Study protocol for two randomised controlled trials evaluating the effects of Cerclage in the reduction of extreme preterm birth and perinatal mortality in twin pregnancies with a short cervix or dilatation: the TWIN Cerclage studies.

INTRODUCTION: Twin pregnancies have a high risk of extreme preterm birth (PTB) at less than 28 weeks of gestation, which is associated with increased risk of neonatal morbidity and mortality. Currently there is a lack of effective treatments for women with a twin pregnancy and a short cervix or cervical dilatation. A possible effective surgical method to reduce extreme PTB in twin pregnancies with an asymptomatic short cervix or dilatation at midpregnancy is the placement of a vaginal cerclage. METHODS AND ANALYSIS: We designed two multicentre randomised trials involving eight hospitals in the Netherlands (sites in other countries may be added at a later date). Women older than 16 years with a twin pregnancy at <24 weeks of gestation and an asymptomatic short cervix of ≤25 mm or cervical dilatation will be randomly allocated (1:1) to both trials on vaginal cerclage and standard treatment according to the current Dutch Society of Obstetrics and Gynaecology guideline (no cerclage). Permuted blocks sized 2 and 4 will be used to minimise the risk of disbalance. The primary outcome measure is PTB of <28 weeks. Analyses will be by intention to treat. The first trial is to demonstrate a risk reduction from 25% to 10% in the short cervix group, for which 194 patients need to be recruited. The second trial is to demonstrate a risk reduction from 80% to 35% in the dilatation group and will recruit 44 women. A cost-effectiveness analysis will be performed from a societal perspective. ETHICS AND DISSEMINATION: This study has been approved by the Research Ethics Committees in the Netherlands on 3/30/2023. Participants will be required to sign an informed consent form. The results will be presented at conferences and published in a peer-reviewed journal. Participants will be informed about the results. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT05968794.

A historical narrative review through the field of tocolysis in threatened preterm birth.

Preterm birth presents a significant challenge in clinical obstetrics, requiring effective strategies to reduce associated mortality and morbidity risks. Tocolytic drugs, aimed at inhibiting uterine contractions, are a key aspect of addressing this challenge. Despite extensive research over many years, determining the most effective tocolytic agents remains a complex task, prompting better understanding of the underlying mechanisms of spontaneous preterm birth and recording meaningful outcome measures. This paper provides a comprehensive review of various obsolete and current tocolytic drug regimens that were instituted over the past century, examining both historical contexts and contemporary challenges in their development and adoption. The examination of historical debates and advancements highlights the complexity of introducing new therapies. While the search for effective tocolytics continues, questions arise regarding their actual benefits in obstetric care and the necessity for ongoing exploration. The presence of methodological limitations in current research emphasizes the importance of well-designed randomized controlled trials with robust endpoints and extended follow-up periods.In response to these complexities, the consideration of shifting towards prevention strategies aimed at addressing the root causes of preterm labor becomes more and more evident. This potential shift may offer a more effective approach than relying solely on tocolytics to delay labor initiation.Ultimately, effectively managing threatened preterm birth necessitates ongoing investigation, innovation, and a willingness to reassess strategies in pursuit of optimal outcomes for mothers, neonates, and long-term child health.

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).

Is it safe to give birth with an activated implantable cardioverter-defibrillator: A multicentre observational study.

OBJECTIVE: Data and guidelines are lacking, so implantable cardioverter-defibrillators (ICDs) are often deactivated during labour to prevent inappropriate shocks. This study aimed to ascertain the safety of an activated ICD during labour. DESIGN: An observational study was performed. SETTING: Dutch hospitals. POPULATION OR SAMPLE: A total of 41 childbirths were included of 26 patients who gave birth between February 2009 and November 2018 after receiving an ICD in our tertiary hospital. Five of these childbirths were attended by the research team between December 2018 and August 2020, during which the ICD remained active. METHODS: Groups were made based on ICD status during labour. Patients who gave birth with an activated ICD at least once were stratified to the activated ICD group. Patients' files were checked and patients received a questionnaire about childbirth perceptions and treatment preferences. The differences in ordinal data resulting from the questionnaire were calculated using a chi-square or Fisher's exact test. MAIN OUTCOME MEASURES: Primary outcome was inappropriate ICD therapy and occurrence of ventricular arrhythmias requiring treatment. RESULTS: During the 41 childbirths, no inappropriate shocks or ventricular arrhythmias occurred during labour. All patients in the activated ICD group (n = 13) preferred this setting, while 8 of the 13 patients in the deactivated ICD group preferred activation (p = 0.002). Reasons included avoiding hemodynamic monitoring, magnet placement, or labour induction to facilitate technician availability. CONCLUSIONS: This study shows no evidence that labour and birth in women with an activated ICD are unsafe, as there were no ventricular arrhythmias or inappropriate therapy. In addition, most patients prefer an activated ICD during labour.

Trends in preterm birth in the Netherlands in 2011-2019: A population-based study among singletons and multiples.

INTRODUCTION: Preterm birth (PTB) is the leading cause of infant mortality and morbidity worldwide. Rates of PTB in the Netherlands are declining, possibly due to the implementation of preventive strategies. In this study we assessed the overall trend in PTB rates in the Netherlands in recent years, and in more detail in specific subgroups to investigate potential groups that require scrutiny in the near future. MATERIAL AND METHODS: Based on the national perinatal registry, we included all pregnancies without severe congenital abnormalities resulting in a birth from 24 to 42 completed weeks of gestation between 2011 and 2019 in the Netherlands. We assessed PTB rates in two different clinical subtypes (spontaneous vs. iatrogenic) and in five gestational age subgroups: 24-27+6 weeks (extreme), 28-31+6 weeks (very), 32-33+6 weeks (moderate, 34-36+6 weeks [late] and, in general, 24-36+6 weeks [overall PTB]). Trend analysis was performed using the Cochran Armitage test. We also compared PTB rates in different subgroups in the first 2 years compared to the last 2 years. Singleton and multiple gestations were analyzed separately. RESULTS: We included 1 447 689 singleton and 23 250 multiple pregnancies in our study. In singletons, we observed a significant decline in PTB from 5.5% to 5.0% (p < 0.0001), mainly due to a decrease in iatrogenic PTBs. When focusing on different gestational age subgroups, there was a decrease in all iatrogenic PTB and in moderate to late spontaneous PTB. However, in spontaneous extreme and very PTB there was an significant increase. When assessing overall PTB risk in different subgroups, the decline was only visible in women with age ≥25 years, nulliparous and primiparous women, women with a medium or high socioeconomic status and hypertensive women. In multiples, the rate of PTB remained fairly stable, from 52.3% in 2011 to 54.1% in 2019 (p = 0.57). CONCLUSIONS: In the Netherlands, between 2011 and 2019, PTB decreased, mainly due to a reduction in late PTB, and more in iatrogenic than in spontaneous PTB. Focus for the near future should be on specific subgroups in which the decline was not visible, such as women with a low socioeconomic status or a young age.

Stress-reducing interventions in pregnancy for the prevention of preterm birth: a systematic review and meta-analysis.

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality. Maternal stress during pregnancy is an established risk factor for PTB. We aimed to review the effects of stress-reducing interventions during pregnancy on PTB. Studies reporting on stress-reducing interventions during pregnancy and PTB rates in general low-risk obstetric populations were included. PTB rates, low birth weight (LBW) rates, mean gestational age and birth weight, maternal anxiety and stress, and adverse perinatal outcomes were investigated. Data were extracted using a standardized extraction form, pooled effect sizes were calculated with the random effects model. Ten studies with a total of 4.816 women were included. The interventions included Pilates, yoga, a multidisciplinary stress reduction program, combination therapy (combining mindfulness, yoga, music, baby bonding, and education), and hypnosis. The incidence of PTB was significantly lower in the intervention group (RR 0.50, 95% CI 0.35 - 0.71). The overall quality of the included studies was low, and the risk of bias was high. In conclusion, this study provides evidence supporting the potential efficacy of stress-reducing interventions in reducing the incidence of PTB in low-risk women. We propose a RCT of high quality to determine the effectiveness of stress-reducing interventions in reducing PTB risk.

Assessment of cervical softening and the prediction of preterm birth (STIPP): protocol for a prospective cohort study.

INTRODUCTION: Preterm birth (PTB) is among the leading causes of perinatal and childhood morbidity and mortality. Therefore, accurate identification of pregnant women at high risk of PTB is key to enable obstetric healthcare professionals to apply interventions that improve perinatal and childhood outcomes. Serial transvaginal cervical length measurement is used to screen asymptomatic pregnant women with a history of PTB and identify those at high risk for a recurrent PTB. Cervical length measurement, fetal fibronectin test or a combination of both can be used to identify women at high risk of PTB presenting with symptoms of threatened PTB. The predictive capacity of these methods can be improved. Cervical softening is a precursor of cervical shortening, effacement and dilatation and could be a new marker to identify women a high risk of PTB. However, the predictive value of cervical softening to predict spontaneous PTB still needs to be determined. METHODS AND ANALYSIS: This is a single-centre, prospective cohort study, conducted at the Amsterdam University Medical Centers in the Netherlands. Cervical softening will be investigated with a non-invasive CE-marked device called the Pregnolia System. This device has been developed to evaluate consistency of the cervix based on tissue elasticity. Two different cohorts will be investigated. The first cohort includes women with a history of spontaneous PTB <34 weeks. These women undergo biweekly measurements between 14 and 24 weeks of gestation. The second cohort includes women with symptoms of threatened PTB. These women will receive the measurement once at presentation between 24 and 34 weeks of gestation. The primary outcome is spontaneous PTB before 34 weeks for women with a history of PTB and delivery within 7 days for women with threatened PTB. The minimum sample size required to analyse the primary outcome is 227 women in the cohort of women with a history of PTB and 163 women in the cohort of women with symptoms of threatened PTB. Once this number is achieved, the study will be continued to investigate secondary objectives. ETHICS AND DISSEMINATION: The study is approved by the Medical Ethics Committee of Amsterdam UMC (METC2022.0226). All patients will give oral and written informed consent prior to study entry. Results will be disseminated via a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05477381.

Long-Term Maternal Mental Health after Spontaneous Preterm Birth.

OBJECTIVE: The aim of this study is to investigate whether a history of spontaneous preterm birth (SPTB) is associated with maternal depressive and anxiety symptoms, or psychosocial distress in the fifth decade of life. STUDY DESIGN: This is a secondary analysis of the PreCaris-study, a prospective observational study in which we included 350 women with a history of SPTB between 220/7 and 366/7 weeks of gestation and compared them to 115 women who had a term birth. Primary outcomes were the Depression and Anxiety scores measured using the Hospital Anxiety Depression Scale and Psychosocial distress assessed with the Distress Thermometer for Parents. Secondary outcomes were self-reported impact of the birth in daily life and psychosocial support after delivery. RESULTS: After a median of 13 years after delivery, no significant differences were found in primary outcomes. Significantly more women with a history of SPTB reported that the birth still had impact in daily life; adjusted odds ratio: 2.46 (95% confidence interval: 1.35-4.48). A total of 57 (16.3%) women after SPTB reported to have needed professional psychosocial support after delivery but did not receive it. These women more often had a high Anxiety score (p = 0.030), psychosocial distress (p = 0.001), and influence of birth in daily life (p = 0.000). CONCLUSION: There are no long-term effects on depressive and anxiety symptoms and psychosocial distress in women who experienced SPTB compared with women who had a full-term pregnancy. A significant part of the women who delivered preterm needed psychosocial support but did not receive it and were at higher risk of anxiety, psychosocial distress, and impact in daily life. We therefore recommend offering all women after SPTB psychosocial support after delivery. KEY POINTS: · No long-term effects on depressive and anxiety symptoms and psychosocial distress after SPTB.. · A total of 16.3% of the cases needed professional psychosocial support after delivery but did not receive it.. · This subgroup was at higher risk of anxiety symptoms, psychosocial distress, and impact on daily life..

Few randomized trials in preterm birth prevention meet predefined usefulness criteria.

OBJECTIVES: We operationalized a research usefulness tool identified through literature searches and consensus and examined if randomized controlled trials (RCTs) addressing preterm birth prevention met predefined criteria for usefulness. STUDY DESIGN AND SETTING: The usefulness tool included eight criteria combining 13 items. RCTs were evaluated for compliance with each item by multiple assessors (reviewer agreement 95-98%). Proportions of compliances with 95% confidence interval (CI) were calculated and change over time was assessed using â‰§ 2010 as a cutoff. RESULTS: Among 347 selected RCTs, published within 56 preterm birth Cochrane reviews, only 36 (10%, 95% CI = 7-14%) met more than half of the usefulness criteria. Compared to trials before 2010, recent trials used composite or surrogate (less informative) outcomes more often (13% vs. 25%, relative risk 1.91, 95% CI = 1.21-3.00). Only 16 trials reflected real practice (pragmatism) in design (5%, 95% CI = 3-7%), with no improvements over time. No trials reported involvement of mothers to reflect patients' research priorities and outcomes selection. Recent trials were more transparent. CONCLUSION: Few preterm birth prevention RCTs met more than half of the usefulness criteria but most of usefulness criteria are improving after 2010. Use of informative outcomes, patient centeredness, pragmatism and transparency should be key targets for future research planning.

Left ventricular diastolic function in the fifth decade of life in women with a history of spontaneous preterm birth.

OBJECTIVE: Cardiovascular disease (CVD) is the number one cause of death in women and defining its risk factors is necessary to reduce its prevalence. A history of preeclampsia is shown to be associated with hypertension and alterations in left ventricular (LV) diastolic function parameters. Because of overlapping mechanisms between preeclampsia and spontaneous preterm birth (SPTB), our most recent study investigated the association between SPTB and hypertension, and found an almost 2 times higher prevalence of hypertension after SPTB. No previous studies have focused on the association between SPTB and LV diastolic function. The aim of this study is to investigate LV diastolic function as potential early parameter of CVD in women with a history of SPTB. STUDY DESIGN: We included cases with a history of SPTB between 22 and 37 weeks and controls who had a term birth. Women with hypertensive disorders or gestational diabetes in any of their pregnancies, were excluded. Both groups underwent cardiovascular risk assessment and transthoracic echocardiography 9 to 16 years after pregnancy. Echocardiographic measures were adjusted using a linear regression analysis accounting for hypertension and other risk factors known to be associated with CVD. A subgroup analysis was performed based on hypertension at follow-up. RESULTS: A total of 94 cases and 94 controls were included, on average 13 years after pregnancy. There were no significant differences in LV diastolic function parameters. Women with a history of SPTB and diagnosed hypertension at follow-up, showed significant higher late diastolic mitral flow velocity, lower e'septal velocity and higher E/e'ratio, compared to women with a history of SPTB without hypertension, although within normal ranges. CONCLUSIONS: When a history of SPTB is accompanied by hypertension at follow-up, significant changes in LV diastolic function were seen. Therefore, hypertension is the central factor in preventive screening methods, and transthoracic echocardiography has no additional value at this follow-up duration.

Spontaneous preterm birth with placental maternal vascular malperfusion is associated with cardiovascular risk in the fifth decade of life.

Women with a history of spontaneous preterm birth (SPTB) have a mildly elevated cardiovascular risk (CVR) later in life and women with a history of preeclampsia have a highly elevated CVR. In placentas of women with preeclampsia pathological signs of maternal vascular malperfusion (MVM) are often seen. These signs of MVM are also seen in a substantial part of the placentas of women with SPTB. We therefore hypothesize that in women with a history of SPTB, the subgroup with placental MVM has an elevated CVR. This study is a secondary analysis of a cohort study including women 9-16 years after a SPTB. Women with pregnancy complications known to be associated with CVR were excluded. The primary outcome was hypertension defined as blood pressure ≥ 130/80 mmHg and/or treatment with antihypertensive medication. Secondary outcomes were mean blood pressure, anthropometrics, blood measurements including cholesterol and HbA1c, and creatinine in urine. Placental histology was available in 210 (60.0%) women. MVM was found in 91 (43.3%) of the placentas, most often diagnosed by the presence of accelerated villous maturation. Hypertension was diagnosed in 44 (48.4%) women with MVM and in 42 (35.3%) women without MVM (aOR 1.76, 95% CI 0.98 - 3.16). Women with a SPTB and placental MVM showed significantly higher mean diastolic blood pressure, mean arterial pressure and HbA1c approximately 13 years after delivery, compared to women with a SPTB without placental MVM. We therefore conclude that placental malperfusion in women with a SPTB might differentiate in CVR later in life.

Progestogen maintenance therapy for prolongation of pregnancy after an episode of preterm labour: A systematic review and meta-analysis.

BACKGROUND: Evidence for progestogen maintenance therapy after an episode of preterm labour (PTL) is contradictory. OBJECTIVES: To assess effectiveness of progestogen maintenance therapy after an episode of PTL. SEARCH STRATEGY: An electronic search in Central Cochrane, Ovid Embase, Ovid Medline and clinical trial databases was performed. SELECTION CRITERIA: Randomised controlled trials (RCT) investigating women between 16+0 and 37+0 weeks of gestation with an episode of PTL who were treated with progestogen maintenance therapy compared with a control group. DATA COLLECTION AND ANALYSIS: Systematic review and meta-analysis were conducted. The primary outcome was latency time in days. Secondary neonatal and maternal outcomes are consistent with the core outcome set for preterm birth studies. Studies were extensively assessed for data trustworthiness (integrity) and risk of bias. MAIN RESULTS: Thirteen RCT (1722 women) were included. Progestogen maintenance therapy demonstrated a longer latency time of 4.32 days compared with controls (mean difference [MD] 4.32, 95% CI 0.40-8.24) and neonates were born with a higher birthweight (MD 124.25 g, 95% CI 8.99-239.51). No differences were found for other perinatal outcomes. However, when analysing studies with low risk of bias only (five RCT, 591 women), a significantly longer latency time could not be shown (MD 2.44 days; 95% CI -4.55 to 9.42). CONCLUSIONS: Progestogen maintenance therapy after PTL might have a modest effect on prolongation of latency time. When analysing low risk of bias studies only, this effect was not demonstrated. Validation through further research, preferably by an individual patient data meta-analysis is highly recommended.

Sexual intercourse during pregnancy and its association with spontaneous preterm birth.

This study investigated whether sexual intercourse during pregnancy is associated with spontaneous preterm birth (SPTB). We included 77 women with SPTB and 145 women with a term birth. A total of 195 (87.8%) women had sexual intercourse during pregnancy, which was comparable between the groups. Primiparas with SPTB tended to report more often having sexual intercourse 3 - 4 times a week compared to primiparas with a term birth (8.8% vs. 0%, p =.082). We advise not to completely discourage sexual intercourse among pregnant women. Yet, high sexual intercourse frequency could be associated with SPTB.

Impact of ethnicity and neighborhood deprivation on preterm birth: How does urban living play a role?

OBJECTIVE: Women of Black and other non-Western ethnicity and women who live in deprived neighborhoods are at increased risk for preterm birth (PTB). These women may live clustered in certain urban areas. If ethnicity reflects a biological rather than a socioeconomic risk factor, women should have a PTB risk independent of the urban area where they live. In this study we explored the association between urban living and the risk of PTB, combined with knowledge on ethnicity and neighborhood deprivation in these specific urban areas in the Netherlands. STUDY DESIGN: National cohort study of 935,381 women (2014-2019) with a singleton pregnancy resulting in live birth between 24.0 and 42.6 weeks. Antepartum death and severe congenital anomalies were excluded. We performed logistic regression analysis and analyzed the impact of living in one of the four main urban areas on PTB. We adjusted for maternal age, parity and fetal gender. We tested for interaction between ethnicity, neighborhood deprivation index (NDI) and urban living. RESULTS: Mean PTB rate among singleton pregnancies in The Netherlands is 5.1%. There was a strong ethnic difference in PTB risk, with the highest prevalence among South Asian women (7.9%) and African women (6.6%). In the most deprived neighborhoods the PTB risk was 5.7%. We found a significant interaction between ethnicity and urban living, and between NDI and urban living. South Asian and African women living in urban areas had the greatest risk of PTB, between 7.0% and 8.8%. CONCLUSION: Ethnicity remains a fixed biological risk for PTB that cannot be fully explained by socioeconomic status or neighborhood deprivation. Independent of ethnicity and neighborhood deprivation, urban living has a great influence on the risk of preterm birth. Future studies and policies should focus on population-based interventions in those urban areas where South Asian and African ethnic groups live and where the preterm birth risk is the highest.

The association between spontaneous preterm birth and maternal hypertension in the fifth decade of life: a retrospective case-control study.

OBJECTIVE: To investigate whether a history of spontaneous preterm birth (SPTB) predisposes to maternal hypertension. DESIGN: Retrospective case-control study. SETTING: Two affiliated university medical hospitals in Amsterdam, the Netherlands. POPULATION: We included 350 women with a history of SPTB between 22 and 36+6  weeks and 166 women with a history of a term birth. Women with pregnancy complications that are known to be associated with cardiovascular disease were excluded. METHODS: Both groups underwent cardiovascular risk assessment 9-16 years after pregnancy. We performed a subgroup analysis based upon the severity of SPTB. MAIN OUTCOME MEASURES: Hypertension. Secondary outcomes - metabolic syndrome, mean blood pressure, anthropometrics, blood and urine sampling, Framingham Risk Score and Systematic Coronary Risk Evaluation. RESULTS: A history of SPTB was significantly associated with hypertension; adjusted odds ratio 1.60 (95% confidence interval 1.04-2.46, p = 0.033). Abdominal obesity was more often diagnosed after SPTB (n = 163, 46.6% versus n = 54, 32.5%, p = 0.003) and was more pronounced with more severe preterm birth (p = 0.002). CONCLUSIONS: The presence of hypertension 9-16 years after pregnancy was statistically significantly higher among women with a history of SPTB than among women with a history of uncomplicated term birth. Women with a history of SPTB were more often diagnosed with abdominal obesity, especially those with a history of extreme preterm birth.

The effect of low-dose aspirin on platelet function during pregnancy compared to placebo: An explorative study.

OBJECTIVES: To evaluate the effect of aspirin 80 mg compared to placebo on platelet function tests in the second and third trimester of pregnancy. STUDY DESIGN: An explorative study was performed to assess laboratory platelet function in a subpopulation of the APRIL trial: a randomized double-blind trial comparing aspirin 80 mg once daily to placebo for the prevention of recurrent preterm birth. Platelet function was measured between 18 and 22, and between 28 and 32 weeks gestational age with three platelet function tests: VerifyNow®, Chronolog light transmission aggregometry (Chronolog LTA) and serum thromboxane B2 (TxB2). Medication adherence was evaluated by pill counts, self-reported diaries and structured interviews. RESULTS: We included 11 women, six in the aspirin and five in the placebo group. In women receiving aspirin, platelet function was significantly lower compared to women receiving placebo for all three tests: VerifyNow® Aspirin Reaction Units (450.5 vs 648.0, p = 0.017); Chronolog LTA (9.5% vs 94.5%, p = 0.009); serum TxB2 levels (11.9 ng/mL versus 175.9 ng/mL, p = 0.030). For all three tests, platelet function did not differ between the second and third trimester of pregnancy in the aspirin group. In the placebo group, serum TxB2 levels were significantly higher in the third trimester. One non-adherent participant in the aspirin group showed results similar to the placebo group. CONCLUSION: Aspirin 80 mg has a clear inhibitory effect on laboratory platelet function during pregnancy compared to placebo. This effect is similar in the second and third trimester of pregnancy.

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

INTRODUCTION: The 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 outcome in the long term. However, antenatal exposure to aspirin could have adverse effects on child development that may manifest later in life. The aim of this follow-up study is to assess the long-term effects of antenatal exposure to low-dose aspirin compared with placebo on survival, (neuro)development, behaviour and general health at 4 years corrected age. METHODS AND ANALYSIS: This is a follow-up study of the Dutch double-blind randomised controlled APRIL trial which assessed the effectiveness of treatment with aspirin (80 mg daily) compared with placebo for the prevention of preterm birth in women with a previous spontaneous preterm birth. Treatment was initiated before 16 weeks of gestation and continued until 36 weeks or birth. We aim to follow-up all 379 children born to women who participated in the APRIL trial and survived the neonatal period, at the corrected age of 4 years. The main outcomes are (neuro)development as assessed by the Ages and Stages Questionnaire, and behaviour as assessed by the Strength and Difficulties Questionnaire. Additional outcomes include mortality, growth and general health from birth up to 4 years, and a composite outcome including mortality, abnormal (neuro)development and problem behaviour. Analyses will be performed by intention-to-treat using a superiority design. ETHICS AND DISSEMINATION: Institutional Review Board approval was obtained from the Medical Research Ethics Committee from Amsterdam Medical Center (no. W20 289#20.325). The results will be published in a peer-reviewed journal and presented at conferences. TRIAL REGISTRATION NUMBER: The APRIL trial (NTR5675, NL5553; EudraCT number 2015-003220-31) and the APRIL follow-up study (NL8950) are registered in the Dutch trial register. The study is funded by the Amsterdam Reproduction & Development research institute.