Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus.

BACKGROUND: Magnesium sulphate is a common therapy in perinatal care. Its benefits when given to women at risk of preterm birth for fetal neuroprotection (prevention of cerebral palsy for children) were shown in a 2009 Cochrane review. Internationally, use of magnesium sulphate for preterm cerebral palsy prevention is now recommended practice. As new randomised controlled trials (RCTs) and longer-term follow-up of prior RCTs have since been conducted, this review updates the previously published version. OBJECTIVES: To assess the effectiveness and safety of magnesium sulphate as a fetal neuroprotective agent when given to women considered to be at risk of preterm birth. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 17 March 2023, as well as reference lists of retrieved studies. SELECTION CRITERIA: We included RCTs and cluster-RCTs of women at risk of preterm birth that assessed prenatal magnesium sulphate for fetal neuroprotection compared with placebo or no treatment. All methods of administration (intravenous, intramuscular, and oral) were eligible. We did not include studies where magnesium sulphate was used with the primary aim of preterm labour tocolysis, or the prevention and/or treatment of eclampsia. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed RCTs for inclusion, extracted data, and assessed risk of bias and trustworthiness. Dichotomous data were presented as summary risk ratios (RR) with 95% confidence intervals (CI), and continuous data were presented as mean differences with 95% CI. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included six RCTs (5917 women and their 6759 fetuses alive at randomisation). All RCTs were conducted in high-income countries. The RCTs compared magnesium sulphate with placebo in women at risk of preterm birth at less than 34 weeks' gestation; however, treatment regimens and inclusion/exclusion criteria varied. Though the RCTs were at an overall low risk of bias, the certainty of evidence ranged from high to very low, due to concerns regarding study limitations, imprecision, and inconsistency. Primary outcomes for infants/children: Up to two years' corrected age, magnesium sulphate compared with placebo reduced cerebral palsy (RR 0.71, 95% CI 0.57 to 0.89; 6 RCTs, 6107 children; number needed to treat for additional beneficial outcome (NNTB) 60, 95% CI 41 to 158) and death or cerebral palsy (RR 0.87, 95% CI 0.77 to 0.98; 6 RCTs, 6481 children; NNTB 56, 95% CI 32 to 363) (both high-certainty evidence). Magnesium sulphate probably resulted in little to no difference in death (fetal, neonatal, or later) (RR 0.96, 95% CI 0.82 to 1.13; 6 RCTs, 6759 children); major neurodevelopmental disability (RR 1.09, 95% CI 0.83 to 1.44; 1 RCT, 987 children); or death or major neurodevelopmental disability (RR 0.95, 95% CI 0.85 to 1.07; 3 RCTs, 4279 children) (all moderate-certainty evidence). At early school age, magnesium sulphate may have resulted in little to no difference in death (fetal, neonatal, or later) (RR 0.82, 95% CI 0.66 to 1.02; 2 RCTs, 1758 children); cerebral palsy (RR 0.99, 95% CI 0.69 to 1.41; 2 RCTs, 1038 children); death or cerebral palsy (RR 0.90, 95% CI 0.67 to 1.20; 1 RCT, 503 children); and death or major neurodevelopmental disability (RR 0.81, 95% CI 0.59 to 1.12; 1 RCT, 503 children) (all low-certainty evidence). Magnesium sulphate may also have resulted in little to no difference in major neurodevelopmental disability, but the evidence is very uncertain (average RR 0.92, 95% CI 0.53 to 1.62; 2 RCTs, 940 children; very low-certainty evidence). Secondary outcomes for infants/children: Magnesium sulphate probably reduced severe intraventricular haemorrhage (grade 3 or 4) (RR 0.76, 95% CI 0.60 to 0.98; 5 RCTs, 5885 infants; NNTB 92, 95% CI 55 to 1102; moderate-certainty evidence) and may have resulted in little to no difference in chronic lung disease/bronchopulmonary dysplasia (average RR 0.92, 95% CI 0.77 to 1.10; 5 RCTs, 6689 infants; low-certainty evidence). Primary outcomes for women: Magnesium sulphate may have resulted in little or no difference in severe maternal outcomes potentially related to treatment (death, cardiac arrest, respiratory arrest) (RR 0.32, 95% CI 0.01 to 7.92; 4 RCTs, 5300 women; low-certainty evidence). However, magnesium sulphate probably increased maternal adverse effects severe enough to stop treatment (average RR 3.21, 95% CI 1.88 to 5.48; 3 RCTs, 4736 women; moderate-certainty evidence). Secondary outcomes for women: Magnesium sulphate probably resulted in little to no difference in caesarean section (RR 0.96, 95% CI 0.91 to 1.02; 5 RCTs, 5861 women) and postpartum haemorrhage (RR 0.94, 95% CI 0.80 to 1.09; 2 RCTs, 2495 women) (both moderate-certainty evidence). Breastfeeding at hospital discharge and women's views of treatment were not reported. AUTHORS' CONCLUSIONS: The currently available evidence indicates that magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus, compared with placebo, reduces cerebral palsy, and death or cerebral palsy, in children up to two years' corrected age, and probably reduces severe intraventricular haemorrhage for infants. Magnesium sulphate may result in little to no difference in outcomes in children at school age. While magnesium sulphate may result in little to no difference in severe maternal outcomes (death, cardiac arrest, respiratory arrest), it probably increases maternal adverse effects severe enough to stop treatment. Further research is needed on the longer-term benefits and harms for children, into adolescence and adulthood. Additional studies to determine variation in effects by characteristics of women treated and magnesium sulphate regimens used, along with the generalisability of findings to low- and middle-income countries, should be considered.

Cervical elastography in predicting spontaneous preterm birth in singleton pregnancy with a short cervix receiving progesterone treatment at 18 to 24 weeks' gestation.

BACKGROUND: A short cervix in the second trimester is known to increase the risk of preterm birth, which can be reduced with the administration of vaginal progesterone. However, some studies have suggested that a significant number of cases still experience preterm birth despite progesterone treatment. OBJECTIVE: This study was aimed to investigate the potential value of transvaginal cervical elasticity measured by E-Cervix as a predictor for spontaneous preterm birth (sPTB) in singleton pregnancies receiving progesterone treatment for a short cervix (CL ≤ 2.5 cm) diagnosed at 18 to 24 weeks' gestation. STUDY DESIGN: This prospective study was conducted at a single center premature high-risk clinic from January 2020 to July 2022. Singleton pregnancies with a short cervix at 18 to 24 weeks' gestation were enrolled. Cervical elastography using E-Cervix was performed, and maternal and neonatal demographic characteristics, cervical length (CL), elasticity contrast index (ECI), cervical hardness ratio, mean internal os strain (IOS), and mean external os strain (EOS) were compared before and after progesterone treatment in sPTB and term birth groups. Multivariate logistic regression was used to analyze the association between elasticity parameters and spontaneous preterm birth. The screening performance of CL and optimal cervical elasticity parameters in predicting sPTB was evaluated using receiver-operating characteristic (ROC) curve analysis. RESULTS: A total of 228 singleton pregnant women were included in the study, among which 26 (11.4%) had sPTB. There were no significant differences in maternal characteristics and gestational age at enrollment between women with and without sPTB. At the start of progesterone treatment, there were no significant differences in cervical elasticity parameters between the two groups. After two weeks of progesterone treatment, women who had sPTB showed significantly higher levels of ECI, IOS, EOS (p = 0.0108, 0.0001, 0.016), and lower hardness ratio (p = 0.011) compared to those who had a full-term birth. Cervical length did not show significant differences between the two groups, regardless of whether progesterone treatment was administered before or after. Among the post-treatment cervical elasticity parameters, IOS and EOS were associated with a 3.38-fold and 2.29-fold increase in the risk of sPTB before 37 weeks (p = 0.032, 0.047, respectively). The AUROC of the combined model including CL, IOS, and EOS (0.761, 95% CI0.589-0.833) was significantly higher than the AUROC of CL alone (0.618, 95% CI 0.359-0.876). At a fixed false-positive of 13%, the addition of IOS and EOS in the CL model increased sensitivity from 34.6% to 57.6%, PPV from 25.7% to 36.5%, and NPV from 91.1% to 94.1%. CONCLUSION: When assessing the risk of sPTB in singleton pregnancies with a short cervix receiving progesterone therapy, relying solely on cervical length is insufficient. It is crucial to also evaluate cervical stiffness, particularly the strain of the internal and external os, using cervical elastography.

Progesterone therapy for prevention of recurrent spontaneous preterm birth in a minority patient population: a retrospective study.

BACKGROUND: Preterm birth is a leading cause of infant morbidity and mortality worldwide. The burden of prematurity underscores the need for effective risk reduction strategies. The purpose of this study is to evaluate the efficacy of progesterone therapy, both intramuscular 17-α-hydroxyprogesterone caproate (IM 17-OHPC) and vaginal progesterone, in the prevention of recurrent spontaneous preterm birth (sPTB). The co-primary outcomes included: recurrent spontaneous PTB < 37 and < 34 weeks' gestation. METHODS: This retrospective cohort study included 637 pregnant patients that delivered at any of the three hospitals within the Los Angeles County healthcare system between October 2015 and June 2021. We compared frequencies of measured variables between each of the progesterone treated groups to no treatment using Pearson chi-squared tests and independent t-tests for categorical and continuous variables, respectively. We estimated crude and adjusted associations between each specific treatment (versus no treatment) and primary outcomes using logistic regression. RESULTS: Recurrent sPTB < 37 weeks' gestation occurred in 22.3% (n = 64) of those in the no treatment group, 29.1% (n = 86, p = .077) in the 17-OHPC group, and 14.3% (n = 6, p = 0.325) in the vaginal progesterone group. Recurrent sPTB < 34 weeks' gestation was 6.6% (n = 19) in the no treatment group, 11.8% (n = 35, p = .043) in the 17-OHPC group, and 7.1% (n = 3, p = 1) in the vaginal progesterone group. Among all participants, neither 17-OHPC nor vaginal progesterone was significantly associated with a reduction in recurrent sPTB at any time point. Among those with a short cervix, IM 17-OHPC was positively associated with recurrent sPTB < 37 weeks' gestation (aOR 5.61; 95% CI 1.16, 42.9). CONCLUSIONS: Progesterone therapy of any type did not reduce the risk of recurrent sPTB < 34 or < 37 weeks' gestation compared to no progesterone therapy.

Analysis of cases of premature rupture of membranes and preterm births to identify effective management measures to prevent them.

OBJECTIVE: Aim: Based on retrospective analysis recognize the key factors of development of premature childbirth and elaborate highly specific criteria for individual prognosis to improve perinatal outcomes. PATIENTS AND METHODS: Materials and Methods: A retrospective analysis of the birth histories of 250 women and their newborns with spontaneous preterm births at 22-36 weeks was conducted using archival data from the department for pregnant women with obstetric pathology of the State Institution "Institute of Pediatrics, Obstetrics and Gynecology named by academician OM Lukianova of the National Academy of Medical Sciences of Ukraine". RESULTS: Results: Important risk factors for premature rupture of membranes (PROM) in preterm pregnancy include the presence of sexually transmitted diseases (χ2=31.188, p=0.001), bacterial vaginosis (χ2=30.913, p=0.0001), a history of abortion and/or preterm birth (χ2=16.62, p=0.0002), SARS during pregnancy (χ2=16.444, p=0.0002), chronic adnexitis in anamnesis (χ2=11.522, p=0.0031), inflammatory cervical disease (χ2=11.437, p=0.0032), anaemia (χ2=10.815, p=0.0044), isthmic-cervical insufficiency (ІСІ) (χ2=10.345, p=0.0057), chronic pyelonephritis with exacerbation (χ2=9.16, p=0.01), smoking during pregnancy (χ2=10.815, p=0.0044). CONCLUSION: Conclusions: The results of a retrospective analysis of 250 cases of preterm birth at 22 to 36 weeks allowed us to identify ways to effectively use existing diagnostic measures to determine readiness for pregnancy and the possibility of prolonging pregnancy to the viability of the newborn. Ways to improve the prevention of preterm birth and the design of further research were identified.

Vaginal Progesterone to Prevent Spontaneous Preterm Birth in Women With a Sonographic Short Cervix: The Story of the PREGNANT Trial.

The PREGNANT trial was a randomized, placebo-controlled, multicenter trial designed to determine the efficacy and safety of vaginal progesterone (VP) to reduce the risk of birth < 33 weeks and of neonatal complications in women with a sonographic short cervix (10 to 20 mm) in the mid-trimester (19 to 23 6/7 wk). Patients allocated to receive VP had a 45% lower rate of preterm birth (8.9% vs 16.1%; relative risk = 0.55; 95% CI: 0.33-0.92). Neonates born to mothers allocated to VP had a 60% reduction in the rate of respiratory distress syndrome. This article reviews the background, design, execution, interpretation, and impact of the PREGNANT Trial.

Cervical pessary versus vaginal progesterone in women with a singleton pregnancy, a short cervix, and no history of spontaneous preterm birth at less than 34 weeks' gestation: open label, multicentre, randomised, controlled trial.

OBJECTIVE: To compare the effectiveness of cervical pessary and vaginal progesterone in the prevention of adverse perinatal outcomes and preterm birth in pregnant women of singletons with no prior spontaneous preterm birth at less than 34 weeks' gestation and who have a short cervix of 35 mm or less. DESIGN: Open label, multicentre, randomised, controlled trial. SETTING: 20 hospitals and five obstetric ultrasound practices in the Netherlands. PARTICIPANTS: Women with a healthy singleton pregnancy and an asymptomatic short cervix of 35 mm or less between 18 and 22 weeks' gestation were eligible. Exclusion criteria were prior spontaneous preterm birth at less than 34 weeks, a cerclage in situ, maternal age of younger than 18 years, major congenital abnormalities, prior participation in this trial, vaginal blood loss, contractions, cervical length of less than 2 mm or cervical dilatation of 3 cm or more. Sample size was set at 628 participants. INTERVENTIONS: 1:1 randomisation to an Arabin cervical pessary or vaginal progesterone 200 mg daily up to 36 weeks' of gestation or earlier in case of ruptured membranes, signs of infection, or preterm labour besides routine obstetric care. MAIN OUTCOME MEASURES: Primary outcome was a composite adverse perinatal outcome. Secondary outcomes were rates of (spontaneous) preterm birth at less than 28, 32, 34, and 37 weeks. A predefined subgroup analysis was planned for cervical length of 25 mm or less. RESULTS: From 1 July 2014 to 31 March 2022, 635 participants were randomly assigned to pessary (n=315) or to progesterone (n=320). 612 were included in the intention to treat analysis. The composite adverse perinatal outcome occurred in 19 (6%) of 303 participants with a pessary versus 17 (6%) of 309 in the progesterone group (crude relative risk 1.1 (95% confidence interval (CI) 0.60 to 2.2)). The rates of spontaneous preterm birth were not significantly different between groups. In the subgroup of cervical length of 25 mm or less, spontaneous preterm birth at less than 28 weeks occurred more often after pessary than after progesterone (10/62 (16%) v 3/69 (4%), relative risk 3.7 (95% CI 1.1 to 12.9)) and adverse perinatal outcomes seemed more frequent in the pessary group (15/62 (24%) v 8/69 (12%), relative risk 2.1 (0.95 to 4.6)). CONCLUSIONS: In women with a singleton pregnancy with no prior spontaneous preterm birth at less than 34 weeks' gestation and with a midtrimester short cervix of 35 mm or less, pessary is not better than vaginal progesterone. In the subgroup of a cervical length of 25 mm or less, a pessary seemed less effective in preventing adverse outcomes. Overall, for women with single baby pregnancies, a short cervix, and no prior spontaneous preterm birth less than 34 weeks' gestation, superiority of a cervical pessary compared with vaginal progesterone to prevent preterm birth and consecutive adverse outcomes could not be proven. TRIAL REGISTRATION: International Clinical Trial Registry Platform (ICTRP, EUCTR2013-002884-24-NL).

Can we improve the outcome of pregnancies with low serum PAPP-A in the first trimester?

OBJECTIVE: This study aimed to assess the impact of micronized progesterone (VMP4) supplementation on pregnancies with low serum pregnancy-associated plasma protein-A (PAPP-A) multiples of the median (MoM) values during first-trimester screening. METHODS: Out of 8933 patients evaluated, 116 pregnant women with low PAPP-A concentrations in their blood and no fetal chromosomal anomalies (CAs) were included. Three groups were formed: group 1 received VMP4 from 11 to 16 weeks (29 women, 25%), group 2 received VMP4 from 11 to 36 weeks (25 women, 21.5%), and group 3 (62 women, 53.5%) served as controls without receiving progesterone. RESULTS: Results indicated that group 3 had higher rates of complications, including miscarriages (16.37%), preterm delivery (17.8%), and fetal developmental abnormalities (19.4%). Birthweight variations were elevated in pregnancies without progesterone, contrasting with lower variations in VMP4 groups. Group 2, receiving VMP4 until 36 weeks, reported the lowest incidence of abortion and preterm birth (PB), along with the highest mean birth weight. CONCLUSIONS: The conclusion suggests that 200 mg per day of VMP4 up to 36 weeks of supplementation led to fewer placental-related complications in women with very low PAPP-A at first-trimester screening (0.399 MoM). By reporting lower rates of miscarriages, PBs, and fetal developmental abnormalities in the micronized progesterone-treated groups, the study suggests a potential reduction in complications.

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

OBJECTIVES: To 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. METHODS: Single 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. RESULTS: Following 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). CONCLUSIONS: Over 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.

Length of hysterotomy for fetal spina bifida repair is associated with prematurity risk.

OBJECTIVE: To investigate whether prenatal repair of spina bifida aperta through mini-hysterotomy results in less prematurity, as compared to standard hysterotomy, when adjusting for known prematurity risks. METHODS: We performed a bi-centric, propensity score matched, controlled study, that is, adjusting for factors earlier reported to result in premature delivery or membrane rupture, in consecutive women having prenatal repair either through stapled hysterotomy or sutured mini-hysterotomy (≤3.5 cm). Matches were pairwise compared and cox-regression analysis was performed to define the hazard ratio of delivery <37 weeks. RESULTS: Of 346 meeting the MOMS-criteria, 78 comparable pairs were available for matched-controlled analysis. Mini-hysterotomy patients were younger and had a higher BMI. Mini-hysterotomy was associated with a 1.67-lower risk of delivery <37 weeks (hazard ratio: 0.60; 95% CI: 0.42-0.85; p = 0.004) and 1.72 for delivery <34 + 6 weeks (hazard ratio: 0.58; 95% CI: 0.34-0.97; p = 0.037). The rate of intact uterine scar at birth (mini-hysterotomy: 98.7% vs. hysterotomy: 90.4%; p = 0.070), the rate of reversal of hindbrain herniation within 1 week after surgery (88.9% vs. 97.4%; p = 0.180) and the rate of cerebrospinal fluid leakage (0% vs. 2.7%; p = 0.50) were comparable. CONCLUSION: Prenatal spina bidifa repair through mini-hysterotomy was associated with a later gestational age at delivery and a comparable intact uterus rate without apparent compromise in neuroprotection.

Nationwide status of progestogen treatment to prevent spontaneous preterm birth: A questionnaire survey for childbirth healthcare facilities in Japan.

AIM: This study aimed to investigate the current status of progestogen treatment for pregnant women at a high risk for preterm birth (PTB) in childbirth healthcare facilities in Japan. METHODS: A web-based nationwide questionnaire survey regarding progestogen use for prevention of PTB was conducted among childbirth healthcare facilities from 2019 to 2021. RESULTS: Valid responses were obtained from 528 facilities (25.2% of those surveyed), including 155 tertiary perinatal facilities (making up 92.3% of all tertiary perinatal care facilities). In the survey period, progestogen treatment was implemented in 207 facilities (39.2%) for PTB prevention. Regarding types of progestogens, 17α-hydroxyprogesterone caproate was used in 170 facilities (82.1%), with a low dose (125 mg/week) administered in 62.9% of the facilities to comply with the regulations of the national health insurance system, although 250 mg/week is considered the best dose. Vaginal progesterone was used in 36 facilities (17.4%), although the cost of vaginal progesterone was not covered by health insurance. Of the facilities not administering progestogen treatment, approximately 40% expressed that vaginal progesterone would be their first choice for PTB prevention in daily practice if it would be covered by health insurance in the future. CONCLUSIONS: Due to the current regulations of the Japanese health insurance system, 17α-hydroxyprogesterone caproate, rather than vaginal progesterone, was mainly used for PTB prevention. Despite global evidence supporting vaginal progesterone as the approach with the highest efficacy, only a limited number of facilities have utilized it due to the current drug use regulations in Japan.

Cost-effectiveness of universal routine sonographic cervical-length measurement at 19 to 25 weeks' gestation.

BACKGROUND: National second-trimester scanning of cervical length was introduced in Israel in 2010, and in the decade thereafter, a significant systematic reduction in preterm birth and in the delivery of low birthweight babies was found among singletons. OBJECTIVE: In this study, we sought to estimate the cost-effectiveness of a national policy mandating second-trimester cervical length screening by ultrasound, followed by vaginal progesterone treatment for short cervical length in comparison with no screening strategy. STUDY DESIGN: We constructed a decision model comparing 2 strategies, namely (1) universal cervical length screening, and (2) no screening strategy. This study used the national delivery registry of Israel's Ministry of Health. All women diagnosed with a second-trimester cervical length <25 mm were treated with vaginal progesterone and were monitored with a bimonthly ultrasound scan for cervical dynamics and threat of early delivery. Preterm birth prevalence associated with short cervical length, the efficacy of progesterone in preterm birth prevention, and the accuracy of cervical length measurements were derived from previous studies. The cost of progesterone and bimonthly sonographic surveillance, low birthweight delivery, newborn admission to intensive care units, the first-year costs of managing preterm birth and low birthweight, and instances of handicaps and the cost of their follow-up were extracted from the publicly posted registry of Israel's Ministry of Health and Israel Social Securities data. Monte Carlo simulations decision tree mode, Tornado diagrams, and 1- and 2-way sensitivity analyses were implemented and the base case and sensitivity to parameters that were predicted to influence cost-effectiveness were calculated. RESULTS: Without cervical length screening, the discounted quality-adjusted life years were 30.179, and with universal cervical length screening, it increased to 30.198 (difference of 0.018 quality-adjusted life years). The average cost of no screening for cervical length strategy was $1047, and for universal cervical length screening, it was reduced to $998. The calculated incremental cost-effectiveness ratio was -$2676 per quality-adjusted life year (dividing the difference in costs by the difference in quality-adjusted life years). Monte Carlo simulation of cervical length screening of 170,000 singleton newborns (rounded large number close to the number of singleton newborns in Israel) showed that 95.17% of all babies were delivered at gestational week ≥37 in comparison with 94.46% of babies with the no screening strategy. Given 170,000 singleton births, the national savings of screening for short cervical length when compared with no cervical length screening amounted to $8.31M annually, equating to $48.84 for a base case, and the incremental cost-effectiveness ratio for each case of low birthweight or very low birthweight avoided was -$14,718. A cervical length <25 mm was measured for 30,090 women, and of those, 24,650 were false positives. The major parameters that affected the incremental cost-effectiveness ratio were the incidence of preterm birth, the specificity of cervical length measurements, and the efficacy of progesterone treatment. At a preterm birth incidence of <3%, universal screening does not lead to a cost saving. CONCLUSION: National universal cervical length screening should be incorporated into the routine anomaly scan in the second trimester, because it leads to a drop in the incidence of preterm birth and low birthweight babies in singleton pregnancies, thereby saving costs related to the newborn and gaining quality-adjusted life years.

Vaginal micronised progesterone for the prevention of hypertensive disorders of pregnancy: A systematic review and meta-analysis.

BACKGROUND: Treatment with vaginal progesterone reduces the risk of miscarriage and preterm birth in selected high-risk women. The hypothesis that vaginal progesterone can reduce the risk of hypertensive disorders of pregnancy (HDP) is unexplored. OBJECTIVES: To summarise the evidence on the effectiveness of vaginal progesterone to reduce the risk of HDP. SEARCH STRATEGY: We searched Embase (OVID), MEDLINE (OVID), PubMed, CENTRAL and clinicaltrials.gov from inception until 20 June 2023. SELECTION CRITERIA: We included placebo-controlled randomised trials (RCTs) of vaginal progesterone for the prevention or treatment of any pregnancy complications. DATA COLLECTION AND ANALYSIS: We extracted absolute event numbers for HDP and pre-eclampsia in women receiving vaginal progesterone or placebo, and meta-analysed the data with a random effects model. We appraised the certainty of the evidence using GRADE methodology. MAIN RESULTS: The quantitative synthesis included 11 RCTs, of which three initiated vaginal progesterone in the first trimester, and eight in the second or third trimesters. Vaginal progesterone started in the first trimester of pregnancy lowered the risk of any HDP (risk ratio [RR] 0.71, 95% confidence interval [CI] 0.53-0.93, 2 RCTs, n = 4431 women, I2 = 0%; moderate-certainty evidence) and pre-eclampsia (RR 0.61, 95% CI 0.41-0.92, 3 RCTs, n = 5267 women, I2 = 0%; moderate-certainty evidence) when compared with placebo. Vaginal progesterone started in the second or third trimesters was not associated with a reduction in HDP (RR 1.19, 95% CI 0.67-2.12, 3 RCTs, n = 1602 women, I2 = 9%; low-certainty evidence) or pre-eclampsia (RR 0.97, 95% CI 0.71-1.31, 5 RCTs, n = 4274 women, I2 = 0%; low-certainty evidence). CONCLUSIONS: Our systematic review found first-trimester initiated vaginal micronised progesterone may reduce the risk of HDP and pre-eclampsia.

Placental histology for targeted risk assessment of recurrent spontaneous preterm birth.

BACKGROUND: Spontaneous preterm birth significantly increases the risk for a recurrent preterm birth. Only a few identifiable clinical risk factors can be referenced in counseling for recurrent preterm birth. Furthermore, treatment using progesterone supplementation has not consistently prevented preterm birth among high-risk patients, but it may be effective in a subset of those patients. Placental pathology from a previous pregnancy may be used to predict which patients will experience a recurrent preterm birth or to identify a subset of patients more likely to respond to treatment with antenatal progesterone. OBJECTIVE: This study aimed to determine if histologic patterns are associated with recurrent preterm birth among patients with an index spontaneous preterm birth. A secondary objective was to determine if placental histologic types and/or progesterone receptor density in the decidua are associated with the response to progesterone supplementation with intramuscular 17-hydroxyprogesterone caproate. STUDY DESIGN: This was a retrospective cohort study at a single institution of women with singleton pregnancies with an index spontaneous preterm birth and a subsequent birth within the same hospital system between 2009 and 2019. Patients were included if placental pathology was available for the index spontaneous preterm birth. A logistic regression was used to determine if there were independent associations between 4 histologic types (acute inflammation, maternal vascular malperfusion, fetal vascular malperfusion, chronic inflammation) and recurrent preterm birth. For the secondary endpoint, 17-hydroxyprogesterone caproate response was defined as prolonging gestation by >3 weeks beyond the gestational age at delivery in the index pregnancy. Patients who delivered <3 weeks beyond the gestational age in the index pregnancy but at ≥39 weeks' gestation were excluded. A logistic regression was used to assess the independent association between placental histology and 17-hydroxyprogesterone caproate response. Sensitivity analyses were completed using only patients with an index birth <36 weeks' gestation, and then excluding those with medically indicated preterm birth in a subsequent pregnancy. A nested case-control immunohistochemical study was done among 20 patients with a subsequent term birth and 20 patients with a subsequent spontaneous preterm birth. The percentage of cells in the maternal decidua positive for progesterone receptors was correlated with the subsequent pregnancy outcome. RESULTS: A total of 352 patients were included. Acute inflammation was the most common histologic type seen among patients with spontaneous preterm birth (44.1%), followed by chronic inflammation (40.9%) and maternal vascular malperfusion (31.3%). No histologic type was independently associated with recurrent preterm birth. A total of 155 patients received 17-hydroxyprogesterone caproate in a second pregnancy. Low-grade acute inflammation was significantly associated with a decreased likelihood of 17-hydroxyprogesterone caproate response. Low-grade maternal vascular malperfusion among those with an index pregnancy delivered at <36 weeks' gestation was significantly associated with a more than 4 times increased likelihood of 17-hydroxyprogesterone caproate response when excluding those with a subsequent iatrogenic preterm birth. Progesterone receptor staining was not associated with recurrent preterm birth. CONCLUSION: Although acute inflammation was prevalent among spontaneous preterm births, more than half of the spontaneous preterm births were not associated with acute inflammation. Low-grade acute inflammation was associated with a significantly decreased response to 17-hydroxyprogesterone caproate supplementation. Low-grade maternal vascular malperfusion was associated with a 4-fold increased likelihood of 17-hydroxyprogesterone caproate response among those with index deliveries <36 weeks' gestation. Further work is needed to determine if placental pathologic examination can be used to target treatment in subsequent pregnancies to prevent recurrent preterm birth.

Cervical assessment certification and its impact on performance quality in the context of universal cervical screening.

OBJECTIVE: To assess the impact of the introduction of universal transvaginal cervical screening and certification on the quality of cervical length ultrasound images. METHODS: The present study included a retrospective cohort of singleton pregnancies that underwent transvaginal cervical length measurement at the anatomical scan (180/7 and 236/7 weeks) before (period A, 2015-2017) and after (period B, 2017-2019) the introduction of universal transvaginal cervical length screening. Independent observers blindly evaluated the images obtained for cervical length using a qualitative scoring method based on five criteria, according to the Fetal Medicine Foundation. RESULTS: In all, 6013 patients met the inclusion criteria, 3333 in period A and 2680 in period B. Maternal characteristics and risk factors for preterm birth were similar between the two periods. The acceptance of transvaginal cervical length measurement in period B was 95.5% in the overall cohort and 100% in the subgroup of high-risk patients. The quality score was significantly higher in period B than in period A. Among the image quality criteria, the anterior/posterior ratio, the correct magnification of the images, and the calipers' placement contributed significantly to the improved quality score in period B. Most of the sonographers performed better in period B, irrespective of the years of experience, but certificate holders obtained higher scores than non-certified sonographers, particularly those in mid-career. The identification of short cervix was significantly higher in period B than in period A. CONCLUSION: The implementation of universal transvaginal cervical length screening and the certification process are associated with improved quality of cervical length images, even among expert sonographers and in the presence of anatomical pitfalls.

Practice variation in timing of antenatal corticosteroid administration in early-onset fetal growth restriction: A secondary analysis of the Dutch STRIDER study.

INTRODUCTION: In early-onset fetal growth restriction the fetus fails to thrive in utero due to unmet fetal metabolic demands. This condition is linked to perinatal mortality and severe neonatal morbidity. Maternal administration of corticosteroids in high-risk pregnancies for preterm birth at a gestational age between 24 and 34 weeks has been shown to reduce perinatal mortality and morbidity. Practice variation exists in the timing of the administration of corticosteroids based on umbilical artery monitoring findings in early-onset fetal growth restriction. The aim of this study was to examine differences in neonatal outcomes when comparing different corticosteroid timing strategies. MATERIAL AND METHODS: This was a post-hoc analysis of the Dutch STRIDER trial. We examined neonatal outcomes when comparing institutional strategies of early (umbilical artery pulsatility index >95th centile) and late (umbilical artery shows absent or reversed end-diastolic flow) administration of corticosteroids. The primary outcomes were neonatal mortality and a composite of neonatal mortality and neonatal morbidity, defined as bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis or retinopathy of prematurity. We also analyzed predictors for adverse neonatal outcomes, including gestational age at delivery, birthweight, maternal hypertensive disorders, and time interval between corticosteroids and birth. RESULTS: A total of 120 patients matched our inclusion criteria. In 69 (57.5%) the early strategy was applied and in 51 (42.5%) patients the late strategy. Median gestational age at delivery was 28 4/7 (± 3, 3/7) weeks. Median birthweight was 708 (± 304) g. Composite primary outcome was found in 57 (47.5%) neonates. No significant differences were observed in the primary outcome between the two strategies (neonatal mortality adjusted odds ratio [OR] 1.22, 95% CI 0.44-3.38; composite primary outcome adjusted OR 1.05, 95% CI 0.42-2.64). Only gestational age at delivery was a significant predictor for improved neonatal outcome (adjusted OR 0.91, 95% CI 0.86-0.96). CONCLUSIONS: No significant differences in neonatal outcomes were observed when comparing early and late strategy of antenatal corticosteroid administration on neonatal outcomes in pregnancies complicated by early-onset fetal growth restriction. We found no apparent risk contribution of interval between corticosteroid administration and delivery in multivariate analysis. Gestational age at delivery was found to be an important predictor of neonatal outcome.

Favorable surgical and obstetrical outcomes in pre- and postconceptional laparoscopic abdominal cerclage: a large multicenter cohort study.

BACKGROUND: Cervical incompetence is an important cause of extremely preterm delivery. Without specialized treatment, cervical incompetence has a 30% chance of recurrence in a subsequent pregnancy. Recently, the first randomized controlled trial showed significant superiority of abdominal cerclage compared with both high and low vaginal cerclage in preventing preterm delivery at <32 weeks of gestation and fetal loss in patients with a previous failed vaginal cerclage. OBJECTIVE: This study aimed to assess surgical and obstetrical outcomes in patients with pre- and postconceptional laparoscopic abdominal cerclage placement. Furthermore, it also aimed to perform subgroup analysis based on the indication for cerclage placement in order to identify patients who benefit the most from an abdominal cerclage. STUDY DESIGN: A retrospective multicenter cohort study with consecutive inclusion of all eligible patients from 1997 onward in the Dutch cohort (104 patients) and from 2007 onward in the Boston cohort (169 patients) was conducted. Eligible patients had at least 1 second- or third-trimester fetal loss due to cervical incompetence and/or a short or absent cervix after cervical surgery. This includes loop electrosurgical excision procedure, conization, or trachelectomy. Patients were divided into the following subgroups based on the indication for cerclage placement: (1) previous failed vaginal cerclage, (2) previous cervical surgery, and (3) other indications. The third group consisted of patients with a history of multiple second- or early third-trimester fetal losses due to cervical incompetence (without a failed vaginal cerclage) and/or multiple dilation and curettage procedures. The primary outcome measure was delivery at ≥34 weeks of gestation with neonatal survival at hospital discharge. Secondary outcome measures included surgical and obstetrical outcomes, such as pregnancy rates after preconceptional surgery, obstetrical complications, and fetal survival rates. RESULTS: A total of 273 patients were included (250 in the preconceptional and 23 in the postconceptional cohort). Surgical outcomes of 273 patients were favorable, with 6 minor complications (2.2%). In the postconceptional cohort, 1 patient (0.4%) had hemorrhage of 650 mL, resulting in conversion to laparotomy. After preconceptional laparoscopic abdominal cerclage (n=250), the pregnancy rate was 74.1% (n=137) with a minimal follow-up of 12 months. Delivery at ³34 weeks of gestation occurred in 90.5% of all ongoing pregnancies. Four patients (3.3%) had a second-trimester fetal loss. The indication for cerclage in all 4 patients was a previous failed vaginal cerclage. The other subgroups showed fetal survival rates of 100% in ongoing pregnancies, with a total fetal survival rate of 96%. After postconceptional placement, 94.1% of all patients with an ongoing pregnancy delivered at ³34 weeks of gestation, with a total fetal survival rate of 100%. Thus, second-trimester fetal losses did not occur in this group. CONCLUSION: Pre- and postconceptional laparoscopic abdominal cerclage is a safe procedure with favorable obstetrical outcomes in patients with increased risk of cervical incompetence. All subgroups showed high fetal survival rates. Second-trimester fetal loss only occurred in the group of patients with a cerclage placed for the indication of previous failed vaginal cerclage, but was nevertheless rare even in this group.

Arabin-pessary or McDonald Cerclage in Cervical Shortening?

OBJECTIVE: The aim of the present study is to compare the effectiveness of Arabin pessary and McDonald cervical cerclage on preterm delivery. METHODS: We conducted a retrospective analysis of data from patients who underwent either Arabin pessary or McDonald cerclage between January 1, 2019, and January 1, 2023. A total of 174 patients were included in the study, with 31 undergoing Arabin pessary and 143 receiving cervical cerclage using the McDonald technique in singleton pregnant women with cervical insufficiency, which applied between 14 and 22 gestational weeks. We included singleton pregnant women with normal morphology, and with normal combined test. The primary outcome was the impact of each method on preterm delivery (< 34 gestational weeks). RESULTS: The weeks of cervical cerclage or pessary application were compatible with each other (p < 0.680). The pessary group had a statistically significant longer time to delivery compared with the Cerclage group (cerclage group mean 30.8 c 7.1 standard deviation [SD] versus pessary group mean 35.1 ± 4.4 SD; p < 0.002). A statistically significant difference was found between the pessary and cerclage groups in terms of delivery at < 34 weeks (p = 0.002). In patients with cervical length between 25 and 15mm and < 15mm, no significant difference was found between the pessary and cerclage groups in terms of delivery week (p < 0.212; p < 0.149). Regardless of the technique applied, no statistically significant difference was observed between cervical length and birth < 34 weeks. CONCLUSION: Our study found that pessary use for cervical insufficiency is statistically more effective than cervical cerclage surgery in preventing preterm births < 34 weeks in singleton pregnancy.

PREVENTION OF REPRODUCTIVE LOSSES ASSOCIATED WITH INTRAPLANTAR ACCUMULATION OF RADIONUCLIDES. / ПРОФІЛАКТИКА РЕПРОДУКТИВНИХ ВТРАТ, ПОВ'ЯЗАНИХ З ВНУТРІШНЬОПЛАЦЕНТАРНИМ НАКОПИЧЕННЯМ РАДІОНУКЛІДІВ.

The materials of the article are based on the results of our past studies of morphological and immunohistochemical features of placental damage due to 137Cs incorporation. OBJECTIVE: to determine the effectiveness of radioprotective therapy in preventing reproductive losses and perinatal consequences associated with the incorporation of radionuclides in the placenta. MATERIALS AND METHODS: According to the research design, the first group consisted of 153 women with reproductive losses in anamnesis and signs of termination of the current pregnancy. The control consisted of 30 women with a physiological pregnancy and an uncomplicated history. Based on the fact that one of the causes of premature termination of pregnancy is the vulnerable effect of 137Cs incorporated in the placenta, «Apple Pectin Antioxidant¼ (the «APA¼) with a high sorption potential was included in preventive measures regarding reproductive losses and perinatal consequences. The effectiveness of therapy with the inclusion of «Apple Pectin Antioxidant¼ was evaluated based on indicators of the fetoplacental complex and pregnancy scenarios. The results were compared with the effectiveness of standard treatment for habitual miscarriage of pregnancy. RESULTS: It was established that the destructive effect of incorporated 137Cs leads to placental dysfunction and fetal distress. Therapy with the inclusion of «APA¼ more significantly than standard treatment increases the progesterone-synthesizing function of the placenta, microcirculation, adaptation potential, and antioxidant protection of cells with the efficiency of 7.5 %, 10.7 %, 17.7 %, and 43.4 %, respectively. «APA¼ has a positive effect on the scenarios of pregnancy. «APA¼ in the composition of therapy to preserve pregnancy contributed to a decrease in the frequency of premature births by 11.4 % and an extension of their term to 34 weeks of gestation. Extending the gestational age of preterm birth reduced the frequency of severe asphyxia by 18.7 %, hypoxic-ischemic central nervous system injury by 13.5 %, respiratory distress by 17.3 %, and intraventricular hemorrhage 2nd and 3rd degrees by 12.7 %.All children were born alive due to the preservation of the compensatory ability of the placenta. CONCLUSIONS: Termination of pregnancy is a universal reaction of the mother and the fetus to negative exogenous and endogenous influences. Placental dysfunction is the most frequent cause of reproductive losses. Incorporated 137Cs is one of the factors that disturb the architecture of the placenta. Extreme effects depend on the number of incorporated 137Cs and the compensatory capacity of the placenta. Today, the possibility of internal exposure to 137Cs is associated due to consumption of agricultural products. Unfortunately, the level of food contamination with radionuclides remains higher than permissible. Living in an area with a standard radiation background does not guarantee a person the radiation safety of agricultural products. The confirmation is the accumulation of 137Cs in the placentas of women from different regions of Ukraine. The high efficiency of therapy with «APA¼ is associated with the removal of radionuclides and the minimization of the effect of internal irradiation, which made it possible to reduce the frequency of termination of pregnancy by 28.0 % due to the reduction of cases of premature births (-11.4 %), spontaneous abortions (-11.0 %), termination of pregnancy (-5.5 %). The «APA¼ is advisable to prescribe from pregravid and during pregnancy to all women, regardless of the region of residence.

Blockade of IL-6R prevents preterm birth and adverse neonatal outcomes.

BACKGROUND: Preterm birth preceded by spontaneous preterm labour often occurs in the clinical setting of sterile intra-amniotic inflammation (SIAI), a condition that currently lacks treatment. METHODS: Proteomic and scRNA-seq human data were analysed to evaluate the role of IL-6 and IL-1α in SIAI. A C57BL/6 murine model of SIAI-induced preterm birth was developed by the ultrasound-guided intra-amniotic injection of IL-1α. The blockade of IL-6R by using an aIL-6R was tested as prenatal treatment for preterm birth and adverse neonatal outcomes. QUEST-MRI evaluated brain oxidative stress in utero. Targeted transcriptomic profiling assessed maternal, foetal, and neonatal inflammation. Neonatal biometrics and neurodevelopment were tested. The neonatal gut immune-microbiome was evaluated using metagenomic sequencing and immunophenotyping. FINDINGS: IL-6 plays a critical role in the human intra-amniotic inflammatory response, which is associated with elevated concentrations of the alarmin IL-1α. Intra-amniotic injection of IL-1α resembles SIAI, inducing preterm birth (7% vs. 50%, p = 0.03, Fisher's exact test) and neonatal mortality (18% vs. 56%, p = 0.02, Mann-Whitney U-test). QUEST-MRI revealed no foetal brain oxidative stress upon in utero IL-1α exposure (p > 0.05, mixed linear model). Prenatal treatment with aIL-6R abrogated IL-1α-induced preterm birth (50% vs. 7%, p = 0.03, Fisher's exact test) by dampening inflammatory processes associated with the common pathway of labour. Importantly, aIL-6R reduces neonatal mortality (56% vs. 22%, p = 0.03, Mann-Whitney U-test) by crossing from the mother to the amniotic cavity, dampening foetal organ inflammation and improving growth. Beneficial effects of prenatal IL-6R blockade carried over to neonatal life, improving survival, growth, neurodevelopment, and gut immune homeostasis. INTERPRETATION: IL-6R blockade can serve as a strategy to treat SIAI, preventing preterm birth and adverse neonatal outcomes. FUNDING: NICHD/NIH/DHHS, Contract HHSN275201300006C. WSU Perinatal Initiative in Maternal, Perinatal and Child Health.

Screening and Prevention of Preterm Birth in Twin Pregnancies.

Twins represent 3.2% of all live births. However, they account for 20% of all preterm deliveries, 60% delivering <37 weeks, 10.7% <32 weeks, and 5 times higher risk of infant death. Risk factors for preterm birth (PTB) include the history of preterm delivery, monochorionic twins, short cervical length, and cervical surgery. Transvaginal cervical length <24 weeks is the best tool to predict PTB. Only vaginal progesterone in women with transvaginal cervical length <25 mm and physical exam indicated cerclage in women with cervical dilation >1 cm have shown a significant decrease in PTB and improvement in neonatal outcomes.