Study protocol for a randomized trial on timely delivery versus expectant management in late preterm small for gestational age pregnancies with an abnormal umbilicocerebral ratio (UCR): the DRIGITAT study.

BACKGROUND: The clinical inability to correctly identify late fetal growth restriction (FGR) within a group of fetuses who are identified as small for gestational age (SGA) is an everyday problem for all obstetrician-gynecologists. This leads to substantial overtreatment of healthy small fetuses but also inadequate detection of the growth-restricted fetuses that may benefit from timely delivery. Redistribution of the fetal circulation, signaled by an abnormal ratio of the Doppler velocity flow profiles of the umbilical artery and the middle cerebral artery, more specifically an increased umbilicocerebral ratio (UCR) (or its inverse: a decreased cerebroplacental ratio (CPR)), is an adaptation to chronic hypoxemia and nutritional scarcity with long-term consequences in survivors. The relevance of an abnormal UCR has been signaled extensively, and there is a general consensus that it is a signal of FGR, independent of size, with a strong association with poor outcomes. Yet, in the current literature, no comparisons of a monitoring-delivery strategy based on unfavorable UCR have been published. The objective of the Doppler Ratio In fetal Growth restriction Intervention Trial At (near) Term (DRIGITAT) is to evaluate if the timing of the delivery based on an abnormal UCR in late preterm fetuses identified as SGA improves neurodevelopmental outcomes at 2 years of age. METHODS: The DRIGITAT study is a national multicenter cohort study of women with singleton pregnancies between 32 and 37 weeks of gestation identified as SGA, with a nested randomized controlled trial (RCT) in case of an abnormal UCR (> 0.8). Recruiting centers are in The Netherlands. In the nested RCT, women are randomized to either immediate induction of labor or expectant management from 34 weeks in case of severely abnormal size (EFW or FAC < p3) and from 36 weeks in case of mildly abnormal size (EFW or FAC p3-p10). The primary outcome measure is the 7-point average difference in the composite cognitive score (CCS) and composite motor score (CMS) on the Bayley-3 at 2 years. Secondary outcome measures include a composite outcome of neonatal morbidity, perinatal mortality, mode of delivery, maternal quality of life, costs, and predictive value of serum biomarkers. Analyses will be by intention to treat. The required sample size is determined for the nested RCT as 185 patients. DISCUSSION: This study will provide insight into the diagnostic efficacy of UCR measurement in the evaluation of SGA fetuses in order to differentiate the healthy SGA fetus from the growth-restricted fetus and to determine if a fetus with abnormal UCR benefits from early delivery. TRIAL REGISTRATION: Healthcare Evaluation Netherlands NTR6663 . Registered on 14 August 2017.

Pessary or surgery for a symptomatic pelvic organ prolapse: the PEOPLE study, a multicentre prospective cohort study.

OBJECTIVE: To compare the 24-month efficacy of pessary or surgery as the primary treatment for symptomatic pelvic organ prolapse (POP). DESIGN: Multicentre prospective comparative cohort study. SETTING: Twenty-two Dutch hospitals. POPULATION: Women referred with symptomatic POP of stage ≥2 and moderate-to-severe POP symptoms. METHODS: The primary outcome was subjective improvement at the 24-month follow-up according to the Patient Global Impression of Improvement (PGI-I) scale. Secondary outcomes included improvement in prolapse-related symptoms measured with the Pelvic Floor Distress Inventory (PFDI-20), improvement in subjective severeness of symptoms according to the Patient Global Impression of Severity (PGI-S) scale and crossover between therapies. The primary safety outcome was the occurrence of adverse events. MAIN OUTCOME MEASURE: PGI-I at 24 months. RESULTS: We included 539 women, with 335 women (62.2%) in the pessary arm and 204 women (37.8%) in the surgery arm. After 24 months, subjective improvement was reported by 134 women (83.8%) in the surgery group compared with 180 women (74.4%) in the pessary group (risk difference 9.4%, 95% CI 1.4-17.3%, P < 0.01). Seventy-nine women (23.6%) switched from pessary to surgery and 22 women (10.8%) in the surgery group underwent additional treatment. Both groups showed a significant reduction in bothersome POP symptoms (P ≤ 0.01) and a reduction in the perceived severity of symptoms (P ≤ 0.001) compared with the baseline. CONCLUSIONS: Significantly more women in the surgery group reported a subjective improvement after 24 months. Both therapies, however, showed a clinically significant improvement of prolapse symptoms. TWEETABLE ABSTRACT: Pessary treatment and vaginal surgery are both efficacious in reducing the presence and severity of prolapse symptoms, although the chance of significant improvement is higher following surgery.

Child outcomes after amnioinfusion compared with no intervention in women with second-trimester rupture of membranes: a long-term follow-up study of the PROMEXIL-III trial.

OBJECTIVE: To assess the effect of transabdominal amnioinfusion or no intervention on long-term outcomes in children born after second-trimester prelabour rupture of the membranes (PROM between 16+0/7 -24+0/7  weeks) and oligohydramnios. POPULATION: Follow up of infants of women who participated in the randomised controlled trial: PPROMEXIL-III (NTR3492). METHODS: Surviving infants were invited for neurodevelopmental assessment up to 5 years of corrected age using a Bayley Scales of Infant and Toddler Development or a Wechsler Preschool and Primary Scale of Intelligence. Parents were asked to complete several questionnaires. MAIN OUTCOME MEASURES: Neurodevelopmental outcomes were measured. Mild delay was defined as -1 standard deviation (SD), severe delay as -2 SD. Healthy long-term survival was defined as survival without neurodevelopmental delay or respiratory problems. RESULTS: In the amnioinfusion group, 18/28 children (64%) died versus 21/28 (75%) in the no intervention group (relative risk 0.86; 95% confidence interval [CI] 0.60-1.22). Follow-up data were obtained from 14/17 (82%) children (10 amnioinfusion, 4 no intervention). In both groups, 2/28 (7.1%) had a mild neurodevelopmental delay. No severe delay was seen. Healthy long-term survival occurred in 5/28 children (17.9%) after amnioinfusion versus 2/28 (7.1%) after no intervention (odds ratio 2.50; 95% CI 0.53-11.83). When analysing data for all assessed survivors, 10/14 (71.4%) survived without mild neurodevelopmental delay and 7/14 (50%) were classified healthy long-term survivor. CONCLUSIONS: In this small sample of women suffering second-trimester PROM and oligohydramnios, amnioinfusion did not improve long-term outcomes. Overall, 71% of survivors had no neurodevelopmental delay. TWEETABLE ABSTRACT: Healthy long-term survival was comparable for children born after second-trimester PROM and treatment with amnioinfusion or no intervention.

Effect of single- versus double-layer uterine closure during caesarean section on postmenstrual spotting (2Close): multicentre, double-blind, randomised controlled superiority trial.

OBJECTIVE: To evaluate whether double-layer uterine closure after a first caesarean section (CS) is superior compared with single-layer uterine closure in terms of postmenstrual spotting and niche development in the uterine caesarean scar. DESIGN: Multicentre, double-blind, randomised controlled superiority trial. SETTING: Thirty-two hospitals in the Netherlands. POPULATION: A total of 2292 women aged ≥18 years undergoing a first CS were randomly assigned to each procedure (1:1): 1144 women were assigned to single-layer uterine closure and 1148 women were assigned to double-layer uterine closure. METHODS: Single-layer unlocked closure and double-layer unlocked closure, with the second layer imbricating the first. MAIN OUTCOME MEASURES: Number of days with postmenstrual spotting during one menstrual cycle 9 months after CS. SECONDARY OUTCOMES: perioperative and menstrual characteristics; transvaginal ultrasound measurements. RESULTS: A total of 774 (67.7%) women from the single-layer group and 770 (67.1%) women from the double-layer group were evaluable for the primary outcome, as a result of drop-out and amenorrhoea. The mean number of postmenstrual spotting days was 1.33 (bootstrapped 95% CI 1.12-1.54) after single-layer closure and 1.26 (bootstrapped 95% CI 1.07-1.45) after double-layer closure (adjusted mean difference -0.07, 95% CI -0.37 to 0.22, P = 0.810). The operative time was 3.9 minutes longer (95% CI 3.0-4.9 minutes, P < 0.001) and niche prevalence was 4.7% higher (95% CI 0.7-8.7%, P = 0.022) after double-layer closure. CONCLUSIONS: The superiority of double-layer closure compared with single-layer closure in terms of postmenstrual spotting after a first CS was not shown. Long-term obstetric follow-up of our trial is needed to assess whether uterine caesarean closure guidelines should be adapted. TWEETABLE ABSTRACT: Double-layer uterine closure is not superior for postmenstrual spotting after a first caesarean; single-layer closure performs slightly better on other outcomes.

Adjuvant VACcination against HPV in surgical treatment of Cervical Intra-epithelial Neoplasia (VACCIN study) a study protocol for a randomised controlled trial.

BACKGROUND: Cervical cancer is caused by Human Papilloma viruses (HPV) and is preceded by precursor stages: Cervical Intraepithelial Neoplasia (CIN). CIN is mostly found in women in their reproductive age and treated with a Loop Electrosurgical Excision Procedure (LEEP). The recurrence or residual disease rate after treatment is up to 17%. These women have a lifelong increased risk of recurrent CIN, cervical cancer and other HPV related malignancies. Furthermore, LEEP treatments are associated with complications such as premature birth. Limited data show that prophylactic HPV vaccination at the time of LEEP reduces recurrence rates, therefore leading to a reduction in repeated surgical interventions and side effect like preterm birth. The primary study objective is to evaluate the efficacy of the nonavalent HPV vaccination in women with a CIN II-III (high-grade squamous intraepithelial lesion (HSIL) lesion who will undergo a LEEP in preventing recurrent CIN II-III after 24 months. METHODS: This study is a randomised, double blinded, placebo controlled trial in 750 patients without prior HPV vaccination or prior treatment for CIN and with histologically proven CIN II-III (independent of their hrHPV status) for whom a LEEP is planned. Included patients will be randomised to receive either three injections with nonavalent (9 HPV types) HPV vaccine or placebo injections (NaCL 0.9%) as a comparator. Treatment and follow-up will be according the current Dutch guidelines. Primary outcome is recurrence of a CIN II or CIN III lesion at 24 months. A normal PAP smear with negative hrHPV test serves as surrogate for absence of CIN. At the start and throughout the study HPV typing, quality of life and cost effectiveness will be tested. DISCUSSION: Although prophylactic HPV vaccines are highly effective, little is known about the effectivity of HPV vaccines on women with CIN. Multiple LEEP treatments are associated with complications. We would like to evaluate the efficacy of HPV vaccination in addition to LEEP treatment to prevent residual or recurrent cervical dysplasia and decrease risks of repeated surgical treatment. TRIAL REGISTRATION: Medical Ethical Committee approval number: NL66775.078.18. Affiliation: Erasmus Medical Centre. Dutch trial register: NL 7938. Date of registration 2019-08-05.

Cognitive outcome in congenital central hypothyroidism: a systematic review with meta-analysis of individual patient data.

Objective: To provide an overview of cognitive and motor outcome, and quality of life (QoL) in patients with congenital central hypothyroidism (CH-C). Design: Systematic review with individual patient data (IPD) meta-analysis. Methods: OVID MEDLINE, EMBASE and PsycInfo were searched from inception to June 11th, 2019. Studies in patients with CH-C, either isolated or with multiple pituitary hormone deficiency (MPHD), were included if CH-C patients could be separated from any additional patient groups. Primary outcomes were full-scale intelligence quotient (FSIQ) and motor outcome; secondary outcome was QoL. Following data-extraction, one-stage IPD meta-analysis was performed, fitting a linear mixed model with FSIQ as dependent variable. Random intercepts were fitted for each study. Results: Six studies measuring FSIQ were eligible for meta-analysis, comprising 30 CH-C patients (20 males; 27 MPHD patients). FSIQ range was wide (64-123). Mean weighted FSIQ was 97 (95% CI: 88-105). Twenty-seven percent had an FSIQ below 85 (≥1 s.d. below norm score), and 10% below 70 (≥2 s.d. below norm score). There was no significant association between FSIQ and sex or age. Age at treatment initiation was available from three studies only, thus impeding a reliable analysis of this parameter. Motor outcome and QoL were each studied in one study; no quantitative analyses could be performed for these outcomes. Conclusion: A wide range in FSIQ scores was observed in CH-C patients. Results should be interpreted with caution, because included patients mainly had MPHD and age at treatment initiation was unknown for the majority of patients.

Risk management plans as a tool for proactive pharmacovigilance: a cohort study of newly approved drugs in Europe.

Risk Management Plans (RMPs) have become a cornerstone in the pharmacovigilance of new drugs in Europe. The RMP was introduced in 2005 to support a proactive approach in gaining knowledge on safety concerns through early planning of pharmacovigilance activities. However, the rate at which uncertainties in the safety profile are resolved through this proactive approach is unknown. We therefore examined the evolution of safety concerns in the RMP after initial approval for a selected cohort of 48 drugs, to provide insight into the knowledge gain over time. We found that 20.7% of the uncertainties existing at approval had been resolved 5 years after approval. Because new uncertainties were included in the RMP at a similar rate, the overall number of uncertainties remained approximately equal. The relatively modest accrual of knowledge, as demonstrated in this study through resolution of uncertainties, suggests that opportunities for optimization exist while ensuring feasible and risk-proportionate pharmacovigilance planning.