Martijn A. Oudijk

Background: To assess the cost-effectiveness of treatment with atosiban compared to placebo for threatened preterm birth from 30 ⁺⁰ to 33 ⁺⁶ weeks of gestation. Methods: We performed an economic evaluation from a societal perspective alongside the multicentre randomised controlled APOSTEL 8 trial, including 755 participants with threatened preterm birth from 30 ⁺⁰ to 33 ⁺⁶ weeks of gestation who were randomised to atosiban or placebo, of whom 752 (884 infants) were included in the intention-to-treat analysis. Costs, collected between randomisation and three months corrected child age, were measured using a combination of hospital records and the self-reported iMTA Medical and Productivity Cost Questionnaires and estimated at infant level. The main outcome measure was cost-effectiveness expressed in terms of incremental cost per severe adverse neonatal outcome prevented. Multiple imputation by chained equations was used to handle missing data. Non-parametric bootstrapping was used to estimate statistical uncertainty surrounding incremental cost-effectiveness outcomes. Findings: The difference in mean costs between the atosiban group (€40,743.1) and the placebo group (€40,793.6) was not statistically significant (mean difference: -€50.5; 95% confidence interval (CI) −4037.6 to 3936.7). The incremental cost per severe adverse neonatal outcome prevented was dominant (-€5286.6), falling in the south-east quadrant of the cost-effectiveness plane, indicating cost-savings and reduced severe adverse neonatal outcomes by atosiban. However, the bootstrapped cost-effect pairs were distributed across all four quadrants of the cost-effectiveness plane, indicating high uncertainty surrounding cost-effectiveness estimates. The probability of cost-effectiveness of atosiban reached 50% at a willingness to pay threshold of €33,023.3 per severe adverse neonatal outcome prevented. Interpretation: This economic evaluation did not demonstrate that atosiban is a cost-effective treatment for threatened PTB from 30 ⁺⁰ to 33 ⁺⁶ weeks gestation. In addition to the absence of clinical benefit, our findings show no economic advantage, further discouraging its routine use at this gestational age. These results contribute to optimizing evidence-based management of threatened preterm birth.

Objective: Long‐term child outcomes after intra‐uterine exposure to 17‐alpha‐hydroxyprogesterone caproate (17‐OHPC) versus placebo. Design: Follow‐up of the AMPHIA randomised controlled trial assessing neonatal outcomes after weekly 17‐OHPC injections compared to placebo in multiple pregnancies. Setting: Multicentre. Population or Sample: Children born in the AMPHIA study. Methods: Children were assessed at 11–14 years of age by record linkage and through self‐reported, parental and teacher questionnaires. Mean differences or odds ratios (OR) with 95% confidence intervals (95% CI) were calculated with cluster robust standard errors for twins and adjustment for confounders using inverse probability weighting (IPW). Main Outcome Measures: Child mortality, educational attainment, cognition, behaviour, gender identity, general health, and a composite of abnormal development. Results: Up to 14 years, 60/1356 children had died ( n = 24 17‐OHPC and n = 36 placebo (OR 0.75 95% CI 0.36–1.53)). Record linkage was completed for 1027/1296 (79%) surviving children ( n = 517 17‐OHPC and n = 510 placebo). No significant difference was found regarding educational attainment. Detailed developmental outcomes through questionnaires were collected for 303/1296 (23%) surviving children ( n = 159 17‐OHPC and n = 144 placebo). No differences in cognition, behaviour, gender identity, and general health up to 14 years of age were found between both groups. The composite of abnormal development did not differ between 17‐OHPC (23.3%) and placebo (20.1%) groups (OR 1.31 95% CI 0.66–2.56). Conclusion: In offspring of women with a multiple pregnancy, the use of 17‐OHPC in pregnancy is unlikely to provide positive or negative effects on child outcome related to mortality, educational attainment, cognition and behaviour.

Background: In absence of direct comparisons, consensus on the preferred preventive treatment for multiple pregnancies with a short cervix is lacking. Therefore, we compared the effectiveness of a cervical pessary and vaginal progesterone in the prevention of adverse perinatal outcomes and preterm birth (PTB) in women with a multiple pregnancy, no prior spontaneous PTB (sPTB) before 34 weeks’ gestation, and an asymptomatic mid-trimester shortened cervix below 38 mm. Methods and findings: This open-label, superiority, multi-centre randomised controlled trial was conducted in 20 hospitals in the Netherlands. Women with a healthy multiple pregnancy and an asymptomatic cervical length (CL) below 38 mm between 16 and 22 weeks’ gestation were eligible, with a target sample size of 332. Following an interim analysis, the study was halted for futility. A total of 276 multiples, including seven triplet pregnancies, were randomised 1:1 to receive either an Arabin cervical pessary ( N = 138) or vaginal progesterone 200 mg daily ( N = 138) until 36 weeks’ gestation or earlier if indicated. The primary outcome was a composite adverse perinatal outcome, with secondary outcomes including rates of (s)PTB before 24, 28, 32, 34, and 37 weeks. Predefined subgroup analyses were conducted based on CL, parity, chorionicity, and number of foetuses. Among 531 neonates (pessary N = 269, progesterone N = 262), the composite adverse perinatal outcome occurred in 19.7% of neonates in the pessary group versus 13.7% in the progesterone group (crude RR 1.43; 95% CI [0.85,2.4], p = 0.18). The rates of (s)PTB were not significantly different between groups. In the subgroup with a CL of ≤25 mm, no significant difference in the composite perinatal outcome was found (41.1% versus 34.7%, RR 1.18; 95% CI [0.60,2.33], interaction p = 0.63). However, among nulliparous women, the composite outcome was more frequent in the pessary group compared to progesterone (30.0% versus 15.9%, RR 1.88; 95% CI [1.03,3.43], interaction p = 0.93). The study’s main limitations include the inability to blind interventions, potentially introducing bias, and low self-reported medication compliance in the progesterone group, which may have led to overestimated adherence and underestimated progesterone’s preventive potential in the per-protocol analysis. Conclusion: In women with multiple pregnancies and a midtrimester short cervix below 38 mm, we found no superiority of a cervical pessary compared to vaginal progesterone the prevention of perinatal complications. While progesterone may have a modest effect, future studies should focus on other interventions in multiple pregnancies such as a cerclage, both ultrasound- and physical examination-indicated. Trial registration: This trial was registered at the International Clinical Trial Registry Platform (ICTRP, EUCTR2013-002884-24-NL, https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2013-002884-24-NL ).

Objective: To identify the long‐term child outcomes after prenatal aspirin exposure. Methods: This study is a follow‐up of a randomized controlled trial (RCT) evaluating low‐dose aspirin in the prevention of recurrent spontaneous preterm labor (the APRIL study) comparing aspirin 80 mg daily ( n = 194) to placebo ( n = 193) in singletons. Children were assessed at 4 years corrected age using the Ages and Stages Questionnaire (third edition, ASQ‐3) and the Strengths and Difficulties Questionnaire (SDQ) for (neuro)development and behavioral outcomes, respectively. Data on mortality, general health, growth and a composite of abnormal child outcome or mortality were also collected. Analyses were performed reporting odds ratio (OR) and 95% confidence intervals (CIs). Results: Eight children were deceased until 4 years follow‐up (all perinatal deaths; n = 6 in aspirin and n = 2 in the placebo group). We included 231/379 (60.9%) children: 111/231 in the aspirin and 120/231 in the placebo groups. Total ASQ‐3 score was higher in the aspirin group (mean 259.3 vs. 248.3, mean difference 10.96, 95% CI: 0.17–21.76). The rate of children with an ASQ‐3 score of ≥1SD below the normative data did not differ between groups (35.2% vs. 47.4%; OR 0.60, 95% CI: 0.33–1.09), nor did a score on the SDQ ≥80th centile (18.3% vs. 14.7%; OR 1.30, 95% CI: 0.64–2.66). General health, growth and the composite outcome of abnormal child development or mortality did not significantly differ between groups. Conclusion: We found no harmful effects of daily prenatal exposure to aspirin 80 mg. Our findings contribute to the existing data confirming the safety of low‐dose aspirin use in pregnancy.

Objective: To evaluate school performance at 12 years of age in children prenatally exposed to maintenance tocolysis with nifedipine versus placebo. Design: 12‐year follow‐up of the multicentre APOSTEL 2 trial, in which participants with threatened preterm birth between 26 ⁺⁰ and 32 ⁺² weeks of gestation, who remained pregnant after initial 48‐h tocolysis, were randomised to nifedipine maintenance tocolysis or placebo for up to 12 days. Setting: The APOSTEL 2 trial was conducted in 11 Dutch hospitals from 2008 to 2010. School outcomes were assessed at age 12. Participants: Children from singleton and multiple pregnancies born to APOSTEL 2 participants. Methods: S chool performance data were received through linkage with a national registry (Statistics Netherlands). Main Outcome Measures: A high track recommendation for secondary school, adjusted for maternal education level, socioeconomic status, and child's biological sex. Results: Of 492 eligible children, 357 were included (follow‐up rate 73%). In the nifedipine group, significantly fewer children received a high track recommendation for secondary school, 67/189 (35.4%), compared to 74/168 (44.0%) in the placebo group (adjusted risk ratio (aRR) 0.76; 95% confidence interval (CI) 0.61–0.95). Outcomes were significantly poorer in children with the longest nifedipine exposure (9–14 days) compared to those not exposed (aRR 0.58; 95% CI 0.41–0.83). Conclusions: Children prenatally exposed to maintenance tocolysis with nifedipine had significantly poorer school performance at 12 years of age compared to those exposed to placebo. These findings further discourage nifedipine's use for maintenance tocolysis, and more research is warranted regarding its long‐term effects on child development.

Linked article: This Correspondence comments on Mustafa et al. Click here to view the article.

Preterm birth(PTB) is a global health problem and selecting pregnancies at risk is still a challenge. This study evaluates characteristics of cervical softening as a novel biomarker to predict birth in patients presenting with symptoms of threatened PTB. This is a single center cohort study. Pregnancies between 24⁺⁰ and 34⁺⁰ weeks presenting with symptoms of threatened PTB and intact membranes were included. The cervical stiffness index (CSI) was measured with the Pregnolia® System, providing a quantitative measure of tissue consistency. Lower CSI indicates a softer cervix. Primary outcome was delivery within seven days. We included 163 patients between August 2022 and October 2024. The primary outcome occurred in 6.5% patients (n=10). Cervical stiffness index was significantly lower in patients delivering within seven days (29.0 mbar [IQR: 24.3-51.8] vs. 69.0 mbar [51.0-90.8]) and adequately discriminated between patients with and without outcome (AUC 0.77 (0.55-0.99)). No correlation between cervical length and CSI was found (ρ=0.12). Patients with a short and soft cervix are most at risk for birth within seven days. A soft cervix, as quantified by a low CSI, in pregnancies with symptoms of threatened PTB is associated with an increased risk of birth within seven days. CSI could be used to distinguish patients with a short cervix who are at risk for preterm birth and could improve risk assessment.