**5. Potential opportunities for preterm birth prevention/delay in preterm cervical changes**

Vaginal progesterone, cervical stitch-cerclage, and pessary are actual opportunities to prevent/delay sPTB, when history, and/or current monitoring indicate gestational cervical untimed progressive changes, discussing them separately or comparing the beneficial/harmful effects of two of them cerclage *vs* P4/pessary, and less all three therapies.

#### **5.1 Progesterone for cervical Remodeling timing and preterm birth prevention**

Progesterone works for "quiescence" or "silencing" uterine contractions [111], and exerts a dominant role for most pregnancies to initiate a loss of tissue strength yet maintain competence in softening, and delays ripening onset, maintaining stiffness [103], and CL > 25 mm, as was proved by RCT [112], a meta-analysis [113], and meta-analysis on individual data [114]. A retrospective study on P4 administration when short cervix <25 mm at 24+0 and 33+6 weeks gestation revealed P4 efficacy in pregnancy prolongation after 34 weeks (**Figure 5**) [115].

Natural micronized progesterone vaginal administration (200 mg/capsule, or 90 mg gel), from early pregnancy up to 36+6 weeks, induced an sPTB<33 weeks reduction of 38% in singleton and 31% in twins, and for sPTB recurrence in cases with sPTB history [11, 116], and sPTB prophylaxis in cases with short cervix (OPPTIMUM study) [117]. Actual data in twins pregnancy prolongation >34 weeks are contradictory on P4 beneficial effects [118]. There is only a 0.02% reduction of sPTB absolute risk in singleton, when short cervix [119]. It is important to add that only vaginal P4 has anti-inflammatory effects on the murine maternal-fetal

#### **Figure 5.**

*Kaplan-Meier plot for days to delivery. The Kaplan-Meier plot of delivery by days from cervical length measurement of the progesterone treatment group (red line) and the non-treatment group (blue line). Adapted from Luxenbourg et al. [115]. Free PMC article. HHS Public access.*

### *Abnormal Cervical Remodeling Early Depiction by Ultrasound Elastography: Potential… DOI: http://dx.doi.org/10.5772/intechopen.113314*

interface [120, 121], which are absent when comparing weekly i.m. 17α-hydroxyprogesterone caproate to vaginal P4 for short cervix [122], and has more side effects, FDA does not recommend it since 2022.

Cervical static/strain elastography (with E-cervix™ program) for entire cervix – IO, EO, ECI was proposed to continue cervical strain assessments, together with conventional ultrasound, 1 week after P4 treatment for CL ≤25 mm at 18–24/16–32 weeks, for PTB <32 weeks better prediction [103, 123]. The South Korea study showed that one could differentiate cerclage needs to avoid delivery <32 weeks by pretreatment elastography IO, and 1 week post-P4 treatment EO assessment, showing significantly higher area under curve (AUC) than CL alone (0.858; P = 0.041), with sPTB delay/ avoidance. P4 direct contact with cervical matrix structures explains the better effects on EO at 1 week post-P4 treatment, and women with no improvement in IO and EO after 1 week, possibly undergo progressive cervical softening.

#### **5.2 Cervical cerclage, cervical pessary for preterm birth prevention**

The mechanical support for an incompetent cervix has a long history, Cochrane Database of Systematic Reviews [124] presents three decisions for cervical cerclage, based on late miscarriages/sPTB history, short cervix ≤25 mm or open/dilated, with bulging membranes risking PROM, at ordinary ultrasound. Cerclage reduces sPTB risk by about 30% in women with a history of sPTB and short cervix, although at least one in three of these women still delivers preterm, as meta-analysis on individual patient-level data shows [125]. Cochrane Database of Systematic Reviews [126] showed that cerclage vs. no cerclage reduced the number of birth <37, <34 weeks (average RR: 0.77, 95% CI: 0.66–0.89) and <28 completed weeks gestation; and probably perinatal death risks.

Stiffness assessment favors a test for cerclage decision by "missing effect of vaginal P4 on cervical stroma remodeling", and continuous cervical softness and shortness (even when CL < 10 mm) with sPTB high risks. A USA multicenter study revealed a gestational age at delivery significantly increased after 34 weeks, when CL < 10 mm while on P4 and cerclage vs. without cerclage, but on vaginal P4 (34+3days weeks vs. 27+2days weeks; P < 0.001), and lower rate sPTB at <37, 35, 32, 28, and 24 weeks in cerclage group (44.1 vs. 84.2%; 38.2 vs. 81.6%; 23.5 vs. 78.9%; 14.7 vs. 63.2%, and 11.8 vs. 39.5%; better neonatal outcomes parallel recorded) [127]. Cerclage decreases local levels of proinflammatory cytokines, adjuvant to P4, and offers a biochemical barrier to membranes, effects added to mechanical support [128]. Post-cerclage CL assessment is very important, according to PTB high risk after elective cerclage vs. general population [129], and a CL ≤ 25 mm after cerclage can make the prognosis differences for the delivery before or after 32 weeks: 91.0% sensitivity, and 30.0% specificity [130], shortening progresses on softness, imposing P4 continuation postcerclage, and a second/"reinforcing" cerclage to delay delivery [131], being mentioned also when amniotic membrane prolapse to or past the level of initial cerclage placement (visualized by direct speculum/ultrasound) [132]. Second/ reinforcement stitch placement is an attempt to prolong pregnancy, imposing much caution, for maternal safety, and to avoid fetal inflammatory syndrome risks [133]. FIGO recommends stitch removal at 36–37 weeks [134] when everything is under medical control.

Vaginal microecology and immunity have great importance for cerclage outcomes [135], the epithelium protective effects on cervical stroma premature progression to ripening is not sufficient when abnormal vaginal microbiota, being recommended

vaginal probiotics/eubiotics, according to *Lactobacillus acidophilus* known protective effects [136], topic therapy against bacterial vaginosis.

Cervical pessaries have a long history since 1961 [137], being reloaded according to new materials and technologies. A meta-analysis for PTB prevention <34 weeks vs. controls revealed that pessary shows a lack in prevention efficacy [138], without the possibility of determining inferiority, when compared to other methods because of studies heterogeneity. When short cervix (<25 mm), P4 works as cerclage [124], confirmed by meta-analyses on singleton [139], and twins, with sPTB history [140], and better than pessary [141], that sustains utero-cervical angle [20]. P4 was added to pessary when a shorter cervix (below 10th percentile) than in a previous sPTB (below 3rd percentile) was not more efficient, did not reduce birth rate <28, <32, <34, or <37 weeks gestation compared with pessary alone, in a German cohort study [142]. The Canadian Soc. Obstet. Gynecol*.* (2020) Guideline No. 398 [143] specifies that in women with a short cervix (<25 mm), when P4 is used for PTB prevention, additional therapies as cervical cerclage (with the exception of a rescue cerclage for an examination-based diagnosis) or a pessary are not recommended (strong/moderate). The choice of treatment in Canada depends on adverse events, interventions cost-effectiveness, and patient/physician's preferences.

RCT systematic review from Cochrane Pregnancy and Childbirth's Trials Register, Clinical Trials.gov and WHO International Clinical Trials Registry Platform to 22 September 2021, evaluated pessaries benefits and harms in preventing sPTB (<34, 37 weeks gestation) compared to no treatment, vaginal P4, cervical cerclage or bedrest [144] revealed that pessary may reduce sPTB risks vs. no treatment [<34 weeks (RR: 0.72, 95% CI: 0.33–1.55); <37 weeks (RR: 0.68, 95% CI: 0.44–1.05), with lowcertainty evidence for studies]; or vs. P4 [<34 weeks (RR: 0.72, 95% CI 0.52–1.02); <37 weeks (RR: 0.89, 95% CI 0.73–1.09), with moderate certainty evidence for studies]; has little or no effect on maternal infection/inflammation risks (RR: 1.04, 95% CI 0.87–1.26); the comparison to cerclage was unclear, from o single study.

#### **5.3 Progesterone, cerclage, pessary for reducing preterm birth risk**

Perinatal outcomes of all three therapeutic opportunities are compared by a multination study [145], on three patient cohorts treated with cerclage (142, USA), vaginal P4 (59, UK), and pessary (42, Spain). The results showed no statistic significant difference in perinatal loss, neonatal morbidity, and sPTB among the three groups, apart from a higher rate of sPTB < 34 weeks, after vaginal P4 treatment in comparison to pessary (32% vs. 12%; RR: 2.70; 95% CI: 1.10–6.67). When one compared only subgroups with CL < 25 mm, irrespective GA, the difference between these two cohorts was not statistically significant (RR: 2.21; 95% CI: 0.83–5.89).

In sPTB < 34 weeks, the three procedures are recommended mainly when cervical softness is not accurately known, when vaginal P4 fails, when CL after cerclage is below 15/10 mm, and one tries pregnancy prolongation by pessary adding, fetal high prematurity avoidance, without maternal and/or fetal risks. A Romanian retrospective study [65] compared PTB reduction, neonatal and maternal outcomes when short cervix (11–25 mm, and <10 mm at 14–23+6 weeks), in cases treated with vaginal P4 and cerclage (8 patients, no CL < 10 mm), vaginal P4 and pessary (62 cases, 10 with CL < 10 mm), and vaginal P4, cerclage, and pessary (13 cases, 3 with CL < 10 mm). P4 was administered from 6 weeks gestation, 200 mg/day, up to 36+6 weeks, bedtime, with supplementation at 16 weeks, or when was considered necessary, pessary was

*Abnormal Cervical Remodeling Early Depiction by Ultrasound Elastography: Potential… DOI: http://dx.doi.org/10.5772/intechopen.113314*

added when postcerclage CL was ≤25 mm. It was recorded pregnancy prolongation >34 weeks (P < 0.0001) when early administered vaginal P4, and P4 increased cerclage or/and of pessary benefits, better neonatal outcome (fetal weight, Apgar score ≥ 7, P < 0.05), reduced neonatal morbidity (only RDS, P < 0.05). All three methods were applied in sPTB before 34 weeks very high risks; average gestational age at delivery was 34.91 weeks vs. 37.37 weeks—P4 and cerclage; 36.58 weeks: P4 and pessary, when late administration of vaginal P4, or when P4 did not influence cervical remodeling. A retrospective cohort multicenter study [146] compared three therapeutic opportunities in four groups of pregnancies, at 15–29 weeks gestation, with CL ≤ 25 mm: A—P4 vaginal, cerclage, pessary ([18], with highest risk for sPTB, and shortest cervix; median (range) 14.5 (0–25)); B—P4 vaginal, and pessary ([141], CL: median (range) 15 (0–25)]); C—P4 vaginal, and cerclage ([38], CL: median: 15.5 (0–25)); D—P4 vaginal ([110], CL: median: 19 (2–25)). The rate of sPTB < 37 weeks was similar: 44.4% vs. 32.5% vs. 36.8% vs. 32.7% (P = 0.665). Their conclusion was that a combined rescue therapy involving vaginal P4, cerclage, and pessary emerges as a promising management strategy when a short cervix and background history for sPTB high risk; pregnancy prolongation was safe.

### **5.4 New proposals for premature cervical remodeling prevention**

There is still much work to understand how well therapy may better influence cervix consistency at cellular and microscopic level, what drug/material can restore stiffness, and sustain IO, ECM, and CSMCs/sphincter on increasing stress/stretch up to 37+1day weeks. There were proposed/tested biomaterials, biodegradable and biocompatible for intracervical injection in rats—purified silk protein-polyethylene glycol, for intrinsic cervix reinforcement/augmentation with no other interference on structure, and to permit labor dilation, not extrinsic as pessary or cerclage [147], or to propose adult stem cells with their bioactive molecules to reinforce cervix, IO sphincter, as intraurethral/intrasphincterian use for postpartum stress urinary incontinence.
