**2.2. Progesterone**

The use of progesterone is the main prophylaxis for preterm birth in singleton pregnancies; however, in twin pregnancies its performance does not seem to be that good. Currently, the most recent study with the highest series of cases—a meta-analysis of individual data—concludes that the utilization of progesterone for twin pregnancies presents favorable evidence when used in twins with short cervix (≤25 mm) as it presents a high number of cases by case studies and different clinical tests participated in this meta-analysis. However, a more detailed case-by-case study shows that 70% of the sample was taken from one clinical study only [24] favorable to utilization and another five studies with lower casuistry (30% of the sample) evidence that the medication does not present benefits in twin pregnancy [25].

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].

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

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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.

permanence with cervical pessary was 10.18 ± 3.6 weeks.

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