Previous Spontaneous Preterm Birth Research Articles

Perinatal and neonatal outcomes of high-risk asymptomatic women from a specialist preterm birth surveillance clinic

ObjectivesTo report the perinatal outcomes of high-risk asymptomatic women who attended a specialist preterm surveillance clinic (PSC) to undergo screening for spontaneous preterm birth (PTB) in Ireland. MethodsSingle center, retrospective cohort study of asymptomatic high risk women who attended the PSC between January 2019 and December 2022. A comprehensive database of all patients who attended the clinic during the study period was constructed and analyzed. Overall outcomes were reported, and stratified per the occurrence of preterm or term birth. Iatrogenic PTBs were included in the outcome data. ResultsFollowing exclusions for loss-to-follow-up, 762 cases were analyzed, constituting 2262 PSC visits. Of those, 183 women were prescribed progesterone (24.0 %), and 100 women underwent cervical cerclage (13.1 %) to prevent spontaneous PTB. Overall, 2.4 %, 6.2 % and 18.6 % of participants gave birth prior to 30 weeks, 34 weeks, and 37 weeks, respectively. The median gestational age at birth for the entire cohort was 38.6 weeks (inter-quartile range (IQR) 37.2–39.6 weeks).Women who delivered < 37 weeks were significantly more likely to be smokers (p = 0.030), have a previous spontaneous PTB (p = 0.016), have multiple pregnancies (p < 0.001), type 1 or 2 diabetes (p = 0.044), or have a previous full dilatation caesarean section birth (p = 0.024). Infants born prior to 37 weeks were more likely to have a lower median birthweight (2270 vs 3300 g, p < 0.001), be admitted to a neonatal intensive care unit (53.8 % vs 2.3 %, p < 0.001) or experience short-term morbidity, including respiratory support (38.0 % vs 1.6 %, p < 0.001). ConclusionsOver 80% of women deemed to be at high risk of PTB gave birth at term gestations following attendance at a PSC during pregnancy. Most women can be successfully managed without interventions, instead employing a policy of serial cervical surveillance, to identify those at greatest risk of PTB.

Biomarkers associated with cardiovascular disease in women with spontaneous preterm birth: A case-control study.

Women with spontaneous preterm birth have an increased risk of cardiovascular disease later in life. Studies suggest potential pathophysiological mechanisms in common, but whether these could be identified by measurement of soluble circulating protein biomarkers in women with spontaneous preterm birth is unknown. The aim of this study was to determine if protein biomarkers associated with cardiovascular disease distinguish women with spontaneous preterm birth from healthy controls, both at pregnancy and at follow up. Study participants were identified in the population-based Uppsala biobank of pregnant women in Sweden, where plasma samples were collected in mid-pregnancy. In a first screening phase, we identified participants who subsequently experienced spontaneous preterm birth (<37 weeks) in the index pregnancy (N = 13) and controls (N = 6). In these samples, differences in protein expression were examined by comparative mass spectrometry. In a second validation phase, we invited 100 cases with previous spontaneous preterm birth in the index pregnancy and 100 controls (matched for age, body mass index, and year of delivery) from the same source population, to a follow-up visit 4-15 years after pregnancy. At follow up, we collected plasma samples and data on cardiovascular risk factors. We measured concentrations of selected biomarkers identified in the screening phase, as well as lipid profiles in samples both from pregnancy (biobank) and follow up. gov registration NCT05693285. In the screening phase, fibrinogen, cadherin-5, complement C5, factor XII, plasma kallikrein, apolipoprotein M, and vitamin D-binding protein differed significantly at pregnancy. In the validation phase, 65 women agreed to participate (35 cases and 30 controls), with a median follow-up time of 11.8 years since pregnancy. The concentration of fibrinogen (p = 0.02) and triglycerides (p = 0.03) were slightly higher in cases compared with matched controls at follow up. Compared with women without preterm birth, those with spontaneous preterm birth had slightly higher concentrations of fibrinogen, both at mid-pregnancy and a decade after pregnancy. Additionally, we found slightly higher concentration of triglycerides at follow up in women with previous spontaneous preterm birth. The relevance of this finding is uncertain but might indicate potential pathophysiological mechanisms in common between spontaneous preterm birth and cardiovascular disease.

A prospective study of antepartum anxiety screening in patients with and without a history of spontaneous preterm birth

Maternal stress has been identified as one of the most common clinical phenotypes associated with preterm birth. The American College of Obstetricians and Gynecologists recommends anxiety screening at least once in the perinatal period. The prevalence of perinatal anxiety is challenged by the absence of formalized screening protocols and underreporting in high-risk populations, such as those with a history of adverse pregnancy outcomes. This study administered a validated anxiety screening tool in a cohort of patients with and without a previous spontaneous preterm birth and compared differences in score and rate of a positive screen between groups. Moreover, this study evaluated perinatal outcomes associated with a positive screen and described a referral protocol involving evaluation by a perinatal mental health counselor and clinical diagnoses. A hypothesis was made that patients with a previous history of spontaneous preterm birth would have higher self-reported anxiety symptoms than controls and that those with recurrent preterm delivery at <35 weeks of gestation would have the highest anxiety screening scores. This was a prospective observational cohort study administering the Generalized Anxiety Disorder 7-item screen to patients enrolled in 2 prenatal care clinics at our institution. The preterm birth cohort consisted of patients with a history of spontaneous preterm labor, premature rupture of membranes, or cervical insufficiency compared with the control cohort without this history. Screening was initiated at entry to prenatal care or referral to our high-risk obstetrical clinic. The inclusion criteria included English- or Spanish-speaking patients and singleton pregnancy, and the exclusion criteria included pregnancies complicated by a major congenital anomaly, enrollment after 34 weeks of gestation, delivery at <20 weeks of gestation, and incomplete delivery data. Referral to a mental health counselor was offered to those with a Generalized Anxiety Disorder 7-item screen score of ≥10. Perinatal outcomes as a comparison between the Generalized Anxiety Disorder 7-item screen-positive group and Generalized Anxiety Disorder 7-item screen-negative group were performed with statistical methods, including the Student t test, chi-square test, and Wilcoxon rank-sum test, with a P value of <.05 to determine significance. Between September 2020 and December 2021, 1349 participants were analyzed, with 143 patients (11%) in the previous preterm birth cohort and 1206 (89%) patients in the control cohort. Patients with a history of preterm birth and subsequent delivery at ≤35 weeks of gestation in the study pregnancy had significantly higher Generalized Anxiety Disorder 7-item screen scores than controls with delivery after 35 weeks of gestation (median score: 4 [interquartile range, 1-9] vs 2 [interquartile range, 0-6], respectively; P=.006). Overall, 187 participants (14%) screened positive with significantly higher rates in the previous preterm birth group than in the control group (20% vs 13%; P=.036). Of note, 117 patients (63%) accepted a referral, and 32 patients (17%) with a positive screen were diagnosed with a perinatal mood disorder. Patients with recurrent preterm birth have higher self-reported anxiety using the Generalized Anxiety Disorder 7-item screen than controls. Of those with a positive screen, 17% were diagnosed with a perinatal mood disorder.

EP02.35: Pessary plus progesterone to prevent preterm birth in women with previous spontaneous preterm birth and short cervix in a low‐income country

EP02.35: Pessary plus progesterone to prevent preterm birth in women with previous spontaneous preterm birth and short cervix in a low‐income country

Relationship between plasma concentration of 17-hydroxyprogesterone caproate and gestational age at preterm delivery

The effectiveness of 17-hydroxyprogesterone caproate is unclear as trials have provided conflicting results. With the absence of fundamental pharmacologic studies addressing dosing or the relationship between drug concentration and gestational age at delivery, the effectiveness of the medication cannot be evaluated. This study aimed to evaluate the relationship between plasma concentrations of 17-hydroxyprogesterone caproate and preterm birth rates and gestational age at preterm delivery and to assess the safety of the 500-mg dose. This study recruited 2 cohorts with previous spontaneous preterm birth; 1 cohort (n=143) was randomly assigned to either 250-mg or 500-mg 17-hydroxyprogesterone caproate, and the other cohort (n=16) was receiving the 250-mg dose for routine care. Steady-state trough plasma concentrations of 17-hydroxyprogesterone caproate obtained at 26 to 30 weeks of gestation were correlated to dose, spontaneous preterm birth rates, and measures of gestational length. Furthermore, maternal and neonatal safety outcomes were evaluated according to dose. There was a dose proportional increase in trough plasma concentrations with the 250-mg (median, 8.6 ng/m; n=66) and 500-mg (median, 16.2 ng/mL; n=55) doses. In 116 compliant participants with blood samples, drug concentration was not related to the spontaneous preterm birth rate (odds ratio, 1.00; 95% confidence interval, 0.93-1.08). However, there was a significant relationship between drug concentration and both the interval from the first administration to delivery (interval A: coefficient, 1.11; 95% confidence interval, 0.00-2.23; P=.05) and the interval from the 26- to 30-week blood draw to delivery (interval B: coefficient, 1.56; 95% confidence interval, 0.25-2.87; P=.02). The spontaneous preterm birth rate or measures of gestational length were not related to dose. Postenrollment cerclage adversely affected all pharmacodynamic assessments because it was a powerful predictor of spontaneous preterm birth (odds ratio, 4.03; 95% confidence interval, 1.24-13.19; P=.021) and both measures of gestational length (interval A [coefficient, -14.9; 95% confidence interval, -26.3 to -3.4; P=.011] and interval B [coefficient, -15.9; 95% confidence interval, -25.8 to -5.9; P=.002]). Initial cervical length was significantly related to the risk of postenrollment cerclage (odds ratio, 0.80; 95% confidence interval, 0.70-0.92; P=.001). Maternal and neonatal safety outcomes were similar in both dosing groups. In this pharmacodynamic study, trough plasma 17-hydroxyprogesterone caproate concentrations were significantly associated with gestational age at preterm birth but not with the preterm birth rate. Postenrollment cerclage was a powerful predictor of spontaneous preterm birth rate and gestational length. Initial cervical length predicted the risk of postenrollment cerclage. Adverse events were similar with the 500-mg and 250-mg doses of 17-hydroxyprogesterone caproate.

Evaluating postpartum cervical remodeling with quantitative ultrasound technology

Having a history of a previous spontaneous preterm birth (sPTB) is the strongest risk factor for recurrent sPTB. It is unknown if there are differences in postpartum cervical remodeling between women who have delivered spontaneous preterm (sPT) and full-term. No studies have evaluated the role of postpartum remodeling between the two groups. Quantitative ultrasound (QUS) is a noninvasive ultrasound technology used to quantify tissue microstructure and function. QUS biomarkers were used to evaluate postpartum cervical microstructure in women who delivered sPT and full-term. Data were collected from 54 women:14 who delivered sPT and 40 who delivered full-term. Transvaginal QUS scans were performed at 6 weeks (±2 weeks) after delivery. Attenuation coefficient (AC), backscatter coefficient (BSC), and shear wave speed (SWS) QUS biomarkers were collected. BSC was significantly higher at six weeks postpartum in women who delivered sPT versus full-term (p = 0.01), while the AC approached statistical significance (p = 0.09). QUS biomarker BSC was able to identify cervical microstructure differences at six weeks postpartum between women who delivered sPT and full-term. QUS technology may improve our understanding of postpartum cervical remodeling and has the potential to noninvasively direct precision-health approaches for recurrent sPTB. [Work supported by NIH 5F31NR019716.]

Efficacy of ultrasound-indicated cerclage in twin pregnancies: a retrospective case-control study matched by cervical length

Twin pregnancies with a progressively shortening cervix in the midterm pregnancy have an increasing risk for spontaneous preterm birth. Currently, there is no known effective method to prevent preterm birth among those women, and the use of an ultrasound-indicated cerclage in twin pregnancies is still controversial. This study aimed to estimate whether a combination of ultrasound-indicated cerclage, indomethacin, and antibiotics in twin pregnancies between 18 and 26 weeks' gestation could extend the pregnancy, reduce the risk for spontaneous preterm birth, and improve perinatal and neonatal outcomes. A retrospective cohort study was conducted. The ultrasound-indicated cerclage group included twin pregnancies with a transvaginal cervical length <25 mm that underwent cerclage at 18 to 26 weeks of gestation in the Women's Hospital, Zhejiang University School of Medicine, from December 2015 through August 2021. Twin pregnancies in our study that underwent cerclage also received antibiotics and indomethacin. A control group of twin pregnancies that were managed expectantly were matched with the treatment group in terms of transvaginal cervical length at diagnosis (±3 mm), gestational age at presentation of diagnosis (±3 weeks), and maternal age (±5 years). An additional subanalysis was performed in which the patients were divided into 2 subgroups based on transvaginal cervical length of either <15 mm or between 15 and 24 mm. The primary outcome was gestational age at delivery. The secondary outcomes were pregnancy latency, the rate of spontaneous preterm birth at <28, <32, <34, <36 weeks' gestation, and neonatal outcomes. A total of 90 twin pregnancies with a transvaginal cervical length <25 mm were managed with either a cerclage (ultrasound-indicated cerclage group, n=45) or expectantly (control group, n=45). Demographic characteristics were not significantly different between the groups. When compared with the control group, the gestational age at delivery was significantly higher (33.11±3.16 vs 30.22±4.12 weeks; P=.001) and the pregnancy latency was significantly longer (72.40±22.51 vs 45.56±28.82 days; P<.001) in the ultrasound-indicated cerclage group. The rates of spontaneous preterm birth at <28, <32, <34, and <36 weeks' gestation were significantly lower in the ultrasound-indicated cerclage group than in the control group. In terms of neonatal outcomes, there were significant reductions in the overall perinatal mortality (4.4% vs 20.0%; P<.001), neonatal intensive care unit admissions (69.0% vs 92.6%; P<.001), and composite adverse neonatal outcomes (43.7% vs 64.7%; P=.010) for the ultrasound-indicated cerclage group when compared with the control group. In the subgroup of women with a transvaginal cervical length of between 15 and 24 mm (with 21 in the ultrasound-indicated cerclage group vs 21 controls), the data were adjusted for maternal age, pregestational body mass index, in vitro fertilization, operative hysteroscopy, previous cervical surgery, previous spontaneous preterm birth, white blood cell counts, C-reactive protein level, neutrophil to lymphocyte ratio, and the shortest transvaginal cervical length measured at diagnosis. In ultrasound-indicated cerclage group, gestational age at delivery was significantly higher (32.95±3.81 vs 30.24±4.01 weeks; beta, 3.34; 95% confidence interval, 0.14-6.55; P=.042), pregnancy latency was significantly prolonged (77.19±24.81 vs 48.52±29.67 days; beta, 33.81; 95% confidence interval, 12.29-55.34; P=.003), and the rates of spontaneous preterm birth <36 weeks' gestation (57.1% vs 95.2%; adjusted odds ratio, 0.03; 95% confidence interval, 0.01-0.69; P=.029) was significantly decreased, and for neonatal outcomes, there were significant reductions in neonatal intensive care unit admissions (53.7% vs 96.7%; adjusted odds ratio, 0.04; 95% confidence interval, 0.01-0.32; P=.003) and the composite adverse neonatal outcomes (39.0% vs 73.3%; adjusted odds ratio, 0.24; 95% confidence interval, 0.08-0.68; P=.008) in the ultrasound-indicated cerclage group when compared with the control group. In the subgroup of women with a transvaginal cervical length <15 mm, gestational age at delivery was higher (33.25±2.52 vs 30.00±4.33 weeks; beta, 3.96; 95% confidence interval, 1.51-6.42; P=.002), pregnancy latency was significantly prolonged (68.21±19.85 vs 42.96±28.43 days; beta, 30.11; 95% confidence interval, 12.42-47.81; P=.001), rates of spontaneous preterm birth at <32 weeks (16.7% vs 54.2%; adjusted odds ratio, 0.10; 95% confidence interval, 0.01-0.61; P=.020) and <34 weeks (54.2% vs 83.3%, adjusted odds ratio, 0.08; 95% confidence interval, 0.01-0.66; P=.019) of gestation was significantly decreased, and neonatal birthweight was significantly increased (2023.96±510.35 vs 1421.77±611.40 g; beta, 702.40; 95% confidence interval, 297.02-1107.78; P=.001) in the ultrasound-indicated cerclage group when compared with the control group. Cerclage among women with twin pregnancies with a transvaginal cervical length <25 mm may reduce the rate of spontaneous preterm birth and improve perinatal and neonatal outcomes when compared with expectant management. It is worth noting that even with a short transvaginal cervical length of 15 to 24 mm, cerclage will significantly decrease the risk of delivery at <36 weeks' gestation and prolong pregnancy latency. Among women with a short transvaginal cervical length <15 mm, cerclage will significantly decrease the risk of delivery at <32 and <34 weeks' gestation and prolong pregnancy latency.

Long-term outcomes following antenatal exposure to low-dose aspirin: study protocol for the 4-year follow-up of the APRIL randomised controlled trial

IntroductionThe use of low-dose aspirin by pregnant women to prevent preterm pre-eclampsia is gradually increasing. The administration of aspirin during pregnancy improves perinatal outcome, which could translate into improved child...

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

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. 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. 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. 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). 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.

Evaluation of low-dose aspirin in the prevention of recurrent spontaneous preterm labour (the APRIL study): A multicentre, randomised, double-blinded, placebo-controlled trial.

Preterm birth is the leading cause of neonatal morbidity and mortality. The recurrence rate of spontaneous preterm birth is high, and additional preventive measures are required. Our objective was to assess the effectiveness of low-dose aspirin compared to placebo in the prevention of preterm birth in women with a previous spontaneous preterm birth. We performed a parallel multicentre, randomised, double-blinded, placebo-controlled trial (the APRIL study). The study was performed in 8 tertiary and 26 secondary care hospitals in the Netherlands. We included women with a singleton pregnancy and a history of spontaneous preterm birth of a singleton between 22 and 37 weeks. Participants were randomly assigned to aspirin 80 mg daily or placebo initiated between 8 and 16 weeks of gestation and continued until 36 weeks or delivery. Randomisation was computer generated, with allocation concealment by using sequentially numbered medication containers. Participants, their healthcare providers, and researchers were blinded for treatment allocation. The primary outcome was preterm birth <37 weeks of gestation. Secondary outcomes included a composite of poor neonatal outcome (bronchopulmonary dysplasia, periventricular leukomalacia > grade 1, intraventricular hemorrhage > grade 2, necrotising enterocolitis > stage 1, retinopathy of prematurity, culture proven sepsis, or perinatal death). Analyses were performed by intention to treat. From May 31, 2016 to June 13, 2019, 406 women were randomised to aspirin (n = 204) or placebo (n = 202). A total of 387 women (81.1% of white ethnic origin, mean age 32.5 ± SD 3.8) were included in the final analysis: 194 women were allocated to aspirin and 193 to placebo. Preterm birth <37 weeks occurred in 41 (21.2%) women in the aspirin group and 49 (25.4%) in the placebo group (relative risk (RR) 0.83, 95% confidence interval (CI) 0.58 to 1.20, p = 0.32). In women with ≥80% medication adherence, preterm birth occurred in 24 (19.2%) versus 30 (24.8%) women (RR 0.77, 95% CI 0.48 to 1.25, p = 0.29). The rate of the composite of poor neonatal outcome was 4.6% (n = 9) versus 2.6% (n = 5) (RR 1.79, 95% CI 0.61 to 5.25, p = 0.29). Among all randomised women, serious adverse events occurred in 11 out of 204 (5.4%) women allocated to aspirin and 11 out of 202 (5.4%) women allocated to placebo. None of these serious adverse events was considered to be associated with treatment allocation. The main study limitation is the underpowered sample size due to the lower than expected preterm birth rates. In this study, we observed that low-dose aspirin did not significantly reduce the preterm birth rate in women with a previous spontaneous preterm birth. However, a modest reduction of preterm birth with aspirin cannot be ruled out. Further research is required to determine a possible beneficial effect of low-dose aspirin for women with a previous spontaneous preterm birth. Dutch Trial Register (NL5553, NTR5675) https://www.trialregister.nl/trial/5553.

Eligibility, Utilization, and Effectiveness of 17-Alpha Hydroxyprogesterone Caproate in a Statewide Population-Based Cohort of Medicaid Enrollees.

The primary objective was to estimate the initiation and adherence rates of 17 α-hydroxyprogesterone caproate (17OHPC) among eligible mothers in a statewide population-based cohort of Medicaid enrollees. The secondary objectives were to (1) determine the association of maternal sociodemographic and clinical characteristics with 17OHPC utilization and (2) assess the real-world effectiveness of 17OHPC on recurrent preterm birth prevention and admission to neonatal intensive care unit (NICU). This is a retrospective cohort study using a linked, longitudinal administrative dataset of birth certificates and medical assistance claims. Medicaid-enrolled mothers in Pennsylvania were included in this study if they had at least one singleton live birth from 2014 to 2016 following at least one spontaneous preterm birth. Maternal Medicaid claims were used to ascertain the use of 17OHPC from various manufacturers, including compounded formulations. Propensity score matching was used to create a covariate balance between 17OHPC treatment and comparison groups. We identified 4,781 Medicaid-covered 17OHPC-eligible pregnancies from 2014 to 2016 in Pennsylvania, 3.4% of all Medicaid-covered singleton live births. The population-based initiation rate was 28.5% among eligible pregnancies. Among initiators, 50% received ≥16 doses as recommended, while 10% received a single dose only. The severity of previous spontaneous preterm birth was the strongest predictor for the initiation and adherence of 17OHPC. In the matched treatment (n = 1,210) and comparison groups (n = 1,210), we found no evidence of 17OHPC effectiveness. The risks of recurrent preterm birth (relative risk [RR] 1.10, 95% confidence interval [CI] 0.97-1.24) and births admitted to NICU (RR 1.00, 95% CI 0.84-1.18) were similar in treated and comparison mothers. The 17OHPC-eligible population represented 3.4% of singleton live births. Less than one-third of eligible mothers initiated treatment. Among initiators, 50% were treatment adherent. We found no difference in the risk of recurrent preterm birth or admission to NICU between treatment and comparison groups. · About 3.4% of singleton live births were eligible for 17OHPC.. · About 30% of eligible mothers initiated treatment.. · We found no association of 17OHPC with recurrent preterm birth..

FIGO good practice recommendations on progestogens for prevention of preterm delivery.

Women at high risk of preterm birth (either a previous spontaneous preterm birth and/or sonographic short cervix) with a singleton gestation should be offered daily vaginal progesterone or weekly 17‐OHPC treatment to prevent preterm birth. Benefit is most significant in those with prior history of preterm birth and a short cervix. For women with a previous spontaneous preterm birth and a cervix ≥30 mm the effectiveness of progesterone is uncertain. In asymptomatic women with no prior history of previous preterm birth, no mid‐trimester loss, or no short cervical length, progesterone therapy is not recommended for the prevention of preterm birth. For those with unselected multiple pregnancies, progesterone therapy is not recommended for the prevention of preterm birth. Daily vaginal progesterone or weekly 17‐OHPC treatment can be used for the prevention of preterm birth. The preparation used should be decided by the woman and her clinician. There is no evidence of neurological or developmental benefit or harm in babies whose mothers use progestogens for preterm birth prevention antenatally.

Cerclage in singleton gestations with an extremely short cervix (≤10 mm) and no history of spontaneous preterm birth

Data regarding the efficacy of a cervical cerclage for preterm birth prevention in patients with a short cervix and no history of spontaneous preterm birth are limited and inconclusive. This study aimed to determine whether cervical cerclage is associated with an increased time interval to delivery in asymptomatic patients with singleton pregnancies with an extremely short cervical length (≤10 mm) and no history of spontaneous preterm birth. This was a multicenter retrospective cohort study of asymptomatic patients with singleton pregnancies with a cervical length of ≤10 mm between 16 and 23 weeks' gestation from January 2014 to December 2019. Patients with previous spontaneous preterm birth, symptoms of preterm labor, cervical dilation of >1 cm, pessary, major fetal structural malformations, or missing data were excluded from the study. The primary outcome of time interval from diagnosis to delivery was compared between those who had a cervical cerclage after diagnosis and those who did not. The secondary outcomes included gestational age at delivery and adverse neonatal outcomes. Moreover, a subgroup analysis of all outcomes in patients already being treated with vaginal progesterone in each group was performed. Statistical analysis included chi-square and Wilcoxon rank-sum tests and a multivariate Cox proportional hazard regression for time interval to delivery. Of the 90 patients included in the study, 52 (57.8%) had cervical cerclage, of which 35 (67.3%) were already being treated with progesterone. Moreover, 38 patients (42.2%) did not have cervical cerclage, of which 21 (55.3%) were already being treated with progesterone. Patients in the cervical cerclage group had an earlier gestational age (21.0 vs 22.0 weeks' gestation; P≤.001) and shorter cervical length (5 vs 7 mm; P=.002) at the diagnosis of a short cervix (cervical length≤10 mm) than those who did not have a cerclage. Cervical cerclage was associated with a longer time interval to delivery (17.0 vs 15.0 weeks; P=.02) and lower hazard of earlier delivery after diagnosis (adjusted hazard ratio, 0.61; 95% confidence interval, 0.38-0.99; P=.04) than no cerclage, after accounting for gestational age and cervical length at diagnosis. In patients already treated with progesterone, cervical cerclage was also associated with a longer time interval to delivery (17.0 vs 13.1 weeks; P=.01) and a lower hazard of earlier delivery after diagnosis (adjusted hazard ratio, 0.49; 95% confidence interval, 0.27-0.87; P=.02) compared to those with no cerclage. Late preterm birth was less common in patients with a cervical cerclage compared with those with no cervical cerclage (11.5% vs 31.6%; P=.03). Cervical cerclage should be considered in asymptomatic patients with an extremely short cervical length (≤10 mm) and no history of spontaneous preterm birth.

Analysis of maternal and neonatal outcomes using cervical cerclage or conservative treatment in singleton gestations with a sonographic short cervix.

To investigate the effect of cervical cerclage or conservative treatment on maternal and neonatal outcomes in singleton gestations with a sonographic short cervix, and further compare the relative treatment value.A retrospective study was conducted among women with singleton gestations who had a short cervical length (<25 mm) determined by ultrasound during the period of 14 to 24 weeks’ gestation in our institution. We collected clinical data and grouped the patients according to a previous spontaneous preterm birth (PTB) at <34 weeks of gestation or second trimester loss (STL) and sub-grouped according to treatment option, further comparing the maternal and neonatal outcomes between different groups.In the PTB or STL history cohort, the cerclage group had a later gestational age at delivery (35.3 ± 3.9 weeks vs 31.6 ± 6.7 weeks) and a lower rate of perinatal deaths (2% vs 29.3%) compared with the conservative treatment group. In the non-PTB-STL history cohort, the maternal and neonatal outcomes were not significantly different between the cerclage group and conservative treatment group. More importantly, for patients with a sonographic short cervix who received cervical cerclage, there was no significant difference in the maternal and neonatal outcomes between the non-PTB-STL group and PTB or STL group.For singleton pregnant with a history of spontaneous PTB or STL and a short cervical length (<25 mm), cervical cerclage can significantly improve maternal and neonatal outcomes; however, conservative treatment (less invasive and expensive than cervical cerclage) was more suitable for those pregnant women without a previous PTB and STL history.

Optimal antenatal corticosteroid exposure in women with history of preterm birth and asymptomatic short cervical length

A proposed benefit of cervical length assessment after 24 weeks' gestation in women with a history of preterm birth is to aid in the timing of antenatal corticosteroids in otherwise asymptomatic women. We sought to investigate whether the use of an ultrasonographic short cervical length as an indication for antenatal corticosteroids in asymptomatic women results in optimal exposure compared with women receiving antenatal corticosteroids for preterm labor symptoms. Retrospective cohort study of all women with a previous spontaneous preterm birth and a singleton gestation who underwent serial cervical length assessment at a large academic tertiary medical center from 2011 to 2016. Patients were included in the analysis if they received antenatal corticosteroids for either an asymptomatic short cervical length or symptoms of preterm labor. The primary outcome was optimal antenatal corticosteroids exposure (latency to delivery of ≤7 days). Poisson regression with robust error variance was used to calculate incidence rate ratios (IRR) and confidence intervals (CI) for primary and secondary outcomes adjusting for primary and secondary outcomes adjusting for race, earliest previous preterm birth, and current cerclage. There were 287 women meeting inclusion criteria, among whom 166 (57.8%) received antenatal corticosteroids for a short cervical length and 121 (42.2%) for preterm labor symptoms. Women who received antenatal corticosteroids for a short cervical length were less likely to have optimal exposure (1.2% vs 19.0%; incidence rate ratios, 0.06; confidence interval, 0.02-0.27) compared with women with preterm labor symptoms. They were also more likely to have exposure with eventual term delivery (43.2% vs 33.4%; incidence rate ratios, 1.6; confidence interval, 1.2-2.0). Importantly, women who received antenatal corticosteroids for a short cervical length were significantly less likely to receive either an initial or rescue antenatal corticosteroids course within 7 days of a preterm delivery of less than 34 weeks' gestation (42.9% vs 76.9%; incidence rate ratios, 0.52; confidence interval, 0.35-0.75). Women with a previous preterm birth who receive antenatal corticosteroids for an asymptomatic short cervical length are less likely to have optimal exposure than women with symptoms of preterm labor. These data challenge the practice of cervical length surveillance for the sole indication of timing antenatal corticosteroids administration.

Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials

Preterm birth is a global health priority. Using a progestogen during high-risk pregnancy could reduce preterm birth and adverse neonatal outcomes.We did a systematic review of randomised trials comparing vaginal progesterone, intramuscular 17-hydroxyprogesterone caproate (17-OHPC), or oral progesterone with control, or with each other, in asymptomatic women at risk of preterm birth. We identified published and unpublished trials that completed primary data collection before July 30, 2016, (12 months before data collection began), by searching MEDLINE, Embase, CINAHL, the Maternity and Infant Care Database, and relevant trial registers between inception and July 30, 2019. Trials of progestogen to prevent early miscarriage or immediately-threatened preterm birth were excluded. Individual participant data were requested from investigators of eligible trials. Outcomes included preterm birth, early preterm birth, and mid-trimester birth. Adverse neonatal sequelae associated with early births were assessed using a composite of serious neonatal complications, and individually. Adverse maternal outcomes were investigated as a composite and individually. Individual participant data were checked and risk of bias assessed independently by two researchers. Primary meta-analyses used one-stage generalised linear mixed models that incorporated random effects to allow for heterogeneity across trials. This meta-analysis is registered with PROSPERO, CRD42017068299.Initial searches identified 47 eligible trials. Individual participant data were available for 30 of these trials. An additional trial was later included in a targeted update. Data were therefore available from a total of 31 trials (11 644 women and 16185 offspring). Trials in singleton pregnancies included mostly women with previous spontaneous preterm birth or short cervix. Preterm birth before 34 weeks was reduced in such women who received vaginal progesterone (nine trials, 3769 women; relative risk [RR] 0·78, 95% CI 0·68-0·90), 17-OHPC (five trials, 3053 women; 0·83, 0·68-1·01), and oral progesterone (two trials, 181 women; 0·60, 0·40-0·90). Results for other birth and neonatal outcomes were consistently favourable, but less certain. A possible increase in maternal complications was suggested, but this was uncertain. We identified no consistent evidence of treatment interaction with any participant characteristics examined, although analyses within subpopulations questioned efficacy in women who did not have a short cervix. Trials in multifetal pregnancies mostly included women without additional risk factors. For twins, vaginal progesterone did not reduce preterm birth before 34 weeks (eight trials, 2046 women: RR 1·01, 95% CI 0·84-1·20) nor did 17-OHPC for twins or triplets (eight trials, 2253 women: 1·04, 0·92-1·18). Preterm premature rupture of membranes was increased with 17-OHPC exposure in multifetal gestations (rupture <34 weeks RR 1·59, 95% CI 1·15-2·22), but we found no consistent evidence of benefit or harm for other outcomes with either vaginal progesterone or 17-OHPC.Vaginal progesterone and 17-OHPC both reduced birth before 34 weeks' gestation in high-risk singleton pregnancies. Given increased underlying risk, absolute risk reduction is greater for women with a short cervix, hence treatment might be most useful for these women. Evidence for oral progesterone is insufficient to support its use. Shared decision making with woman with high-risk singleton pregnancies should discuss an individual's risk, potential benefits, harms and practicalities of intervention. Treatment of unselected multifetal pregnancies with a progestogen is not supported by the evidence.Patient-Centered Outcomes Research Institute.

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

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. 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. 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). 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). 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.

9 Low dose aspirin for the prevention of recurrent preterm labor (APRIL): a randomized controlled trial

To evaluate the effectiveness of aspirin compared to placebo for the prevention of preterm birth (PTB) when initiated in early pregnancy in women with a previous spontaneous preterm birth (SPTB). We performed a multicenter, double-blind, randomized controlled trial (APRIL, NTR 5675). We recruited women with a singleton pregnancy and a history of SPTB (singleton pregnancy 22+0 - 37+0 weeks) following either preterm prelabor rupture of membranes or spontaneous contractions. After informed consent, participants were randomly assigned to daily aspirin (80 mg) or placebo started between 8+0 and 16+0 weeks gestation. Treatment was continued until 36+0 weeks gestation or delivery. Primary outcome was PTB before 37+0 weeks gestation. Secondary outcomes included a composite of poor neonatal outcome (bronchopulmonary dysplasia, periventricular leukomalacia >grade 1, intraventricular hemorrhage >grade 2, necrotizing enterocolitis >stage 1, retinopathy of prematurity, culture proven sepsis or perinatal death). A sample of 384 women was required to detect a PTB reduction from 36 to 23% (α-error 0.05, β-error 0.2). Analyses were performed by intention to treat. Between May 2016 and June 2019, we randomly allocated 194 women to aspirin and 193 to placebo. The PTB rate was 21.2% in the aspirin group versus 25.4% in the placebo group (RR 0.83; 95% CI 0.58-1.2). SPTB occurred in 20.1% versus 23.8% of women (RR 0.84; 95% CI 0.58-1.2). For women who were ≥80% compliant with study medication, PTB rates were 18.5% versus 24.8% (RR 0.75; 95% CI 0.46-1.2). The poor neonatal outcome rate was 4.6% versus 2.6% (RR 1.79; 95% CI 0.61 to 5.3). There were no significant differences in maternal morbidities such as hypertensive disorders and postpartum hemorrhage. Our data did not demonstrate a reduction of PTB in women with a previous SPTB who used aspirin 80 mg. The RR for PTB is comparable to larger studies on aspirin in other groups of women. A small reduction of PTB from aspirin in women with a previous SPTB cannot be excluded with the current sample size.

Pregnancy duration with use of 17-α-hydroxyprogesterone caproate in a retrospective cohort at high risk of recurrent preterm birth

The use of 17-α-hydroxyprogesterone caproate for the prevention of recurrent spontaneous preterm birth has become widespread, yet there are conflicting data regarding its efficacy. We sought to determine whether administration of 17-α-hydroxyprogesterone caproate was associated with pregnancy prolongation in women at a high risk of recurrent spontaneous preterm birth. This is a retrospective cohort study of women with singleton pregnancies and a history of spontaneous preterm birth at <37 weeks' gestation who received care at our academic tertiary care center between 2009 and 2019. We included women with gestations that progressed beyond 16 weeks. We excluded those who underwent history-indicated cerclage placement. We first examined the characteristics of women who received 17-α-hydroxyprogesterone caproate and those who did not. Covariates with a P value of ≤.2 on this univariate analysis were considered for incorporation into a Cox proportional hazards model to assess the association between 17-α-hydroxyprogesterone caproate use and pregnancy prolongation up to 35 weeks. Of 861 women included in the study, 570 (66.2%) reported non-Hispanic black racial identity, 237 (27.5%) lived in zip codes with a high infant mortality rate (≥12.1/1000 infants), 287 (33.3%) had more than 1 previous spontaneous preterm birth, 372 (43.2%) had previous spontaneous preterm birth at ≤32 weeks' gestation, and 242 (28.1%) were smokers. Here, 152 pregnancies (17.6%) were complicated by spontaneous preterm birth at <35 weeks' gestation. Factors independently associated with pregnancy duration up to 35 weeks included weight gain of <0.2 kg (0.5 lb) per week, first recorded weight of <98 kg (215 lb), obstetrical history, non-Hispanic white racial identity, lack of prenatal care, and vaginal bleeding. Gestational age at delivery was also independently associated with interventions typically employed for midtrimester cervical shortening and/or dilation, including ultrasound- and examination-indicated cerclage, pessary placement, and vaginal progesterone administration. The use of 17-α-hydroxyprogesterone caproate was not associated with pregnancy prolongation (adjusted hazard ratio, 0.83; 95% confidence interval, 0.60-1.15). The risk profile of our cohort is similar to that of women enrolled in the landmark trial that led to the Food and Drug Administration's approval of 17-α-hydroxyprogesterone caproate. Despite the high-risk nature of the pregnancies examined, we found no association between use of the medication in daily clinical practice and pregnancy prolongation up to 35 weeks. This finding adds to the mounting evidence that calls into question the drug's efficacy in reducing the risk of recurrent spontaneous preterm birth.

Cervical length change as a predictor of preterm birth in symptomatic patients

Distinguishing between true and false preterm labor remains a challenge. The shortening in cervical length throughout a gestation has been theorized to be a possible predictor of spontaneous preterm birth. Although there are some studies evaluating cervical length shortening as a predictor of spontaneous preterm birth, it is not known whether the shortening in cervical length from an asymptomatic to symptomatic state, when a patient presents with preterm labor symptoms, is predictive of spontaneous preterm birth. This study aimed to determine the utility of cervical length shortening from an asymptomatic time point (anatomic ultrasound) to when a patient presents with preterm labor symptoms as a predictor of spontaneous preterm birth. A prospective cohort study was performed to evaluate the use of transvaginal cervical length assessment in symptomatic women in predicting spontaneous preterm birth from January 2013 to March 2015. Women with singleton gestations who presented to our institution between 22 0/7 weeks and 33 6/7 weeks of gestation with preterm labor symptoms were included in the overall cohort. This was a planned secondary analysis to evaluate the shortening in cervical length from an asymptomatic state (anatomic ultrasound) to a symptomatic state as a predictor of preterm birth. For this analysis, inclusion criteria were known delivery status, cervical length screening performed at anatomic ultrasound, and a valid cervical length measurement at the time of preterm labor symptoms. Women with preterm rupture of membranes, cervical dilation of >2 cm, or moderate to severe bleeding were excluded. Cervical length shortening was defined as a decrease in cervical length of >10 mm from anatomic ultrasound to the time of presentation with preterm labor symptoms. The outcome evaluated was spontaneous preterm birth before 37 weeks of gestation. Chi-square test and receiver operating characteristic curves were used to evaluate the data. Multivariable logistic regression was used to calculate the odds. Test characteristics of cervical length shortening of >10 mm were determined. A total of 549 women were included in the original cohort, and 277 women were included in this secondary analysis. The overall rate of spontaneous preterm birth was 8.3%. There were 52 women (19%) with cervical length shortening of >10 mm. The rate of spontaneous preterm birth was significantly higher for those with cervical length shortening of >10 mm than those with cervical length shortening of ≤10 mm (21.2% vs 5.3%; P=.001). This higher risk of spontaneous preterm birth remained after adjusting for confounders including maternal age and previous spontaneous preterm birth (adjusted odds ratio, 4.71; 95% confidence interval, 1.84-12.09). Using cervical length shortening of >10 mm as a screening test had a sensitivity of 47.8%, a specificity of 83.9%, a positive predictive value of 21.2%, and a negative predictive value of 94.7%. In women presenting with preterm labor symptoms, a cervical length that is >10 mm shorter from anatomic ultrasound is associated with an increased risk of spontaneous preterm birth.