Should phenotype of previous preterm birth influence management of women with short cervix in subsequent pregnancy? Comparison of vaginal progesterone and Arabin pessary

Pessari Arabin; Coll uterí curt; Progesterona vaginalPesario de Arabin; Cuello uterino corto; Progesterona vaginalArabin pessary; Short cervix; Vaginal progesteroneObjective To investigate whether the classification of a previous spontaneous preterm birth (sPTB) as preterm labor (PTL) with intact membranes (IM) or as preterm prelabor rupture of membranes (PPROM) impacts the efficacy of cervical pessary or vaginal progesterone for prevention of sPTB in pregnant women with short cervix on transvaginal ultrasound. Methods This was a retrospective cohort study of asymptomatic high‐risk singleton pregnancies with a short cervix and history of sPTB, treated using Arabin pessary or vaginal progesterone for primary PTB prevention, conducted at four European hospitals. A log‐rank test on Kaplan–Meier curves was used to assess the difference in performance of pessary and progesterone, according to history of PTL‐IM or PPROM. Linear regression analysis was used to evaluate significant predictors of gestational age at delivery. Results Between 2008 and 2015, 170 women were treated with a pessary and 88 with vaginal progesterone. In women treated with a pessary, rate of sPTB < 34 weeks was 16% in those with a history of PTL‐IM and 55% in those with a history of PPROM. In women treated with progesterone, rate of sPTB < 34 weeks was 13% in those with a history of PTL‐IM and 21% in those with a history of PPROM. Treatment with a pessary resulted in earlier delivery in women with previous PPROM than in any other subgroup (P < 0.0001). Linear regression analysis showed a clear effect of PPROM history (P < 0.0001), combination of PPROM history and treatment (P = 0.0003) and cervical length (P = 0.0004) on gestational age at birth. Conclusions Cervical pessary may be a less efficacious treatment option for women with previous PPROM; however, these results require prospective validation before change in practice is recommended. Phenotype of previous preterm birth may be an important risk predictor and treatment effect modifier; this information should be reported in future clinical trials

Assessment of an intervention to optimise antenatal management of women admitted with preterm labour and intact membranes using amniocentesis-based predictive risk models: study protocol for a randomised controlled trial (OPTIM-PTL Study)

Fetal medicine; Maternal medicine; UltrasonographyMedicina fetal; Medicina materna; EcografíaMedicina fetal; Medicina materna; EcografiaIntroduction The majority of women admitted with threatened preterm labour (PTL) do not delivery prematurely. While those with microbial invasion of the amniotic cavity (MIAC) represent the highest risk group, this is a condition that is not routinely ruled out since it requires amniocentesis. Identification of low-risk or high-risk cases might allow individualisation of care, that is, reducing overtreatment with corticosteroids and shorten hospital stay in low-risk women, while allowing early antibiotic therapy in those with MIAC. Benefits versus risks of amniocentesis-based predictor models of spontaneous delivery within 7 days and/or MIAC have not been evaluated. Methods and analysis This will be a Spanish randomised, multicentre clinical trial in singleton pregnancies (23.0–34.6 weeks) with PTL, conducted in 13 tertiary centres. The intervention arm will consist in the use of amniocentesis-based predictor models: if low risk, hospital discharge within 24 hours of results with no further medication will be recommended. If high risk, antibiotics will be added to standard management. The control group will be managed according to standard institutional protocols, without performing amniocentesis for this indication. The primary outcome will be total antenatal doses of corticosteroids, and secondary outcomes will be days of maternal stay and the occurrence of clinical chorioamnionitis. A cost analysis will be undertaken. To observe a reduction from 90% to 70% in corticosteroid doses, a reduction in 1 day of hospital stay (SD of 2) and a reduction from 24% to 12% of clinical chorioamnionitis, a total of 340 eligible patients randomised 1 to 1 to each study arm is required (power of 80%, with type I error α=0.05 and two-sided test, considering a dropout rate of 20%). Randomisation will be stratified by gestational age and centre. Ethics and dissemination Prior to receiving approval from the Ethics Committee (HCB/2020/1356) and the Spanish Agency of Medicines and Medical Devices (AEMPS) (identification number: 2020-005-202-26), the trial was registered in the European Union Drug Regulating Authorities Clinical Trials database (2020-005202-26). AEMPS approved the trial as a low-intervention trial. All participants will be required to provide written informed consent. Findings will be disseminated through workshops, peer-reviewed publications and national/international conferences.This research has received a grant from the Instituto Carlos III (PI21/00972)

Risk factors of early spontaneous preterm birth despite carrying a cervical pessary in singleton pregnancies with a short cervix: Development of a risk prediction model

Cervical pessary; Short cervical length; Spontaneous preterm birthPesario cervical; Longitud cervical corta; Parto prematuro espontáneoPessari cervical; Longitud cervical curta; Part prematur espontaniIntroduction: We aimed to identify the incidence and risk factors of spontaneous preterm birth in pessary carriers with singleton pregnancies and a short cervix in the mid-trimester of pregnancy. Material and methods: Patient data were obtained from the PECEP Trial. We analyzed singleton pregnancies in pessary carriers with a short cervix (≤25 mm) between 18 and 22 gestational weeks. Demographics and obstetric history were compared to identify risk factors for spontaneous preterm birth < 34 gestational weeks. Each demographic and obstetric variable was compared between spontaneous preterm birth < 34 and ≥ 34 weeks of gestation.Regression analysis was used to identify risk factors. A risk score model was generated using the odds ratio for significant factors. The risk score model and spontaneous preterm birth risk were assessed using the receiver operating characteristic curve. Perinatal outcomes were compared by risk score. Results: Among 190 pregnant individuals, 12 (6.3%) had spontaneous preterm birth < 34 gestational weeks. In the bivariate analysis, statistically significant differences between those with and without spontaneous preterm birth were only observed for mean cervical length at diagnosis and mean cervical length after pessary placement. By multiple logistic regression analysis, maternal age (OR 0.818; 95% CI 0.69-0.97; P 0.020), cervical length at diagnosis (OR 0.560; 95% CI 0.43-0.73; P < 0.001) and smoking status (OR 7.276; 95% CI 1.02-51.80; P 0.048) remained significantly associated with spontaneous preterm birth.The ROC curve from the multiple logistic regression analysis, including cervical length, maternal age and smoking status, had an area under the curve (AUC) of 0.952 (P < 0.001). The ROC curve for the risk score model incorporating all three variables had an AUC of 0.864 (95% CI 0.77-0.96; P < 0.001). A high-risk score was predictive of spontaneous preterm birth with a sensitivity of 75%, specificity of 84%, positive predictive value of 24%, and negative predictive value of 98%.Women with a high-risk score had a significantly reduced latency to delivery and poorer neonatal outcomes than those with a low-risk score. Conclusions: Patients at a high risk for spontaneous preterm birth despite pessary therapy may be identified using cervical length at diagnosis added to maternal age and smoking status

Cervical pessary and cerclage placement for preterm birth prevention and cervicovaginal microbiome changes

Cervical length; Microbial diversity; PessaryLongitud cervical; Diversidad microbiana; PesarioLongitud cervical; Diversitat microbiana; PessariIntroduction Our objective was to compare the vaginal microbiome in low-risk and high-risk pregnant women and to explore a potential association between vaginal microbiome and preterm birth. Material and methods A pilot, consecutive, longitudinal, multicenter study was conducted in pregnant women at 18–22 weeks of gestation. Participants were assigned to one of three groups: control (normal cervix), pessary (cervical length ≤25 mm) and cerclage (cervical length ≤25 mm or history of preterm birth). Analysis and comparison of vaginal microbiota as a primary outcome was performed at inclusion and at 30 weeks of gestation, along with a follow-up of pregnancy and perinatal outcomes. We assessed the vaginal microbiome of pregnant women presenting a short cervix with that of pregnant women having a normal cervix, and compared the vaginal microbiome of women with a short cervix before and after placement of a cervical pessary or a cervical cerclage. Results The microbiome of our control cohort was dominated by Lactobacillus crispatus and inners. Five community state types were identified and microbiome diversity did not change significantly over 10 weeks in controls. On the other hand, a short cervix was associated with a lower microbial load and higher microbial richness, and was not correlated with Lactobacillus relative abundance. After intervention, the cerclage group (n = 19) had a significant increase in microbial richness and a shift towards community state types driven by various bacterial species, including Lactobacillus mulieris, unidentified Bifidobacterium or Enterococcus. These changes were not significantly observed in the pessary (n = 26) and control (n = 35) groups. The cerclage group had more threatened preterm labor episodes and poorer outcomes than the control and pessary groups. Conclusions These findings indicate that a short cervix is associated with an altered vaginal microbiome community structure. The use of a cerclage for preterm birth prevention, as compared with a pessary, was associated with a microbial community harboring a relatively low abundance of Lactobacillus, with more threatened preterm labor episodes, and with poorer clinical outcomes.This study was supported by the Instituto de Salud Carlos III/FEDER FIS PI15/02043; Beca Dexeus Mujer 2015. Francisca Yáñez was supported by a grant from ANID, BECAS Chile, N° 72190278. Zixuan Xie received a fellowship from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie Action, Innovative Training Network: FunHoMic; grant number 812969

Abnormal Maternal Body Mass Index and Customized Fetal Weight Charts: Improving the Identification of Small for Gestational Age Fetuses and Newborns

Maternal body mass index; Newborn weight; ObesityÍndice de masa corporal materno; Peso del neonato; ObesidadÍndex de massa corporal matern; Pes del nounat; ObesitatBackground: Obesity and thinness are serious diseases, but cases with abnormal maternal weight have not been excluded from the calculations in the construction of customized fetal growth curves (CCs). Method: To determine if the new CCs, built excluding mothers with an abnormal weight, are better than standard CCs at identifying SGA. A total of 16,122 neonates were identified as SGA, LGA, or AGA, using the two models. Logistic regression and analysis of covariance were used to calculate the OR and CI for adverse outcomes by group. Gestational age was considered as a covariable. Results: The SGA rates by the new CCs and by the standard CCs were 11.8% and 9.7%, respectively. The SGA rate only by the new CCs was 18% and the SGA rate only by the standard CCs was 0.01%. Compared to AGA by both models, SGA by the new CCs had increased rates of cesarean section, (OR 1.53 (95% CI 1.19, 1.96)), prematurity (OR 2.84 (95% CI 2.09, 3.85)), NICU admission (OR 5.41 (95% CI 3.47, 8.43), and adverse outcomes (OR 1.76 (95% CI 1.06, 2.60). The strength of these associations decreased with gestational age. Conclusion: The use of the new CCs allowed for a more accurate identification of SGA at risk of adverse perinatal outcomes as compared to the standard CCs

Reference values for interleukin-6 in the amniotic fluid of asymptomatic pregnant women

Amniocentesis; Interleukin-6; Intra-amniotic inflammationAmniocentesi; Interleucina-6; Inflamació intraamniòticaAmniocentesis; Interleucina-6; Inflamación intraamnióticaIntroduction Nowadays, proinflammatory factors are considered to play an important role in the pathophysiology of threatened preterm labor or chorioamnionitis. The aim of this study was to establish the normal reference range for interleukin-6 (IL-6) levels in the amniotic fluid and to identify factors which may alter this value. Material and methods Prospective study in a tertiary-level center including asymptomatic pregnant women undergoing amniocentesis for genetic studies from October 2016 to September 2019. IL-6 measurements in amniotic fluid were performed using a fluorescence immunoassay with microfluidic technology (ELLA Proteinsimple, Bio Techne). Maternal history and pregnancy data were also recorded. Results This study included 140 pregnant women. Of those, women who underwent termination of pregnancy were excluded. Therefore, a total of 98 pregnancies were included in the final statistical analysis. The mean gestational age was 21.86 weeks (range: 15–38.7) at the time of amniocentesis, and 38.6 weeks (range: 30.9–41.4) at delivery. No cases of chorioamnionitis were reported. The log10 IL-6 values follow a normal distribution (W = 0.990, p = 0.692). The median, and the 5th, 10th, 90th, and 95th percentiles for IL-6 levels were 573, 105, 130, 1645, and 2260 pg/mL, respectively. The log10 IL-6 values were not affected by gestational age (p = 0.395), maternal age (p = 0.376), body mass index (p = 0.551), ethnicity (p = 0.467), smoking status (p = 0.933), parity (p = 0.557), method of conception (p = 0.322), or diabetes mellitus (p = 0.381). Conclusions The log10 IL-6 values follow a normal distribution. IL-6 values are independent of gestational age, maternal age, body mass index, ethnicity, smoking status, parity and method of conception. Our study provides a normal reference range for IL-6 levels in the amniotic fluid that can be used in future studies. We also observed that normal IL-6 values were higher in the amniotic fluid than in serum.Some of the authors are members of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA (EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516)