Simulation-based team training for healthcare professionals in pediatric departments: study protocol for a nonrandomized controlled trial.

BACKGROUND: Healthcare systems worldwide face challenges related to patient safety, quality of care, and interprofessional collaboration. Simulation-based team training has emerged as a promising approach to address some of these challenges by providing healthcare professionals with a controlled and safe environment to enhance their teamwork and communication skills. The purpose of this study protocol is to describe an intervention using simulation-based team training in pediatric departments. METHODS: Using a parallel-group, non-randomized controlled trial design, a simulation-based team training intervention will be implemented across four pediatric departments in Denmark. Another four pediatric departments will serve as controls. The intervention implies that healthcare professionals engage in simulation-based team training at a higher quantity and frequency than they did previously. Development of the intervention occurred from April 2022 to April 2023. Implementation of the intervention occurs from April 2023 to April 2024. Evaluation of the intervention is planned from April 2024 to April 2025. All simulation activity both before and during the intervention will be registered, making it possible to compare outcomes across time periods (before versus after) and across groups (intervention versus control). To evaluate the effects of the intervention, we will conduct four analyses. Analysis 1 investigates if simulation-based team training is related to sick leave among healthcare professionals. Analysis 2 explores if the simulation intervention has an impact on patient safety culture. Analysis 3 examines if simulation-based team training is associated with the treatment of critically ill newborns. Finally, Analysis 4 conducts a cost-benefit analysis, highlighting the potential return on investment. DISCUSSION: The implemented simulation-based team training intervention can be defined as a complex intervention. Following the Medical Research Council framework and guidelines, the intervention in this project encompasses feasibility assessment, planning of intervention, implementation of intervention, and rigorous data analysis. Furthermore, the project emphasizes practical considerations such as stakeholder collaboration, facilitator training, and equipment management. TRIAL REGISTRATION: Registered as a clinical trial on clinicaltrials.gov, with the identifier NCT06064045.

Fertility treatment with clomiphene citrate and childhood epilepsy: a nationwide cohort study.

STUDY QUESTION: Is fertility treatment with clomiphene citrate associated with an increased risk of childhood epilepsy, including specific subtypes of epilepsy? SUMMARY ANSWER: Fertility treatment with clomiphene citrate may be associated with a small increased risk of idiopathic generalized epilepsy and focal epilepsy in childhood. WHAT IS KNOWN ALREADY: Clomiphene citrate is among the most commonly prescribed drugs for fertility treatment. However, concerns have been raised as to whether the treatment may harm the developing fetus. STUDY DESIGN, SIZE, DURATION: This nationwide cohort study included all pregnancies in Denmark from 1 July 1995 resulting in a live-born singleton child before 31 December 2013. The children were followed until 31 December 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Children conceived after fertility treatment with clomiphene citrate were identified from the Danish National Prescription Registry. The primary outcomes were childhood epilepsy, idiopathic generalized epilepsy, and focal epilepsy identified from the Danish National Patient Register and from antiepileptic drug prescriptions in the Danish National Prescription Registry. All analyses were conducted using Cox proportional hazards regression. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1 081 291 pregnancies were included; 12 644 children (1.2%) developed epilepsy. Fertility treatment with clomiphene citrate was associated with a small increased risk of childhood epilepsy (hazard ratio [HR]: 1.10; 95% CI: 1.00-1.22), idiopathic generalized epilepsy (HR: 1.41; 95% CI: 1.16-1.72), and focal epilepsy (HR: 1.26; 95% CI: 1.04-1.53). LIMITATIONS, REASONS FOR CAUTION: The increased risk of idiopathic generalized epilepsy may be due to confounding from time stable parental characteristics related to treatment with clomiphene citrate, since the association was strongest with the lowest administered dosage of clomiphene citrate prior to conception, and the association disappeared in a sibling analysis. WIDER IMPLICATIONS OF THE FINDINGS: The increased risk of focal epilepsy may be related to the hormonal treatment, since the association tended to increase with increasing cumulative dosage of clomiphene citrate prior to conception, and the association persisted in a sibling analysis. This finding may be of clinical importance, since alternative hormones are available for fertility treatment. STUDY FUNDING/COMPETING INTEREST(S): Financial support from Aarhus University and the Aase and Ejnar Danielsen Foundation. U.S.K. received personal teaching fees from Merck, outside the submitted work. TRIAL REGISTRATION NUMBER: N/A.

Magnesium sulphate for fetal neuroprotection at imminent risk for preterm delivery: a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Ordinary meta-analyses indicate that magnesium sulphate (MgSO4 ) treatment in women at imminent risk for preterm delivery decreases the offspring's risk of cerebral palsy (CP). However, repetitive testing of cumulative data calls for statistical caution, e.g. by trial sequential analysis (TSA), for which there are previously insufficient samples to draw a firm conclusion. Recently, a randomised controlled trial (RCT) provided additional data that potentially increased the sample size such that a new TSA might detect a statistically significant effect. OBJECTIVES: To assess the possible fetal neuroprotective effect of MgSO4 for women at imminent risk for preterm delivery in an updated systematic review with meta-analysis and TSA. SEARCH STRATEGY: We searched MEDLINE, Embase, Cochrane and ClinicalTrials.gov on 8 October 2019. The search strategy clustered terms describing the MgSO4 intervention and preterm delivery. SELECTION CRITERIA: RCTs. DATA COLLECTION AND ANALYSIS: Two reviewers extracted the data. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using fixed-effects models. A TSA was applied to the primary outcome, CP. The quality of the evidence was assessed using GRADE. The protocol was registered in PROSPERO (registration: CRD42019151441). MAIN RESULTS: We identified six eligible trials (5917 women). MgSO4 intervention in women at imminent risk for preterm birth decreased the offspring's CP risk (meta-analysis RR 0.68, 95% CI 0.54-0.85; TSA RR 0.69, 95% CI 0.48-0.97). CONCLUSIONS: This systematic review with meta-analysis and TSA shows conclusively that MgSO4 , when given to women at imminent risk for preterm delivery, decreases the offspring's CP risk. TWEETABLE ABSTRACT: Antenatal magnesium sulphate decreases the risk of cerebral palsy in children born preterm.

Antenatal magnesium sulphate for the prevention of cerebral palsy in infants born preterm: a double-blind, randomised, placebo-controlled, multi-centre trial.

OBJECTIVE: To study the effect of antenatal magnesium sulphate (MgSO4 ) on cerebral palsy (CP) in a manner that also provides adequate power for a linked trial sequential analysis. DESIGN: Double-blind, randomised, placebo-controlled, multi-centre trial. SETTING: Fourteen Danish obstetric departments. POPULATION: In total, 560 pregnant women at risk for preterm delivery before 32 weeks of gestation were randomised from December 2011 to January 2018. Those women gave birth to 680 children. METHODS: Women were randomised to receive either a loading dose of 5 g MgSO4 followed by 1 g/hour or a placebo in identical volumes. The children were followed up at a corrected age of 18 months or older with a review of their medical charts and with the Ages and Stages Questionnaire. MAIN OUTCOME MEASURE: The primary outcome measure was moderate to severe CP. Secondary outcomes included mortality, neonatal morbidity, blindness and mild CP. RESULTS: The crude rates of moderate to severe CP in the MgSO4 group and the placebo group were 2.0% and 3.3%, respectively. The adjusted odds of moderate to severe CP were lower in the MgSO4 group than in the placebo group (odds ratio 0.61; 95% CI 0.23-1.65). CONCLUSIONS: Antenatal MgSO4 before 32 weeks of gestation decreases the likelihood of moderate to severe CP; these results are entirely consistent with other randomised evidence summarised in the linked trial sequential analysis. TWEETABLE ABSTRACT: Antenatal magnesium sulphate may decrease the risk of moderate to severe cerebral palsy in children born before 32 weeks of gestation.

Birth by cesarean section in relation to adult offspring overweight and biomarkers of cardiometabolic risk.

BACKGROUND: Birth by Cesarean section (C-section) may increase the risk for non-communicable diseases. We aimed to examine the relation of birth by C-section with offspring overweight and markers of cardiometabolic risk in a prospective observational cohort with 20 years of follow-up. METHODS: The Danish Fetal Origins Cohort enrolled 965 pregnant women in 1988-1989. In 2008, a follow-up study of the offspring was completed. The offspring were invited to participate in a clinical examination with measurements of anthropometry and a fasting blood sample (n=443). In addition, 252 offspring completed a self-administered questionnaire with questions on height and weight, leaving us with a study sample of 695 offspring. Offspring overweight at 20 years was defined as body mass index (BMI)⩾25 kg m-2. We also analyzed blood pressure and fasting blood samples for cardiometabolic risk factors including insulin, leptin and adiponectin, and lipid concentrations. RESULTS: In the cohort, 7% were born by C-section, and at age 20 years, 18% of the offspring had a BMI ⩾25 kg m-2. Birth by C-section was associated with increased odds of overweight or obesity at 20 years (Odds ratio=2.17 (95% confidence interval (CI): 1.10, 4.27)) after adjustment for potential confounders. Birth by C-section was also associated with higher serum concentrations of total cholesterol (8.5%, 95% CI: 1.1-16.5), low-density lipoprotein cholesterol (12.6%, 95% CI: 1.0, 25.5), leptin (73.1%, 95% CI: 5.9, 183.1) and Apolipoprotein B (0.08 g l-1, 95% CI: 0.04, 0.15). In contrast, birth by C-section was not related to blood pressure or serum concentrations of insulin, adiponectin, triglycerides, high-density lipoprotein or Apolipoprotein A. CONCLUSION: Birth by C-section was associated with higher frequency of dysmetabolic traits in offspring independently of shared risk factors. Further research aimed at replicating these findings and elucidating the underlying biological mechanisms of this relation is needed.

Leisure time physical activity in 9- to 11-year-old children born moderately preterm: a cohort study.

BACKGROUND: Physical activity is one of the best documented activities with impacts on health in children and adults. Children born preterm show reduced physical and psychosocial function compared to children born at term. This may influence their level of physical activity. Reports on moderately preterm children's physical activities during childhood are limited. Thus, the aim of this study was to compare the leisure time physical activity at age 9-11 years of moderately preterm children with that of children born at term. METHODS: Data from 4941 mother-child pairs from the Aarhus Birth Cohort (1989-91) were used. The cohort gathered clinical information, including gestational age at delivery. Information about parental socio-demographic and lifestyle factors was obtained from questionnaires completed during the second trimester of pregnancy. Information about children's physical activities was reported in a 9- to 11-year follow-up questionnaire completed by parents detailing how many times per week their child participated in sports activities outside of school, hours spent per week playing outside, and hours per week engaged in sedentary activities. Data were analysed using multiple logistic regression with the lowest activity group as a reference group. RESULTS: A total of 158 children (3.2%) were born moderately preterm, i.e., between 32 and 36 completed weeks. Children born moderately preterm participated in sports activities as often as their peers born at term; they also participated in frequent sports activities (≥ 4 times per week) as often as their peers. There were no differences in hours per week spent playing outside or in sedentary activities between the two groups. CONCLUSIONS: Nine- to 11-year-old moderately preterm children participated in sports activities outside school to a similar extent as their peers and engaged in outdoor activities and sedentary activities for the same duration of time per week as their peers born at term.

Hypothermia at neonatal intensive care unit admission was not associated with respiratory disease or death in very preterm infants.

AIM: This study investigated the association between hypothermia and respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD) or death in very preterm infants admitted to a Danish neonatal intensive care unit (NICU). METHODS: We studied 675 infants born at Aalborg University Hospital before 32 weeks and admitted to the NICU from April 1997 to December 2011. Hypothermia was defined as a core temperature of <36.5°C on admission. The primary outcome was severe RDS or death within the first three days of life, and the secondary outcome was BPD or death before 36 postmenstrual weeks. The multivariable logistic regression was adjusted for early-onset infection, gestational age, Apgar score, sex, treatment year and birth weight. RESULTS: Infants with hypothermia had a twofold increase (OR) in the odds for RDS or death (2.03), but the adjusted OR was not statistically significant (1.36). They also demonstrated a twofold increase (OR) in the odds for BPD or death (2.28), but again the adjusted OR was not statistically significant (1.03). CONCLUSION: After adjusting for confounders, we found that the association between hypothermia on admission to the NICU and RDS or death, or BPD or death was statistically insignificant.

Prenatal antidepressant exposure and child behavioural outcomes at 7 years of age: a study within the Danish National Birth Cohort.

OBJECTIVE: To investigate the impact of prenatal antidepressant exposure on behavioural problems in children at 7 years of age. DESIGN: Nationwide population-based study. SETTING: Danish National Birth Cohort. POPULATION: A cohort of 49 178 pregnant women recruited between 1996 and 2002. METHODS: Data obtained from computer-assisted telephone interviews twice during pregnancy were used to identify children born to: (i) depressed women who took antidepressants during pregnancy (n = 210); (ii) depressed women who did not take any antidepressants during pregnancy (n = 231); and (iii) healthy women who were not depressed (n = 48 737). Childhood behavioural problems at 7 years of age were examined using the validated Danish parent-report version of the Strengths and Difficulties Questionnaire (SDQ). MAIN OUTCOME MEASURES: SDQ scores. RESULTS: No associations were observed between prenatal antidepressant exposure and abnormal SDQ scores for overall problem behaviour (adjusted relative risk, aRR 1.00; 95% confidence interval, 95% CI 0.49-2.05), hyperactivity/inattention (aRR 0.99; 95% CI 0.56-1.75), or peer problems (aRR 1.04; 95% CI 0.57-1.91). Although prenatal antidepressant exposure appeared to be associated with abnormal SDQ scores on the subscales of emotional symptoms (aRR 1.68; 95% CI 1.18-2.38) and conduct problems (aRR 1.58; 95% CI 1.03-2.42), these associations were significantly attenuated following adjustment for antenatal mood status (aRR 1.20; 95% CI 0.85-1.70 and aRR 1.19; 95% CI 0.77 1.83, respectively). Untreated prenatal depression was associated with an increased risk of all behavioural outcomes evaluated, compared with unexposed children, with significant attenuation following adjustment for antenatal mood status. CONCLUSIONS: The results of this study suggest that independent of maternal illness, prenatal antidepressant exposure is not associated with an increased risk of behavioural problems in children at 7 years of age. TWEETABLE ABSTRACT: Prenatal antidepressant exposure is not associated with an increased risk of child behavioural problems.

Gestational weight gain in normal weight women and offspring cardio-metabolic risk factors at 20 years of age.

OBJECTIVE: Limited knowledge exists on the long-term implications of maternal gestational weight gain (GWG) on offspring health. Our objective was to examine whether high GWG in normal weight women is associated with adult offspring cardio-metabolic risk factors. METHODS: We used a cohort of 308 Danish women who gave birth in 1988-89 and whose offspring participated in a clinical examination at 20 years of age. Main outcome measures were offspring body mass index (BMI), waist circumference, weight-regulating hormones, blood lipids and glucose metabolism. Associations were assessed using multivariable linear and logistic regression models. RESULTS: A weak positive association was observed between GWG during the first 30 weeks and offspring anthropometry. Each 1-kg increase in maternal GWG was associated with 0.1-kg m(-2) higher (95% confidence interval (CI): 0.01, 0.2) offspring BMI and 10% (95% CI: 0.1%, 20%) higher odds of offspring overweight at the age of 20 years, with similar associations observed in both sexes. However, sex differences were observed for the association between maternal GWG and specific cardio-metabolic risk factors. Hence, a 1-kg increase in GWG was associated with 3.4% (95% CI; 0.8, 6.0%) higher homeostasis model assessment-estimated insulin resistance (HOMA-IR), 3.7% (95% CI: 1.4%, 6.2%) higher insulin and 10.7% (95% CI: 5.7%, 15.9%) higher leptin levels in male offspring. These associations were not observed in females, which may partly be explained by more frequent reports of dieting and physical exercise at follow-up among female offspring. CONCLUSIONS: In normal-weight women, high GWG may have modest long-term implications on offspring cardio-metabolic risk factors at adult age.

Time to subsequent live birth according to mode of delivery in the first birth.

OBJECTIVE: To estimate the rate and time to next live birth by mode of delivery. DESIGN: Hospital-based cohort. SETTING: Aarhus University Hospital (AUH), Denmark. POPULATION: All pregnant women attending AUH were invited to enroll in the Aarhus Birth Cohort (ABC) study between 1989 and 2010 (n = 91,625). METHODS: Women were followed from their first live birth until the subsequent live birth or until censoring due to study end using Cox regression models. MAIN OUTCOME MEASURES: Rate and time to subsequent live birth according to mode of delivery. RESULTS: 46,162 index live births were identified, of which 22,462 (49%) had a subsequent live birth. Women with any type of caesarean had a 6% reduction in the rate of subsequent live birth (HR 0.94, 95% CI 0.89, 0.98), which remained unchanged in the analysis by type (emergency, HR 0.95, 95% CI 0.89, 1.02; elective, HR 0.91, 95% CI 0.85, 0.98) compared with women who had a spontaneous vaginal delivery (SVD). Operative vaginal delivery was associated with an 8% reduction in subsequent live birth rates (HR 0.92, 95% CI 0.86, 0.98) and vaginal delivery complicated by shoulder dystocia with a 19% reduction compared with SVD. Median time to next birth in days was shortest in women with a first caesarean (994 days, 95% CI 973, 1026) and longest in women with a vaginal delivery complicated by shoulder dystocia (1065 days, 95% CI 994, 1191). In women with planned pregnancies, the shortest median time to second birth was in women with breech vaginal deliveries (859 days, 95% CI 737, 1089) and the longest in women with vaginal deliveries complicated by shoulder dystocia (1193 days, 95% CI 1028, 1430). CONCLUSION: The impact of mode of delivery on subsequent rate and time to next birth was minimal in this study. The greatest reduction was among women with assisted vaginal delivery complicated by shoulder dystocia. This study is strengthened by data on pregnancy planning as well as information on complications of pregnancy, delivery and neonatal morbidities, all of which may influence a woman's decision on subsequent birth.

Body mass index in young school-age children in relation to organochlorine compounds in early life: a prospective study.

OBJECTIVE: To investigate the association between maternal pregnancy and estimated postnatal serum concentrations of the organochlorines 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) and body mass index (BMI) z-scores in 5- to 9-year-old children. METHODS: Maternal sera from the INUENDO birth cohort (2002-2004) comprising mother-child pairs (N=1109) from Greenland, Warsaw (Poland), and Kharkiv (Ukraine) were analysed for CB-153 and p,p'-DDE, using gas chromatography-mass-spectrometry, and were grouped into tertiles for statistical analyses. A toxicokinetic model was used to estimate the first 12 months cumulative exposure to the compounds. Associations between these compounds and child age- and sex-specific BMI z-scores were calculated at follow-up (2010-2012), using multiple linear regression analysis. RESULTS: No clear associations between pregnancy CB-153 and p,p'-DDE and child BMI were observed (the pooled differences in BMI z-score (95% confidence interval) comparing 3rd tertile to 1st tertile were -0.07 (-0.32 to 0.18) and -0.10 (-0.30 to 0.10) kg m(-2), respectively). For postnatal CB-153 and p,p'-DDE and BMI, the overall differences in BMI z-score comparing 3rd tertile to 1st tertile were 0.12 (-0.15 to 0.39) and -0.03 (-0.20 to 0.27) kg m(-2), respectively. CONCLUSIONS: This follow-up study of Greenlandic, Polish and Ukrainian populations showed no clear association between pregnancy and postnatal exposure to p,p'-DDE and CB-153 and BMI at the age of 5-9 years.

Risk of adverse pregnancy outcome in women exposed to livestock: a study within the Danish National Birth Cohort.

Maternal infection in pregnancy is a known risk factor for adverse pregnancy outcome, and a number of zoonotic pathogens may constitute a risk to pregnant women and their fetuses. With animal contact as a proxy for the risk of zoonotic infection, this study aimed to evaluate pregnancy outcome in women with self-reported occupational or domestic contact with livestock compared to pregnant women without such contact. The Danish National Birth Cohort collected information on pregnancy outcome from 100 418 pregnant women (1996-2002) from which three study populations with occupational and/or domestic exposure to livestock and a reference group of women with no animal contact was sampled. Outcome measures were miscarriage, very preterm birth (before gestational week 32), preterm birth (before 37 gestational weeks), small for gestational age (SGA), and perinatal death. Adverse reproductive outcomes were assessed in four different exposure groups of women with occupational or domestic exposure to livestock with no association found between exposure to livestock and miscarriage, preterm birth, SGA or perinatal death. These findings should diminish general occupational health concerns for pregnant women with exposures to a range of different farm animals.

Longer time-to-pregnancy in spontaneously conceived pregnancies is associated with lower PAPP-A and free ß-hCG in first trimester screening for Down syndrome.

OBJECTIVE: The aim of this study was to investigate whether subfertility, measured as longer time-to-pregnancy (TTP) in spontaneously conceived pregnancies, affects the first trimester levels of pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotrophin (ß-hCG) and hence the risk estimates in Down syndrome screening. METHODS: The study included a cohort of 10 469 singleton pregnant women who underwent first trimester combined screening and responded to a questionnaire regarding TTP. PAPP-A and free ß-hCG levels were measured between gestational week 8 + 0 and 13 + 6 and were related to TTP. RESULTS: The median PAPP-A and free ß-hCG MoMs were significantly lower in women with a TTP ≥24 months compared with the reference group with a TTP <6 months (PAPP-A: 0.96 vs 1.06 MoM, p = 0.003; free ß-hCG: 1.04 vs 1.12 MoM, p = 0.03). This led to an increased odds for trisomy 21 risk ≥1 : 300 for TTP ≥24 months compared with TTP <6 months, but when adjusting for potential confounders, the odds ratio (OR) lost significance (OR 1.4, 95% confidence interval; 0.8-2.4). CONCLUSION: Time-to-pregnancy ≥24 months in spontaneously conceived pregnancies is associated with decreased levels of PAPP-A and free ß-hCG.

Prenatal antidepressant exposure and behavioral problems in early childhood--a cohort study.

OBJECTIVE: To estimate a potential association between in utero exposure to antidepressants and behavioral problems in childhood. METHOD: Information on exposures was obtained from the Danish National Birth Cohort. We studied the children of 127 mothers who had used antidepressants during pregnancy and compared these to 98 children of mothers with a prenatal depression with no use of antidepressants during pregnancy and 723 children of mothers with no prenatal depression and no use of antidepressant during pregnancy (unexposed). Behavioral problems were assessed at 4 or 5 years of age by the parent-reported Strengths and Difficulties Questionnaire (SDQ). RESULTS: Prenatal antidepressant exposure was not associated with abnormal SDQ scores compared with prenatal exposure to untreated prenatal depression or to no exposure. Untreated prenatal depression was associated with abnormal SDQ scores in the subscales of conduct [adjusted odds ratio (aOR) 2.3 (95% CI, 1.2-4.5)] and prosocial problems [aOR 3.0 (95% CI, 1.2-7.8)] compared with unexposed children. Total SDQ score was higher in children of mothers with untreated prenatal depression. These associations attenuated after adjusting for postnatal maternal psychiatric disease. CONCLUSION: Prenatal antidepressant exposure was not associated with behavioral or emotional problems in early childhood.

Caesarean section and subsequent ectopic pregnancy: a systematic review and meta-analysis.

BACKGROUND: Caesarean section rates are increasing worldwide, and the long-term effects are unknown. OBJECTIVE: To evaluate the risk of subsequent ectopic pregnancy in women with a previous caesarean section, compared with vaginal delivery. SEARCH STRATEGY: Systematic review of the literature using CINAHL, the Cochrane Library, Embase, Medline, PubMed, SCOPUS and Web of Knowledge, published from 1945 until 17 July 2011. SELECTION CRITERIA: Cohort and case-control designs reporting on the mode of delivery and subsequent ectopic pregnancy. Two reviewers independently assessed the titles, abstracts, and full articles to identify eligible studies, using a standardised data collection form, and also assessed the study quality. Reference lists of the studies included were also cross-checked. DATA COLLECTION AND ANALYSIS: Odds ratios (ORs) were combined using a random-effect model to estimate the overall association between caesarean section delivery and the risk of subsequent ectopic pregnancy. MAIN RESULTS: Thirteen studies were included, which recruited a total of 61,978 women. Five studies reported adjustment for confounding factors, and the pooled OR of subsequent ectopic pregnancy following a caesarean section was 1.05 (95% CI 0.51-2.15). The removal of one study that reported outlier results yielded a pooled OR of 0.82 (95% CI 0.42-1.61). The pooled crude OR for all 13 studies was 1.36 (95% CI 0.99-1.88). AUTHOR'S CONCLUSIONS: This review found no evidence of an association between prior caesarean section delivery and the occurrence of a subsequent ectopic pregnancy, but the studies included were of poor or variable quality, and only a small number adjusted for potential confounding factors. Further research of a higher methodological quality is required to assess any potential association between mode of delivery and subsequent ectopic pregnancy.

Randomised trial of cervical cerclage, with and without occlusion, for the prevention of preterm birth in women suspected for cervical insufficiency.

OBJECTIVE: To evaluate the effect of cerclage, with and without cervical occlusion. DESIGN: Multicentre, stratified, randomised controlled trial. SETTING: Hospital-based multicentre study with 18 tertiary centres from nine countries. POPULATION: Women with a history of cervical insufficiency (prophylactic trial) and women with a short cervix (therapeutic trial) were recruited from August 2006 to August 2011. METHODS: A centralised telephone randomisation service with a computer system was used to randomise women to cervical cerclage with or without cervical occlusion. Only the analyst performing the interim analyses was blinded. MAIN OUTCOME MEASURES: The take-home baby rate (number of infants discharged alive from the hospital), gestational age at delivery, and the number of days in the neonatal intensive care unit (NICU). RESULTS: Women (n = 309) were stratified into the prophylactic trial (n = 213) or the therapeutic trial (n = 96). The trial stopped early due to slow recruitment and an interim analysis showing no benefit of occlusion. Final analysis comprised 197 women in the prophylactic trial and 87 women in the therapeutic trial. No added effect of cervical occlusion was found in terms of the take-home baby rate in the prophylactic trial (92 versus 90%, RR 1.03, 95% CI 0.94-1.12) or in the therapeutic trial (81 versus 85%, RR 0.96, 95% CI 0.79-1.16). No effect of cervical occlusion was found in terms of gestational age at delivery and number of days the neonate spent in the NICU. Cervical occlusion was associated with no harm. CONCLUSIONS: Cervical occlusion with cerclage had no significant additional effect.

Elective caesarean section at 38 weeks versus 39 weeks: neonatal and maternal outcomes in a randomised controlled trial.

OBJECTIVES: To investigate whether elective caesarean section before 39 completed weeks of gestation increases the risk of adverse neonatal or maternal outcomes. DESIGN: Randomised controlled multicentre open-label trial. SETTING: Seven Danish tertiary hospitals from March 2009 to June 2011. POPULATION: Women with uncomplicated pregnancies, a single fetus, and a date of delivery estimated by ultrasound scheduled for delivery by elective caesarean section. METHODS: Perinatal outcomes after elective caesarean section scheduled at a gestational age of 38 weeks and 3 days versus 39 weeks and 3 days (in both groups ±2 days). MAIN OUTCOME MEASURES: The primary outcome was neonatal intensive care unit (NICU) admission within 48 hours of birth. Secondary outcomes were neonatal depression, NICU admission within 7 days, NICU length of stay, neonatal treatment, and maternal surgical or postpartum adverse events. RESULTS: Among women scheduled for elective caesarean section at 38⁺³ weeks 88/635 neonates (13.9%) were admitted to the NICU, whereas in the 39⁺³ weeks group 76/637 neonates (11.9%) were admitted (relative risk [RR] 0.86, 95% confidence interval [95% CI] 0.65-1.15). Neonatal treatment with continuous oxygen for more than 1 day (RR 0.31; 95% CI 0.10-0.94) and maternal bleeding of more than 500 ml (RR 0.79; 95% CI 0.63-0.99) were less frequent in the 39 weeks group, but these findings were insignificant after adjustment for multiple comparisons. The risk of adverse neonatal or maternal outcomes, or a maternal composite outcome (RR 1.1; 95% CI 0.79-1.53) was similar in the two intervention groups. CONCLUSIONS: This study found no significant reduction in neonatal admission rate after ECS scheduled at 39 weeks compared with 38 weeks of gestation.

Accuracy of cryptorchidism diagnoses and corrective surgical treatment registration in the Danish National Patient Registry.

PURPOSE: In recent years several Danish studies of the etiology, time trends and long-term health consequences of cryptorchidism have relied on diagnoses and surgical treatments registered in the National Patient Registry. We evaluated the diagnostic accuracy of these registry data. MATERIALS AND METHODS: According to the Danish National Patient Registry, 16,168 males were diagnosed with cryptorchidism and 9,244 surgical treatments for cryptorchidism were performed between January 1, 1995 and October 10, 2009. We randomly selected 500 diagnosed cases, of which 284 had been managed surgically. We requested the medical records from the departments making the diagnoses and performing the surgery. RESULTS: We successfully retrieved medical records for 452 diagnosed cases (90%) and 249 operations (88%). Overall positive predictive value of a registry diagnosis of cryptorchidism was 80% (95% CI 77-84) using the testicular position described by the physician performing the clinical examination as the gold standard. Similarly the positive predictive value of the surgical treatment registration was 99% (95% CI 98-100) using the type of procedure performed. CONCLUSIONS: The data on cryptorchidism in the Danish National Patient Registry are quite accurate. In etiological research the limited misclassification will in most cases only slightly attenuate estimates of the true relative association. Thus, the registry has the potential to serve as a valuable research tool, although caution should be exercised when studying time trends or geographical differences.

Early fetal growth, PAPP-A and free ß-hCG in relation to risk of delivering a small-for-gestational age infant.

OBJECTIVES: To examine early fetal growth, pregnancy-associated plasma protein-A (PAPP-A) and free ß-human chorionic gonadotropin (ß-hCG) in relation to the risk of delivering a small-for-gestational age (SGA) infant. METHODS: Included in the study were 9450 singleton pregnant women who attended the prenatal screening program at Aarhus University Hospital, Denmark, between January 2005 and December 2007. Maternal serum levels of PAPP-A and free ß-hCG were measured between gestational weeks 8 and 13. Two ultrasound examinations were performed, the first at 11-13 weeks and the second at 18-22 weeks, from which gestational age was estimated based on crown-rump length and biparietal diameter, respectively. Early fetal growth was expressed as an index: the ratio between the estimated number of days from the first to the second scan and the actual calendar time elapsed in days. SGA was defined as birth weight < 5(th) centile for gestational age, and the risk of SGA was evaluated according to different cut-offs of the early fetal growth index and the serum markers. RESULTS: PAPP-A < 0.4 MoM combined with an early fetal growth index < 10(th) centile resulted in an increased risk of SGA (odds ratio (OR), 5.8; 95% CI, 2.7-12.7). Low PAPP-A, low free ß-hCG and slow early fetal growth were statistically, independently associated with SGA, and the association between free ß-hCG < 0.3 MoM and SGA was as strong as that between PAPP-A < 0.3 MoM and SGA (OR, 3.1 and 3.0, respectively). CONCLUSION: The combination of slow early fetal growth and low PAPP-A resulted in a nearly six-fold increased risk of delivery of an SGA infant. These findings might improve our chances of early identification of fetuses at increased risk of growth restriction.

Challenges in conducting paediatric trials with off-patent drugs.

INTRODUCTION: For more than two decades several initiatives have emerged to increase recruitment of paediatric patients in drug trials. While trials of newly approved drugs have successfully included paediatric patients in their drug development plan, the collection of safety and efficacy data in paediatric patients treated with off-patent drugs poses a major challenge. AIM: This paper aims to draw attention to problems and solutions across countries in investigator-initiated trials with off-patent drugs and recommendations for improvement. DISCUSSION: Off-patent drugs represent a particular challenge when they are included in a paediatric trial; these trials are frequently investigator-initiated and have limited resources, off-patent drugs are used in clinical settings and the trial protocol must accommodate e.g. flexible dosing and specimen sampling schedules, off-patent drugs typically exist in few formulations and concentrations which necessitates special or imported formulations. Paediatric trials are in some countries confined by e.g. consent from both parents, regardless of whether the Investigational Medicinal Product (IMP) is a well-known drug or a new experimental drug. CONCLUSION: Facilitation of research in off-patent drugs can improve evidence-based and safe treatment for the paediatric population. The following supportive initiatives are recommended: Harmonised regulatory change that improves the consent process in low risk trials to prevent inadequate recruitment. Pharmaceutical expertise should be prioritized to secure the best choice of IMP and supply. Constant focus on flexibility in design to accommodate a multifaceted paediatric population and ensure that trial protocols fit in well with routine clinical care and family life.