short cervix [30], corroborating our data.

**3. Tocolysis in multiple gestation**

**Figure 1.** Comparison of percentage of SPB per gestational age between twin pregnancy from El-refaie's trial with short cervix (expectant and progesterone group) and UNIFESP twin pregnancy treated by pessary plus progesterone for short cervix and UNIFESP controls without selection by cervix.

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**Table 2.** Comparison of birthweight and discordance of weight between groups with short cervix/treated by pessary plus progesterone twin pregnancy *versus* not selected/not treated twin pregnancy.

**Figure 2.** Comparison between the Arabin cervical pessary (blue) and the AM-Ingamed cervical pessary (yellow): They are similar regarding design, size, and texture. The dimensions (largest lower diameter × smallest upper diameter x height) of the most frequently used Arabin pessary are 70 × 32 × 25 mm, and of the Ingamed cervical pessary the dimensions are 70 × 30 × 25 mm.

Pregnant women (n = 137) with a sonographic cervical length (≤25 mm) were randomly selected to receive an Arabin cervical pessary (**Figure 2**) or expectant management (1:1 ratio). SPB < 34 weeks of pregnancy was significantly less frequent in the pessary group than in the expectant group (16.2% *vs*. 39.4%); relative risk, 0.41. No significant differences were observed in composite neonatal morbidity outcome (5.9% *vs.* 9.1%); relative risk, 0.64. No serious adverse effects associated with the use of a cervical pessary were observed or neonatal mortality (none) between the groups.

So, the insertion of a cervical pessary was associated with a significant reduction in the SPB rate. They propose the use of a cervical pessary for preventing preterm birth in twin pregnancies with short cervix [30], corroborating our data.
