Concurrent progestogen and cerclage to reduce preterm birth: a multicenter international retrospective cohort.

BACKGROUND: Both progestogens and cerclage are individually effective in preterm birth prevention in high risk pregnancies. However, national and international guidelines cite a lack of data available to comment on the potential benefit of concurrent progestogen therapy after cerclage has been placed. Studies to date have been small with mixed results regarding benefit of concurrent progestogen with cerclage leaving uncertainty regarding best clinical practice. OBJECTIVE: This study aimed to evaluate whether cerclage with progestogen therapy was superior to cerclage alone in the prevention of spontaneous preterm birth in singleton pregnancies. METHODS: This is an international retrospective cohort study of singleton pregnancies, without major anomaly or aneuploidy, and with cerclage placed at 10 different institutions in the United States and Colombia from June 2016 to June 2020. Exclusion criteria were lack of documentation regarding whether progestogen was prescribed, unavailable delivery outcome, and pregnancy termination (spontaneous or induced) before 16 weeks' gestation. The exposure of interest was progestogen use with cerclage placement, which included those who continued to use progestogen or who started progestogen after cerclage. The comparison group consisted of those without progestogen use after cerclage placement, which included those who had no progestogen use during the entire pregnancy or who initiated progestogen and then stopped it after cerclage placement. Progestogen type, cerclage indication, maternal baseline characteristics, and maternal/neonatal outcomes were collected. The primary outcome was spontaneous preterm birth at <37 weeks. The secondary outcomes were spontaneous preterm birth at <34 weeks, gestational age at delivery, and a composite neonatal outcome including ≥1 of the following: perinatal mortality, confirmed sepsis, grade III or IV intraventricular hemorrhage, retinopathy of prematurity, respiratory distress syndrome, and bronchopulmonary dysplasia. There were planned subgroup analyses by cerclage indication, progestogen type (vaginal progesterone vs 17-hydroxyprogesterone caproate), preterm birth history, and site. Continuous variables were compared in adjusted analyses with analysis of covariance, and categorical variables were compared with multivariable logistic regression, adjusting for potential confounders with adjusted odds ratio. A Cox regression survival curve was generated to compare latency to spontaneous delivery, censored after 37 weeks. RESULTS: During the study period, a total of 699 singletons met the inclusion criteria: 561 in the progestogen with cerclage group and 138 with cerclage alone. Baseline characteristics were similar, except the higher likelihood of previous spontaneous preterm birth in the progestogen group (61% vs 41%; P<.001). Within the progestogen group, 52% were on 17-hydroxyprogesterone caproate weekly, 44% on vaginal progesterone daily, and 3% on oral progesterone daily. Progestogen with cerclage was associated with a significantly lower frequency of spontaneous preterm birth <37 weeks (31% vs 39%; adjusted odds ratio, 0.59 [0.39-0.89]; P=.01) and <34 weeks (19% vs 27%; adjusted odds ratio, 0.55 [0.35-0.87]; P=.01), increased latency to spontaneous delivery (hazard ratio for spontaneous preterm birth <37 weeks, 0.66 [0.49-0.90]; P=.009), and lower frequency of perinatal death (7% vs 16%; adjusted odds ratio, 0.37 [0.20-0.67]; P=.001). In planned subgroup analyses, association with reduced odds of preterm birth <37 weeks persisted in those on vaginal progesterone, those without a previous preterm birth, those with ultrasound- or examination-indicated cerclage, those who started progestogen therapy before cerclage, and in sites restricted to the United States. CONCLUSION: Use of progestogen with cerclage was associated with reduced rates of spontaneous preterm birth and early spontaneous preterm birth compared with cerclage alone. Although this study was not sufficiently powered for subgroup analysis, the strength of evidence for benefit appeared greatest for those with ultrasound- or examination-indicated cerclage, and with vaginal progesterone.

Obstetric Indications for Progestin Therapy.

Specifically, meta-analyses of randomized trials demonstrate that vaginal progesterone reduces the risk of preterm birth in selected high-risk singleton pregnancies. 17-OHPC may also reduce the risk of recurrent preterm birth in singletons. Finally, one trial suggests that vaginal progesterone may also be beneficial in improving live birth rates in singletons with prior miscarriages and early pregnancy bleeding.

COVID-19 Infection During Pregnancy Induces Differential Gene Expression in Human Cord Blood Cells From Term Neonates.

Background: The COVID-19 pandemic continues worldwide with fluctuating case numbers in the United States. This pandemic has affected every segment of the population with more recent hospitalizations in the pediatric population. Vertical transmission of COVID-19 is uncommon, but reports show that there are thrombotic, vascular, and inflammatory changes in the placenta to which neonates are prenatally exposed. Individuals exposed in utero to influenza during the 1918 pandemic had increased risk for heart disease, kidney disease, diabetes, stomach disease and hypertension. Early exposure of COVID-19 during fetal life may lead to altered gene expression with potential long-term consequences. Objective: To determine if gene expression is altered in cord blood cells from term neonates who were exposed to COVID-19 during pregnancy and to identify potential gene pathways impacted by maternal COVID-19. Methods: Cord blood was collected from 16 term neonates (8 exposed to COVID-19 during pregnancy and 8 controls without exposure to COVID-19). Genome-wide gene expression screening was performed using Human Clariom S gene chips on total RNA extracted from cord blood cells. Results: We identified 510 differentially expressed genes (374 genes up-regulated, 136 genes down-regulated, fold change ≥1.5, p-value ≤ 0.05) in cord blood cells associated with exposure to COVID-19 during pregnancy. Ingenuity Pathway Analysis identified important canonical pathways associated with diseases such as cardiovascular disease, hematological disease, embryonic cancer and cellular development. Tox functions related to cardiotoxicity, hepatotoxicity and nephrotoxicity were also altered after exposure to COVID-19 during pregnancy. Conclusions: Exposure to COVID-19 during pregnancy induces differential gene expression in cord blood cells. The differentially expressed genes may potentially contribute to cardiac, hepatic, renal and immunological disorders in offspring exposed to COVID-19 during pregnancy. These findings lead to a further understanding of the effects of COVID-19 exposure at an early stage of life and its potential long-term consequences as well as therapeutic targets.

Vaginal progesterone compared with intramuscular 17-alpha-hydroxyprogesterone caproate for prevention of recurrent preterm birth in singleton gestations: a systematic review and meta-analysis.

OBJECTIVE: Randomized trials have found benefits of both vaginal progesterone and 17-alpha-hydroxyprogesterone caproate in the prevention of recurrent preterm birth. A previous meta-analysis directly comparing the two was limited by low-quality evidence, and national and international society guidelines remain conflicting regarding progestin formulation recommended for prevention of recurrent preterm birth. The aim of this updated systematic review with meta-analysis was to evaluate the efficacy of vaginal progesterone compared with 17-alpha-hydroxyprogesterone caproate in the prevention of spontaneous preterm birth in patients with singleton gestations and previous spontaneous preterm birth. DATA SOURCES: Searches were performed in MEDLINE, Ovid, Scopus, ClinicalTrials.gov, the International Prospective Register of Systematic Reviews (PROSPERO), SciELO, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) with the use of a combination of keywords and text words related to "preterm birth," "preterm delivery," "singleton," "cervical length," "progesterone," "progestogens," "vaginal," "17-alpha-hydroxy-progesterone caproate," and "intramuscular" from inception of each database to September 2021. No restrictions for language or geographic location were applied. STUDY ELIGIBILITY CRITERIA: We included all randomized controlled trials of asymptomatic singleton gestations with previous spontaneous preterm birth that were randomized to prophylactic treatment with either vaginal progesterone (ie, intervention group) or intramuscular 17-alpha-hydroxyprogesterone caproate (ie, comparison group). Post hoc sensitivity analysis was performed for studies with low risk of bias and studies with protocol registration. METHODS: The primary outcome was preterm birth <34 weeks' gestation. The summary measures were reported as relative risks with 95% confidence intervals. RESULTS: Seven randomized controlled trials including 1910 patients were included in the meta-analysis. Patients who received vaginal progesterone had a significantly lower rate of preterm birth at <34 weeks (14.7% vs 19.9%; relative risk, 0.74; 95% confidence interval, 0.57-0.96), preterm birth at <37 weeks (36.0% vs 46.6%; relative risk, 0.76; 95% confidence interval, 0.69-0.85), and preterm birth at <32 weeks of gestation (7.9% vs 13.6%; relative risk, 0.58; 95% confidence interval, 0.39-0.86), compared with women who received intramuscular 17-alpha-hydroxyprogesterone caproate. There were no significant differences in the rate of preterm birth at <28 weeks' gestation. Adverse drug reactions were significantly lower in the vaginal progesterone group than in the 17-alpha-hydroxyprogesterone caproate group (15.6% vs 22.2%; relative risk, 0.71; 95% confidence interval, 0.54-0.92). Perinatal mortality was lower in the vaginal progesterone group than in the 17-alpha-hydroxyprogesterone caproate group (2.2% vs 4.4%; relative risk, 0.51; 95% confidence interval, 0.25-1.01). In sensitivity analysis including trials rated with at least 4 Cochrane tools as of "low risk of bias," 4 trials were included (N=575), and there was no longer a significant difference in preterm birth at <34 weeks' gestation between vaginal progesterone and 17-alpha-hydroxyprogesterone caproate (12.2% vs 13.9%; relative risk, 0.87; 95% confidence interval, 0.57-1.32). CONCLUSION: Overall, vaginal progesterone was superior to 17-alpha-hydroxyprogesterone caproate in the prevention of preterm birth at <34 weeks' gestation in singleton pregnancies with previous spontaneous preterm birth. Although sensitivity analysis of high-fidelity studies showed the same trend, findings were no longer statistically significant.

Vaginal progesterone vs intramuscular 17-hydroxyprogesterone caproate for prevention of recurrent preterm birth: a randomized controlled trial.

BACKGROUND: Preterm birth is the leading cause of neonatal morbidity and mortality, and previous preterm birth is one of the strongest risk factors for preterm birth. National and international obstetrical societies have different recommendations regarding progesterone formulation for the prevention of recurrent preterm birth. OBJECTIVE: This study aimed to determine whether vaginal progesterone is superior to 17-hydroxyprogesterone caproate in the prevention of recurrent preterm birth in patients with singleton pregnancies who had a previous spontaneous preterm birth. STUDY DESIGN: This was an open-label multicenter pragmatic randomized controlled trial at 5 US centers of patients with singleton pregnancies at <24 weeks of gestation who had a previous spontaneous preterm birth randomized 1:1 to either 200 mg vaginal progesterone suppository nightly or 250 mg intramuscular 17-hydroxyprogesterone caproate weekly from 16 to 36 weeks of gestation. Based on the estimated recurrent preterm birth rate of 36% with 17-hydroxyprogesterone caproate, 95 participants were needed in each arm to detect a 50% reduction in preterm birth rate with vaginal progesterone, with 80% power and 2-sided alpha of 0.05. The primary outcome was preterm birth at <37 weeks of gestation. Prespecified secondary outcomes included preterm birth at <34 and <28 weeks of gestation, mean gestational age at delivery, neonatal morbidity and mortality, and measures of adherence. Analysis was by intention to treat. The chi-square test and Student t test were used as appropriate. P<.05 was considered significant. RESULTS: Overall, 205 participants were randomized; 94 participants in the vaginal progesterone group and 94 participants in 17-hydroxyprogesterone caproate group were included. Although gestational age at enrollment was similar, those assigned to vaginal progesterone initiated therapy earlier (16.9±1.4 vs 17.8±2.5 weeks; P=.001). Overall continuation of assigned formulation until delivery was similar (73% vs 69%; P=.61). There was no significant difference in preterm birth at <37 (31% vs 38%; P=.28; relative risk, 0.81 [95% confidence interval, 0.54-1.20]), <34 (9.6% vs 14.9%; P=.26; relative risk, 0.64 [95% confidence interval, 0.29-1.41]), or <28 (1.1% vs 4.3%; P=.37; relative risk, 0.25 [95% confidence interval, 0.03-2.20]) weeks of gestation. Participants in the vaginal progesterone group had a later mean gestational age at delivery than participants in the 17-hydroxyprogesterone caproate group (37.36±2.72 vs 36.34±4.10 weeks; mean difference, 1.02 [95% confidence interval, 0.01-2.01]; P=.047). CONCLUSION: Vaginal progesterone did not reduce the risk of recurrent preterm birth by 50% compared with 17-OHPC; however, vaginal progesterone may lead to increased latency to delivery. This trial was underpowered to detect a smaller, but still clinically significant, difference in the efficacy of preterm birth prevention. Patient factors that impact adherence and ability to obtain medication in a timely fashion should be included in counseling on progesterone selection.

Utility of follow-up cervical length screening in low-risk women with a cervical length of 26 to 29 mm.

BACKGROUND: In women with a previous preterm birth, a protocol for serial cervical length screening has been studied and recommended for the identification and treatment of a short cervix. Cervical length screening along with vaginal progesterone has been suggested for low-risk women with singleton pregnancies to treat a short cervix and reduce preterm birth. However, specific protocols for single vs serial ultrasound measuring cervical length in this population are not established. Cost-effectiveness of universal cervical length screening depends on the cost of screening; follow-up of borderline measurements can contribute to increased costs with uncertain benefit. OBJECTIVE: This study aimed to determine the utility of follow-up cervical length screening in otherwise low-risk women with singleton pregnancies with a midtrimester cervical length measurement of 26 to 29 mm through the assessment of the rate of short cervix (≤25 mm) on follow-up ultrasound and subsequent delivery outcomes. STUDY DESIGN: This was a 2-year retrospective cohort study at a single urban institution of women with singleton pregnancies with no previous spontaneous preterm birth and an initial transvaginal ultrasound cervical length measurement of 26 to 29 mm identified during universal cervical length screening at time of anatomy ultrasound (18 0/7 to 22 6/7 weeks' gestation). The primary outcome was the rate of short cervix (defined as ≤25 mm on transvaginal ultrasound) on follow-up ultrasound at <24 weeks' gestation. Secondary outcomes included the rate of spontaneous preterm birth (<37 and <34 weeks' gestation). RESULTS: During the study period, there were 2801 women with singleton pregnancies at 18 0/7 to 22 6/7 weeks' gestation with transvaginal ultrasound cervical length screening at time of anatomy scan. Among those women, 201 had a cervical length of 26 of 29 mm, and 184 (7%) had no previous spontaneous preterm birth and were included in the study. Furthermore, 144 women (78%) had a follow-up cervical length completed before 24 weeks' gestation. The mean follow-up interval was 1.5±0.6 weeks. Overall, the percentage of short cervix (≤25 mm) on follow-up was 15% (n=21). Baseline characteristics were similar, but the initial cervical length measurement was shorter in women who subsequently developed a short cervix (26.7±0.8 vs 27.8±1.0; P<.01). Delivery outcomes were available for 126 patients. The rate of spontaneous preterm birth at <37 weeks' gestation in women with an initial cervical length 26 to 29 mm and subsequent short cervix was significantly higher than the rate of spontaneous preterm birth in a historical cohort of low risk women with an initial cervical length >25 mm (16% vs 3%; P=.03). The rate of spontaneous preterm birth at <34 weeks' gestation in women with a subsequent short cervix was 11% (2 of 19). CONCLUSION: Here, approximately 15% of low-risk women with singleton pregnancies with a midtrimester cervical length measurement of 26 to 29 mm will experience cervical shortening of ≤25 mm before 24 weeks' gestation. Compared to women with singleton pregnancies without a history of preterm birth, the rate of spontaneous preterm birth (16%) in women with an initial cervical length of 26 to 29 mm and a subsequent cervical shortening of ≤25 mm is significantly higher. A total of 111 follow-up ultrasounds measuring cervical length would be required to prevent 1 early preterm birth at <34 weeks' gestation.

Intramuscular progesterone in women with twins and a prior singleton spontaneous preterm birth.

BACKGROUND: Although the use of 17-alpha-hydroxyprogesterone caproate is one of the most commonly used strategies to reduce the risk of preterm birth since its approval by the Food and Drug Administration in 2011, there has been controversy recently that there may be no benefit associated with its use in singleton pregnancies in women with a prior history of spontaneous preterm birth. However, very few of these investigations evaluated the use of intramuscular progesterone in twin pregnancies. A few studies that used 17-alpha-hydroxyprogesterone caproate in twin pregnancies had mainly included unselected twin pregnancies. Although a twin pregnancy is independently associated with an increased likelihood of preterm birth, the primary indication for the use of supplemental progesterone in pregnancy is prior history of spontaneous preterm birth. Therefore, our investigation of weekly intramuscular progesterone in twin pregnancies with this birth history best addresses this question using a selected cohort. OBJECTIVE: To assess whether weekly 17-alpha-hydroxyprogesterone caproate prevents recurrent preterm birth in women with a current twin pregnancy and a prior singleton spontaneous preterm birth. STUDY DESIGN: This was a retrospective cohort study of women with twin pregnancy and a prior singleton spontaneous preterm birth in 2 institutions between January 2005 and December 2016. One group (intervention group) consisted of women who received weekly 17-alpha-hydroxyprogesterone caproate, whereas the other (control group) did not. The primary outcome was twin spontaneous preterm birth <34 weeks compared with odds ratio and adjusted odds ratio, adjusting for potential confounders. Secondary outcomes included composite neonatal morbidity such as respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, admission to the neonatal intensive care nursery, and fetal or neonatal death before hospital discharge. RESULTS: A total of 79 patients were included; 27 women received weekly 17-alpha-hydroxyprogesterone caproate and 52 did not. There were no statistically significant differences in maternal demographics except for age. Spontaneous preterm birth <34 weeks occurred in 16 patients (59%) in the intervention group vs 24 (46%) in the control group (odds ratio, 1.69; 95% confidence interval, 0.68-4.54). Composite neonatal morbidity occurred in 20 pregnancies (74%) in the intervention group and 41 pregnancies (79%) in the control group (odds ratio, 0.76; 95% confidence interval, 0.27-2.12). There remained no differences in outcomes after adjusting for potential confounders. CONCLUSION: In our study, weekly 17-alpha-hydroxyprogesterone caproate did not prevent spontaneous preterm birth or neonatal morbidity in women with twins and a prior singleton spontaneous preterm birth; however, further research with larger numbers and prospective design is needed.

Labor and delivery guidance for COVID-19.

This document addresses the current coronavirus disease 2019 (COVID-19) pandemic for providers and patients in labor and delivery (L&D). The goals are to provide guidance regarding methods to appropriately screen and test pregnant patients for COVID-19 prior to, and at admission to L&D reduce risk of maternal and neonatal COVID-19 disease through minimizing hospital contact and appropriate isolation; and provide specific guidance for management of L&D of the COVID-19-positive woman, as well as the critically ill COVID-19-positive woman. The first 5 sections deal with L&D issues in general, for all women, during the COVID-19 pandemic. These include Section 1: Appropriate screening, testing, and preparation of pregnant women for COVID-19 before visit and/or admission to L&D Section 2: Screening of patients coming to L&D triage; Section 3: General changes to routine L&D work flow; Section 4: Intrapartum care; Section 5: Postpartum care; Section 6 deals with special care for the COVID-19-positive or suspected pregnant woman in L&D and Section 7 deals with the COVID-19-positive/suspected woman who is critically ill. These are suggestions, which can be adapted to local needs and capabilities.

Predictors of Early Preterm Birth Despite Vaginal Progesterone Therapy in Singletons with Short Cervix.

OBJECTIVE: This study aimed to identify the incidence of and risk factors for early preterm birth (PTB) (delivery <34 weeks) in women without prior PTB and current short cervix (≤20 mm) prescribed vaginal progesterone. STUDY DESIGN: Retrospective cohort study of singletons without prior PTB diagnosed with short cervix (≤20 mm) between 180/7 and 236/7 weeks. Women who accepted vaginal progesterone and had delivery outcomes available were included. Demographic/obstetric history, cervical length, and pregnancy characteristics compared between women with early PTB versus delivery ≥34 weeks. Multiple logistic regression analysis used to identify predictors; odds ratio for significant factors used to generate a risk score. Risk score and risk of early PTB assessed with receiver operating characteristic curve (ROCC). Perinatal outcomes compared by risk score. RESULTS: Among 109 patients included, 29 (27%) had a spontaneous PTB <34 weeks. In univariate analysis, only gestational age at ultrasound, presence funneling, and mean cervical length were significantly different between those with and without early sPTB. With multiple logistic regression analysis, only gestational age at diagnosis (odds ratio [OR]: 0.66; 95% confidence interval [CI]: 0.46-0.96; p = 0.028) and index cervical length (OR: 0.84; 95% CI: 0.76-0.93; p = 0.001) remained significantly associated with early PTB. ROCC for the risk score incorporating cervical length and gestational age was predictive of early PTB with an AUC of 0.76 (95% CI: 0.67-0.86; p < 0.001). A high-risk score was predictive of early PTB with a sensitivity of 79%, specificity of 75%, positive predictive value of 54%, and negative predictive value of 91%. Women with a high-risk score had worse perinatal outcomes compared with those with low-risk score. CONCLUSION: A total of 27% of patients with short cervix prescribed vaginal progesterone will have a sPTB < 34 weeks. Patients at high risk for early PTB despite vaginal progesterone therapy may be identified using gestational age and cervical length at diagnosis of short cervix. Given the narrow window for intervention after diagnosis of short cervix, this has important implications for clinical care.

Oral progesterone for the prevention of recurrent preterm birth: systematic review and metaanalysis.

OBJECTIVE DATA: The purpose of this study was to perform a systematic review and metaanalysis of randomized controlled trials on oral progesterone compared with placebo or other interventions for preterm birth prevention in singleton pregnancies with previous spontaneous preterm birth. The primary outcome was preterm birth at <37 weeks gestation; the secondary outcomes included preterm birth rate at <34 weeks gestation, neonatal morbidity/death, and maternal side-effects. STUDY: Searches were performed in PubMed, Scopus, ClinicalTrials.gov, PROSPERO, EMBASE, and the Cochrane Register with the use of a combination of words related to "preterm birth," "preterm delivery," "progesterone," "progestogens," and "oral" from inception of each database to April 2018. Additionally, systematic reviews on progesterone for preterm birth prevention that were identified in our search were also reviewed for additional studies. We included all randomized trials of asymptomatic singleton gestations with previous spontaneous singleton preterm birth that had been randomized to prophylactic treatment with oral progesterone vs placebo, no treatment, or other preterm birth intervention. Exclusion criteria included quasirandomized trials, trials that involved women with preterm labor/membrane rupture at the time of randomization or multiple gestations. STUDY APPRAISAL AND SYNTHESIS METHODS: The risk of bias and quality of evidence were assessed for each study. All analyses were done with an intention-to-treat approach. The primary outcome was incidence of preterm birth at <37 weeks gestation; the secondary outcomes included preterm birth at <34 and <28 weeks gestation, maternal adverse events, maternal serum progesterone level, and neonatal morbidity and death. Summary measures were reported as relative risk or mean difference. I2 >30% was used to identify heterogeneity. RESULTS: The search strategy identified 79 distinct studies. Three trials on oral progesterone vs placebo (involved 386 patients: 196 in oral progesterone and 190 in placebo) met the inclusion criteria; there were no studies on oral progesterone vs other intervention that met inclusion criteria. Metaanalysis demonstrated a significantly decreased risk of preterm birth at <37 weeks gestation (42% vs 63%; P=.0005; relative risk, 0.68; 95% confidence interval, 0.55-0.84), preterm birth at <34 weeks gestation (29% vs 53%; P<.00001; relative risk, 0.55; 95% confidence interval, 0.43-0.71), and increased gestational age of delivery (mean difference, 1.71 weeks; 95% confidence interval, 1.11-2.30) with oral progesterone compared with placebo. There was a significantly lower rate of perinatal death (5% vs 17%; P=.001; relative risk 0.32; 95% confidence interval, 0.16-0.63), neonatal intensive care admission (relative risk, 0.39; 95% confidence interval, 0.25-0.61), respiratory distress syndrome (relative risk, 0.21; 95% confidence interval, 0.05-0.93), and higher birthweight (mean difference, 435.06 g; 95% confidence interval, 324.59-545.52) with oral progesterone. There was a higher rate of maternal adverse effects with oral progesterone that included dizziness (relative risk, 2.95; 95% confidence interval, 1.47-5.90), somnolence (relative risk, 2.06; 95% confidence interval, 1.29-3.30), and vaginal dryness (relative risk, 2.37; 95% confidence interval, 1.10-5.11); no serious adverse effects were noted. CONCLUSION: Oral progesterone appears to be effective for the prevention of recurrent preterm birth and a reduction in perinatal morbidity and mortality rates in asymptomatic singleton gestations with a history of previous spontaneous preterm birth compared with placebo. There were also increased adverse effects with oral progesterone therapy compared with placebo, although none were serious. Further randomized study on oral progesterone compared with other established therapies for the prevention of recurrent preterm birth are warranted.

Pharmacokinetics of vaginal progesterone in pregnancy.

BACKGROUND: Characterization of pharmacokinetics is lacking for vaginal progesterone in pregnancy. Dosing of vaginal progesterone for preterm birth prevention has been empirical. Owing to pregnancy-related changes in vaginal and uterine blood flow, hepatic metabolism, renal clearance, and endogenously elevated serum progesterone, studies outside of pregnancy may not be applicable. The lack of the pharmacokinetics profile of vaginally administered progesterone in pregnancy limits the ability to define the exposure-response relationship needed to optimize dosing, which has implications for its use in research and clinical care regarding management of short cervix, prevention of recurrent preterm birth, and prevention of recurrent miscarriage. OBJECTIVE: This was a study to establish the feasibility of using serum progesterone to establish basic pharmacokinetic parameters of vaginal progesterone in pregnancy for preterm birth prevention. STUDY DESIGN: This is a prospective study of 6 low-risk singletons at 18 0/7 to 23 6/7 weeks' gestation with body mass index 20-40. Exclusion criteria were current vaginitis, abnormal Pap smear, prescription medication use, cervical length ≤25 mm, prior preterm birth, and contraindication to progesterone. Participants received a single dose of 200 mg micronized vaginal progesterone and serum progesterone levels were evaluated every 2 hours from 0 to 12 hours and then 24 hours post dose. Primary outcome was concentration/time profile of serum progesterone. RESULTS: Median (range) maternal age was 27 (21.5-33.3) years, median body mass index was 26.5 (23.3-29.0) kg/m2, and median gestational age was 22.9 (21.0-23.4) weeks. Median baseline serum progesterone was 47 (40-52) ng/mL, median peak concentration was 54 (48-68) ng/mL, and median time to peak was 12 (4-15) hours. There was a trend in rising serum progesterone over baseline with a median change in peak concentration of 11 ng/mL and interquartile range of 2-22. Median percent change from baseline was an increase by 24% (interquartile range, 4%-53%). However, there was no clear elimination phase and the median area under the curve was 112 ng*h/mL with an interquartile range of -43 to 239. CONCLUSION: Unlike in nonpregnant individuals, administration of vaginal progesterone in pregnant individuals only minimally impacts systemic exposure. There is a limited trend of rising serum progesterone over baseline levels, with significant inter-individual variability. Serum progesterone is unlikely to be a good candidate for establishing pharmacokinetics or dosing of vaginal progesterone in pregnancy for preterm birth prevention.

Utilization of progesterone and cervical length screening for prevention of recurrent preterm birth.

Objective: To assess utilization of progesterone and cervical length (CL) screening among women with prior spontaneous preterm birth (sPTB).Methods: This is a retrospective cohort study of women with prior sPTB. Primary outcomes were the use of progesterone and CL screening. Secondary outcomes were reasons for failure to utilize interventions and factors associated with use of recommended interventions.Results: 180 women had a prior sPTB. Of 171 women eligible for progesterone, 125 (74%) utilized it. Women who utilized progesterone were more likely to have a prior sPTB <28 weeks (50% vs 26%, OR 2.54 (1.18-5.42) p = .006) and a higher number of prior sPTB (1.5 ± 0.9 vs 1.2 ± 0.5, p = .02), and less likely to have a prior full term delivery (54% vs 72%, OR 0.47 (0.22-0.99), p = .04). Of 176 women eligible for CL screening, 157 (89%) utilized it. Women who utilized CL screening were less likely to have a prior full term delivery (59% vs 84%, OR 0.27 (0.07-0.95, p = .01)). The most frequent reason for lack of progesterone and CL screening was patient declining.Conclusion: Most women with prior sPTB received progesterone and CL screening. Those at highest risk for PTB based on obstetric history are more likely to utilize recommended interventions.

Prior Uterine Evacuation and the Risk of Short Cervical Length: A Retrospective Cohort Study.

OBJECTIVES: To determine whether a prior uterine evacuation procedure is associated with an increased risk of short cervical length (≤20 mm) in women without prior spontaneous preterm birth. METHODS: This work was a retrospective cohort study from January 2012 to December 2014 of singletons without prior spontaneous preterm birth with cervical length screening between 18 weeks and 23 weeks 6 days. Women with a prior miscarriage/abortion were excluded if management (medical, surgical, or expectant) was not specified. Prior uterine evacuation was defined as dilation and curettage or dilation and evacuation of a spontaneous or induced abortion. The primary outcome was the risk of short cervical length (≤20 mm) among women with and without 1 of more prior uterine evacuations at any gestational age, assessed by the odds ratio and adjusted odds ratio for confounders. RESULTS: Of 2672 women included, 714 (27%) had at least 1 prior uterine evacuation. The overall incidence of short cervical length in the cohort was 1% (n = 27). Women with at least 1 prior uterine evacuation were more likely to be African American (64% versus 41%; P < .001), smoke (14% versus 8%; P < .001), have a higher body mass index (mean ± SD, 28.1 ± 7.1 versus 26.8 ± 7.1 kg/m2 ; P < .001), and have had prior full-term delivery (60% versus 41%; P < .001). Women with at least 1 prior uterine evacuation had a significantly higher incidence of short cervical length (2% versus 0.7%; P = .003; odds ratio, 2.99 [95% confidence interval, 1.40-6.40]). After adjustment for confounders, prior uterine evacuation remained a source of increased risk of short cervical length (adjusted odds ratio, 2.63 [95% confidence interval, 1.19-5.80]). CONCLUSIONS: Although the overall incidence of short cervical length is low (1%-2%), women with at least 1 prior uterine evacuation have at least a 2-fold increased risk of a short second-trimester cervical length compared to women without a prior uterine evacuation.

Second-trimester cervical length and outcomes of induction of labor at term.

OBJECTIVE: To evaluate whether second-trimester cervical length (CL) is associated with induction of labor (IOL) outcomes. METHODS: Retrospective cohort study of nulliparous singletons undergoing CL screening at 18 0/7-23 6/7 weeks from 1/1/2012 to 12/31/2013. Women induced at term (≥37 weeks) were included. Primary outcome was vaginal delivery (VD) within 24 h. The effect of CL on outcomes was assessed by incidence across CL quartiles and a receiver operating characteristics (ROC) curve. Odds ratios (OR) were adjusted (aOR) for confounders. RESULTS: Two-hundred-and-sixty-eight women were included. Aside from a difference in incidence of prior cervical surgery between CL quartiles (p <. 02), other characteristics were similar. Ninety-two women (35%) had a VD within 24 h (versus a CD or VD >24 h). A longer a CL was associated with a decreased likelihood of a VD within 24 h with aORs of the third and fourth quartiles of 0.35 (0.16-0.75) and 0.43 (0.21-0.90), respectively, compared to the first quartile. A CL >40 mm was predictive of not having a VD within 24 h with a sensitivity of 56%, specificity of 58% and a positive predictive value of 72%. CONCLUSION: A second-trimester CL >40 mm is associated with a decreased likelihood of VD within 24 h in an IOL.

Current options for mechanical prevention of preterm birth.

Cervical insufficiency can be defined by a combination of obstetric history, cervical dilation on exam, and/or short cervical length in women with prior preterm birth. Options for mechanical intervention include cerclage and pessary. There is evidence to support the benefit of a cervical cerclage in women with singleton gestations who have a diagnosis of cervical insufficiency either based on second trimester painless cervical dilatation leading to recurrent early preterm births, or a history of early spontaneous preterm birth and a second trimester transvaginal ultrasound short cervical length or cervical dilation on exam. For women with multiple gestations, the benefit of a cerclage is uncertain, and further study is warranted. The pessary has also been studied for mechanical prevention of preterm birth in various populations, however the results so far have been mixed and warrants further study prior to routine use.

Cervical Length Screening in Asymptomatic Women at High Risk and Low Risk for Spontaneous Preterm Birth.

Cervical length (CL) screening should be offered to singletons because there are interventions for those with a short CL. A transvaginal ultrasound (TVU) is the "gold standard" for CL. In singletons with prior spontaneous preterm birth, serial TVU CL screening is recommended between 16 and 23 6/7 weeks. Universal TVU CL screening between 18 and 24 weeks may be considered for low-risk singletons with the administration of vaginal progesterone for TVU CL≤20 mm; alternatively, transabdominal ultrasound CL screening may be considered with reflux to TVU CL screening for a transabdominal ultrasound CL<35 mm or inadequate visualization. CL screening is not recommended in multiples.