Cytokine quantification and association with cervical length in a prospective cohort of pregnant women.

BACKGROUND: Preterm birth is a leading cause of infant morbidity and mortality; its multifactorial causes are an obstacle to understanding etiology and pathogenesis. The importance of cytokines and inflammation in its etiology and association with the short cervix is nowadays well-proven. To date, there are no reliable biological or biochemical markers to predict preterm birth; even though the length of the cervix has high specificity, its sensitivity with the cervix below 2.5 cm is low. OBJECTIVE: We study the association of plasma cytokine levels and cervical length in search of predictors of preterm birth. STUDY DESIGN: We evaluated a total of 1400 pregnant women carrying a single fetus between 20 and 25 weeks of gestation, and 1370 of them after childbirth in a nested case-control study of a prenatal cohort. Eligible pregnant women were interviewed and submitted to obstetric morphological and transvaginal ultrasound with cervical length measurement, gynecological examination, and blood collection. Preterm birth occurred in 133 women, 129 included in the study, and a control group randomly selected at a 2:1 ratio. A total of 41 cytokines with a higher probability of being associated with preterm birth or being of significance during labor were determined. RESULTS: Cytokine and cervical length analysis by multivariate analysis of the conditional interference tree revealed that growth-related oncogene values of less than 2293 pg/mL were significantly associated with a cervical length of less than 2.5 cm. CONCLUSIONS: As well as a cervical length shorter than 2.5 cm, growth-related oncogene levels of less than 2293 pg/ml may be associated with an increased risk of PB. Analysis based on the association of biomarkers and of the interaction between cytokines is a promising pathway in search of a predictor of preterm birth.

Association between cervical length and gestational age at birth in singleton pregnancies: a multicentric prospective cohort study in the Brazilian population.

BACKGROUND: Short cervical length measured during the second trimester of pregnancy is an important risk factor for spontaneous preterm birth (sPTB). The aim of this study is to identify the association between mid-pregnancy cervical length (CL) and gestational age at birth in asymptomatic singleton pregnant women. METHODS: This is a prospective cohort study involving singleton pregnant women who participated in the screening phase of a Brazilian multicenter randomized controlled trial (P5 trial) between July 2015 and March 2019. Transvaginal ultrasound to measure CL was performed from 18 to 22 + 6 weeks. Women with CL ≤ 30 mm received vaginal progesterone (200 mg/day) until 36 weeks' gestation. For this analysis we considered all women with CL ≤ 30 mm receiving progesterone and a random selection of women with CL > 30 mm, keeping the populational distribution of CL. We obtained prognostic effectiveness data (area under receive operating characteristic curve (AUC), sensitivity and specificity and estimated Kaplan-Meier curves for preterm birth using different CL cutoff points. RESULTS: We report on 3139 women and identified a negative association between cervical length and sPTB. CL ≤ 25 mm was associated with sPTB < 28, sPTB < 34 and sPTB < 37 weeks, whereas a CL 25-30 mm was directly associated with late sPTB. CL by transvaginal ultrasound presented an AUC of 0.82 to predict sPTB < 28 weeks and 0.67 for sPTB < 34 weeks. Almost half of the sPTB occurred in nulliparous women and CL ≤ 30 mm was associated with sPTB at < 37 weeks (OR = 7.84; 95%CI = 5.5-11.1). The number needed to screen to detect one sPTB < 34 weeks in women with CL ≤ 25 mm is 121 and we estimated that 248 screening tests are necessary to prevent one sPTB < 34 weeks using progesterone prophylaxis. CONCLUSIONS: CL measured by transvaginal ultrasound should be used to predict sPTB < 34 weeks. Women with CL ≤ 30 mm are at increased risk for late sPTB.

Cervical pessary plus vaginal progesterone in a singleton pregnancy with a short cervix: an experience-based analysis of cervical pessary's efficacy.

BACKGROUND: Several studies were published about cervical pessary, with controversial results. These studies demonstrated that the patient follow-up after pessary insertion is very different between the study centers and the number of pessary insertions per center was often <30 cases. This study aims to determine cervical pessary performance in singleton pregnancies with a short cervix based on a single center learning curve. METHODS: Between 2011 and 2018, 128 singleton pregnancies between 18 and 24 gestational weeks with a short cervix (<25 mm) were referred to our clinic. All cases were treated with progesterone, and when available in our supplies (due to low resources) cervical pessary was also offered. Three groups were created for statistical analysis: Group 1 (n = 33), treated with progesterone-only; Groups 2 and 3, treated with cervical pessary plus progesterone. Group 2 included the first cases (n = 30) of pessary, defined by a learning curve and cumulative sum analysis, while Group 3 included the subsequent 65 cases. The primary outcome was preterm birth (PTB) < 34 gestational weeks. RESULTS: The learning curve was performed with all cases of pessary plus progesterone, and 30 patients were obtained as the number needed for learning, in our study with two operators. The PTB rate < 34 weeks was 27.3, 20, and 4.6% in groups 1, 2, and 3, respectively. There was no significant difference between Group 1 and 2 (OR 1.1; 95% CI 0.066 - 18.45; p = .945). When comparing Groups 1 and 3 there was a significant difference in PTB rates (OR 0.08; CI95% 0.01-0.42; p = .003). Considering Kaplan-Meyer Survival analysis, we can observe that the performance of progesterone alone (Group 1) was similar to Group 2 (progesterone + first 30 cases of pessary) (p = .432), but the performance of Group 3 (progesterone + subsequent 65 cases of pessary) and Group 1 shows a statistically significant difference (p = .011). CONCLUSION: Learning curve and cumulative sum analysis determined that the application and surveillance of at least 30 patients is required to see significant improvements in the primary outcome of PTB < 34 weeks.

Preoperative Cervical Length Predicts the Risk of Delivery within One Week after Pleuroamniotic Shunt in Fetuses with Severe Hydrothorax.

OBJECTIVE: The objective of this study was to assess the predictive performance of preoperative cervical length (CL) for delivery within 1 week after pleuroamniotic shunting (PAS) in fetuses with severe hydrothorax. METHODS: A prospective cohort of fetuses with severe hydrothorax referred to our fetal surgery center in Querétaro, Mexico from January 2012 to July 2020. Severe fetal hydrothorax was diagnosed as an accumulation of fluid within the fetal pleural space accompanied with severe bilateral lung compression, mediastinal shift, polyhydramnios, and/or hydrops. Transvaginal CL was measured immediately before PAS, and a short cervix was defined as that <25 mm. The interval from fetal intervention to delivery, prevalence of preterm prelabor rupture of membranes (PPROMs), and associations with delivery within the first week after PAS according to a short or a normal CL, were evaluated. RESULTS: Thirty-five pregnancies with severe fetal hydrothorax treated with PAS were evaluated. Median gestational age at PAS was (weeks + days) 31+2 (range, 26+0-36+1). Two (5.7%) and 7 (20.0%) cases delivered within the first 24 h and 1 week after PAS, respectively. Ten (28.6%) women had a short cervix before PAS, while 25 (71.4%) had normal preoperative CL. Women with a short cervix showed lower mean interval between fetal intervention and delivery (2.4 vs. 5.5 weeks, p = 0.01), and higher prevalence of PPROM (50 vs. 12%, p = 0.01), as compared to women with a nonshort cervix. Preoperative short cervix was associated with significantly higher risk of delivery within the first 24 h (20.0 vs. 0%, respectively, p < 0.05) and 1 week after PAS (50.0 vs. 8.0%, respectively, p < 0.01) compared with pregnancies with normal preoperative CL. CONCLUSION: In pregnancies with severe fetal hydrothorax candidates for pleuroamniotic shunt, identification of a short cervix before fetal intervention can predict delivery within 1 week after the surgical procedure.

Cervical pessary plus progesterone for twin pregnancy with short cervix compared to unselected and non-treated twin pregnancy: a historical equivalence cohort study (EPM twin pessary study) / Pessário cervical associado a progesterona em gestações gemelares com colo curto comparado a gestações gemelares não selecionadas e não tratadas: estudo de coorte histórica de equivalência (Estudo de Pessário em Gêmeos EPM)

Abstract Objective The present study aims to determine if the use of cervical pessary plus progesterone in short-cervix (≤ 25 mm) dichorionic-diamniotic (DC-DA) twin pregnancies is equivalent to the rate of preterm births (PBs) with no intervention in unselected DC-DA twin pregnancies. Methods A historical cohort study was performed between 2010 and 2018, including a total of 57 pregnant women with DC-DA twin pregnancies. The women admitted from 2010 to 2012 (n = 32) received no treatment, and were not selected by cervical length (Non-Treated group, NTG), whereas those admitted from 2013 to 2018 (n = 25), were routinely submitted to cervical pessary plus progesterone after the diagnosis of short cervix from the 18th to the 27th weeks of gestation (Pessary-Progesterone group, PPG). The primary outcome analyzed was the rate of PBs before 34 weeks. Results There were no statistical differences between the NTG and the PPG regarding PB < 34 weeks (18.8%; versus 40.0%; respectively; p = 0.07) and the mean birthweight of the smallest twin (2,037 ± 425 g versus 2,195 ± 665 g; p = 0.327). The Kaplan-Meyer Survival analysis was performed, and there were no differences between the groups before 31.5 weeks. Logistic regression showed that a previous PB (< 37 weeks) presented an odds ratio (OR) of 15.951 (95%; confidence interval [95%;CI]: 1.294-196.557; p = 0.031*) for PB < 34 weeks in the PPG. Conclusion In DC-DA twin pregnancies with a short cervix, (which means a higher risk of PB), the treatment with cervical pessary plus progesterone could be considered equivalent in several aspects related to PB in the NTG, despite the big difference between these groups.

Resumo Objetivo Este estudo tem como objetivo determinar se o uso de pessário cervical associado a progesterona em gestações de gêmeos dicoriônicos-diamnióticos (DC-DAs) com colo do útero curto (≤ 25 mm) apresenta taxa de parto prematuro (PP) equivalente à de gestações gemelares DC-DA sem nenhuma intervenção/não selecionadas. Métodos Um estudo de coorte histórica foi realizado entre 2010 e 2018, incluindo um total de 57 mulheres grávidas com gestações gemelares DC-DA. As mulheres admitidas de 2010 a 2012 (n = 32) não receberam tratamento, e não foram selecionadas pelo comprimento cervical (grupo Não Tratado, GNT), enquanto as admitidas de 2013 a 2018 (n = 25) receberam pessário cervical rotineiramente associado a progesterona após o diagnóstico de colo curto entre a 18a e a 27ª semanas de gestação (grupo Pessário-Progesterona, GPP). O desfecho primário analisado foi a taxa de PP antes de 34 semanas. Resultados Não houve diferenças estatísticas entre o GNT e o GPP em relação ao PP < 34 semanas (respectivamente, 18,8%; versus 40,0%;; p = 0,07) e ao peso médio ao nascer do gêmeo menor (2.037 ± 425 g versus 2.195 ± 665 g; p = 0,327). A análise de Kaplan-Meyer foi realizada, e não houve diferenças entre os grupos antes de 31,5 semanas. A regressão logística demonstrou que o nascimento prematuro anterior (< 37 semanas) apresentou razão de probabilidades (odds ratio, OR) de 15,951 (intervalo de confiança de 95%; [IC95%;]: 1,294-196,557; p = 0,031*) para o nascimento prematuro < 34 semanas no GPP. Conclusão Em gêmeos DC-DA com colo uterino curto (o que significa maior risco de nascimento prematuro), o tratamento com pessário cervical associado a progesterona pode ser considerado equivalente em diversos aspectos relacionados à prematuridade no GNT, apesar da grande diferença entre os grupos.

Uso de pesario cervical y prevención de parto pretérmino / Cervical pessary use and preterm labor prevention

Introducción: El parto pretérmino constituye una causa importante de morbimortalidad perinatal con repercusiones sociales y económicas a nivel mundial. La intervención oportuna ante la identificación de factores de riesgo y un adecuado manejo consiguen reducir su incidencia y evitar las consecuencias de la prematurez. Objetivo: El presente trabajo se realiza con el objetivo de destacar al pesario cervical como una herramienta mecánica en la prevención del parto pretérmino, y una opción de tratamiento en embarazos mayores de 25 semanas con insuficiencia cervical. Presentación del caso: Se trata de una paciente de 38 años de edad con antecedente de parto pretérmino espontaneo (de 33 semanas), que ingresa a las 21 semanas de embarazo con dilatación cervical de 3cm y acortamiento de la longitud cervical de 14mm, signos ecográficos: sludge y funneling. Se optó por manejo expectante con medidas complementarias: administración de antibiótico, progesterona y uso de pesario cervical. Tras el control clínico de la infección y mayor acortamiento cervical a 7mm a pesar del uso de progesterona, se colocó un pesario cervical a las 25,5 semanas, a las 27,5 semanas fue dada de alta, a las 36,6 semanas se retiró el pesario tras inicio de actividad uterina. Discusión: La progesterona y el cerclaje son medidas de elección en casos de insuficiencia cervical, sin embargo, ante las dificultades técnicas de colocación; el pesario representó una alternativa. El uso de pesario permitió que el embarazo progrese al término con resultados beneficiosos y sin evidencia de efectos adversos.

Introduction: Preterm delivery is an important cause of perinatal morbidity and mortality with global social and economic repercussions. Timely intervention in the identification of risk factors and proper management reduce their incidence and avoid the consequences of prematurity. Objective:This work is carried out with the aim of highlight the cervical pessary as a mechanical tool in the prevention of preterm birth and a treatment option in pregnancies over 25 weeks with cervical insufficiency. Case presentation: This is a 38-year-old patient with a history of spontaneous preterm delivery (33 weeks), who was admitted at 21 weeks of pregnancy with cervical dilation of 3cm and shortening of the cervical length of 14mm, ultrasound signs: sludge and funneling. Expectant management was opted, with complementary measures: administration of antibiotics, progesterone and use of a cervical pessary. After clinical control of the infection and greater cervical shortening to 7mm despite the use of progesterone, a cervical pessary was placed at 25.5 weeks, at 27.5 weeks she was discharged, at 36.6 weeks she was discharged. The pessary was removed after the start of uterine activity. Discussion: Progesterone and cerclage are the measures of choice in cases of cervical insufficiency, however, given the technical difficulties of placement; the pessary represented an alternative. Conclusion: The use of the pessary allowed the pregnancy to progress to term with beneficial results and without evidence of adverse effects.

Antibiotic treatment for patients with amniotic fluid "sludge" to prevent spontaneous preterm birth: A historically controlled observational study.

INTRODUCTION: Amniotic fluid "sludge" has been associated with an increased rate of spontaneous preterm delivery before 35 weeks, a higher frequency of clinical and histologic chorioamnionitis in a high-risk population. Only one study evaluating the use of antibiotics in the presence of amniotic fluid "sludge" showed reduced rates of spontaneous preterm birth at <34 weeks. The objective of this study was to evaluate routine antibiotic treatment in the presence of amniotic fluid "sludge" for prevention of preterm delivery. MATERIAL AND METHODS: A historically controlled observational study was performed between October 2010 and January 2015, including a total of 86 pregnant women with singleton pregnancies and the presence of amniotic fluid "sludge" at ultrasound. Women admitted from October 2010 to September 2012 received no treatment with antibiotics, whereas those admitted from October 2012 to January 2015, received routinely clindamycin and first-generation cephalosporin. The groups were compared considering the incidence of spontaneous preterm delivery. The effect of antimicrobials was also compared in the subgroup of women at high risk for spontaneous preterm birth (ie, cervical length ≤25 mm, history of spontaneous preterm birth, previous spontaneous loss in the second trimester, Mullerian malformations or cervical conization). RESULTS: Antibiotic therapy reduced the incidence of spontaneous preterm birth at <34 weeks (13.2% vs 38.5%, P = 0.047) in women at high-risk for preterm birth, with an odds ratio of 0.24 (95% confidence interval [CI] 0.06-0.99). Birthweight was significantly different between the study groups (2961 ± 705 vs. 2554 ± 819 g, respectively; P = 0.028), with no statistical significance for others variables. CONCLUSIONS: This study suggests that antibiotic treatment in high-risk pregnant women with amniotic fluid "sludge" can be effective in the reduction of the frequency of spontaneous preterm delivery and can increase the birthweight.

Use of the pessary in the prevention of preterm delivery / Uso do pessário na prevenção de parto pretermo

Abstract Objective The gestational complication most associated with perinatalmortality and morbidity is spontaneous preterm birth with gestational age < 37 weeks. Therefore, it is necessary to identify its risk factors and attempt its prevention. The benefits of the pessary in prematurity are under investigation. Our objective was to analyze the use of the pessary in the prevention of preterm births in published studies, and to compare its efficacy with other methods. Methods Randomized clinical trials published between 2010 and 2018 were selected from electronic databases. Studies on multiple gestations were excluded. Results Two studies were in favor of the pessary as a preventive method, one study was contrary to the method and another two showed no statistically significant difference. Themeta-analysis showed no statistical difference with the use of a cervical pessary in the reduction of births < 37 (odds ratio [OR]: 0.63; confidence interval [95% CI]: 0.38-1.06) and < 34 weeks (OR: 0.74; 95% CI: 0.35-1.57) Conclusion The pooled data available to date seems to show a lack of efficacy of the cervical pessary in the prevention of preterm birth, although the heterogeneity of the studies made comparisons more difficult.

Resumo Objetivo O parto com idade gestacional < 37 semanas é a complicação gestacional mais associada à mortalidade e morbidade perinatal, sendo necessária a identificação de seus fatores de risco e a tentativa de sua prevenção. Os benefícios do pessário na prematuridade estão sendo investigados. Nosso objetivo foi analisar os estudos publicados sobre uso do pessário na prevenção do parto pretermo e comparar sua eficácia perante outros métodos. Métodos Foramselecionados estudos clínicos randomizados publicados entre 2010 e 2018, extraídos de bases eletrônicas de dados. Estudos de gestações múltiplas foram excluídos. Resultados Dois estudos semostraram a favor do pessário comométodo preventivo, um estudo foi contrário ao método, e outros dois não demonstraram diferença estatisticamente significativa. A meta-análise não mostrou diferença significativa no Conclusão Os dados agrupados disponíveis até o momento parecem mostrar uma falta de eficácia do pessário cervical na prevenção do parto pretermo, embora a heterogeneidade dos estudos tenha dificultado as comparações.

Efficacy of midtrimester short cervix interventions is conditional on intraamniotic inflammation.

BACKGROUND: Midtrimester ultrasound is a valuable method for identifying asymptomatic women at risk for spontaneous preterm delivery (PTD). However, response to various treatments (cerclage, progestogen) has been variable in the clinical setting. It remains unclear how other biomarkers may be used to guide intervention strategies. OBJECTIVE: We applied an amniotic fluid inflammatory scoring system to determine if the degree of inflammation is associated with intervention efficacy in patients with midtrimester short cervix. STUDY DESIGN: Women carrying a singleton fetus between 16-24 weeks' gestation with a short cervix (≤25 mm) on transvaginal ultrasound underwent amniocentesis and were assigned to McDonald cerclage, no cerclage, or weekly 17-alpha hydroxyprogesterone caproate (17OHP-C). Our previously described inflammatory risk score (comprised of 14 inflammatory markers) was used to classify patients as high (score ≥8) or low (score <8) risk for inflammation. Gestational age at delivery was compared for each intervention and risk score status. Risk of delivering as a function of the remaining gestation was evaluated using modified Cox proportional hazards models with incorporation of methods to account for both left and right truncation bias. RESULTS: Ninety patients were included: 24 were in the nonintervention control group, 51 received cerclage, and 15 received 17OHP-C. Inflammation status at time of sampling influenced the efficacy of the treatment (P < .001). Compared to the nonintervention control group, in patients with low inflammation (score < 8), both cerclage (adjusted hazard ratio [HR], 2.86; 95% confidence interval [CI], 1.28-6.37) and 17OHP-C (HR, 3.11; 95% CI, 1.04-9.30) were associated with increased hazard of PTD. In contrast, in patients with high inflammation (score ≥8) both cerclage (HR, 0.22; 95% CI, 0.08-0.65) and 17OHP-C (HR, 0.20; 95% CI, 0.05-0.81) were associated with lower hazard of delivering preterm. CONCLUSION: Cerclage placement or administration of 17OHP-C therapy for midtrimester short cervix for PTD prevention appears beneficial only in the subset of patients with high inflammation. Knowledge of the amniotic fluid inflammatory status may aid in guiding the appropriate therapy for women presenting with midtrimester short cervix who are at increased risk of PTD.

Association of progesterone, pessary, and antibiotic for treating pregnant woman with short cervix syndrome: importance of magnetic resonance imaging in the assessment of pessary position.

Preterm delivery (PD) is the most important cause of neonatal mortality, particularly before the 32(nd) week of pregnancy. A short cervix is the most important quantitative marker for predicting PD. However, there are other qualitative markers such as cervical gland area, cervical funneling, and sludge. We present the case of a pregnant woman who was diagnosed with a short cervix at 14-weeks and demonstrate the use of triple therapy, which helped to achieve a good perinatal result. A 37-year-old pregnant woman (G3P0) was referred to our service at 14-weeks of pregnancy presenting with a short cervix (20 mm) and a positive sludge sign. She was hospitalized; a pessary was inserted, and started on antibiotic therapy (clindamycin and cefalotin for 10 days). At 20 weeks, she was again admitted to the hospital, and this time presented with a further shortened cervix (9 mm), cervical funneling, and a positive sludge sign, with the pessary in position. The following procedures were performed: Amniocentesis on the sludge (negative bacterioscopy), another cycle of antibiotics, administration of oral progesterone, and imaging to determine retention of pessary position. The patient was placed in the Trendelenburg position and remained hospitalized for 82 days. At 32 + 1 weeks, the fetus presented distress (tachycardia). C-section was performed, producing a live female newborn weighing 2,180 g and presenting Apgar indexes of 8/8. This case report demonstrates the importance of magnetic resonance imaging to assess the position of pessary in a pregnant woman with short cervix.