Lene Drasbek Huusom

Multiple birth and cerebral palsy in Europe: a multicenter study

Background.  A European multicenter study (Surveillance of Cerebral Palsy in Europe, SCPE) was used to describe changes over time in multiple birth rates and cerebral palsy (CP) rates among multiple born infants, to compare CP rates and clinical types between multiples and singletons, and to analyse the influence of birth order in twins.

Use of evidence based practices to improve survival without severe morbidity for very preterm infants: results from the EPICE population based cohort

Objectives To evaluate the implementation of four high evidence practices for the care of very preterm infants to assess their use and impact in routine clinical practice and whether they constitute a driver for reducing mortality and neonatal morbidity. Design Prospective multinational population based observational study. Setting 19 regions from 11 European countries covering 850 000 annual births participating in the EPICE (Effective Perinatal Intensive Care in Europe for very preterm births) project. Participants 7336 infants born between 24+0 and 31+6 weeks’ gestation in 2011/12 without serious congenital anomalies and surviving to neonatal admission. Main outcome measures Combined use of four evidence based practices for infants born before 28 weeks’ gestation using an “all or none” approach: delivery in a maternity unit with appropriate level of neonatal care; administration of antenatal corticosteroids; prevention of hypothermia (temperature on admission to neonatal unit ≥36°C); surfactant used within two hours of birth or early nasal continuous positive airway pressure. Infant outcomes were in-hospital mortality, severe neonatal morbidity at discharge, and a composite measure of death or severe morbidity, or both. We modelled associations using risk ratios, with propensity score weighting to account for potential confounding bias. Analyses were adjusted for clustering within delivery hospital. Results Only 58.3% (n=4275) of infants received all evidence based practices for which they were eligible. Infants with low gestational age, growth restriction, low Apgar scores, and who were born on the day of maternal admission to hospital were less likely to receive evidence based care. After adjustment, evidence based care was associated with lower in-hospital mortality (risk ratio 0.72, 95% confidence interval 0.60 to 0.87) and in-hospital mortality or severe morbidity, or both (0.82, 0.73 to 0.92), corresponding to an estimated 18% decrease in all deaths without an increase in severe morbidity if these interventions had been provided to all infants. Conclusions More comprehensive use of evidence based practices in perinatal medicine could result in considerable gains for very preterm infants, in terms of increased survival without severe morbidity.

Association of reproductive factors, oral contraceptive use and selected lifestyle factors with the risk of ovarian borderline tumors: A Danish case-control study

ObjectiveThe aim was to examine risk factors for ovarian borderline tumors overall, and according to histological subtype (serous vs. mucinous), in a large Danish population-based case-control study.MethodsOvarian borderline cases and controls were recruited from 1995 to 1999, and personal interviews were conducted. In all, 202 cases and 1,564 randomly selected controls were included. The analysis was performed using multiple logistic regression models.ResultsThe risk of ovarian borderline disease decreased with increasing parity (OR=0.79 per birth, 95% CI: 0.63–0.98) and older age at first birth (OR=0.67 per 5 years, 95% CI: 0.53–0.84). Both a history of breastfeeding and use of oral contraceptives reduced the risk of borderline tumor, the effect being most pronounced for serous tumors. Increasing body mass index (BMI) was associated with elevated risk of serous borderline tumor (OR=1.05 per BMI unit; 95% CI: 1.00–1.10), whereas current smoking was a strong risk factor only for mucinous tumors (OR=2.10; 95% CI: 1.22–3.60). Finally, increasing consumption of milk (all types) was found to increase the risk of borderline disease (OR=1.04 per glass milk per week; 95% CI: 1.02–1.06), and increasing intake of total lactose also increased the risk significantly (OR=1.16 per 50 gram lactose per week; 95% CI: 1.06–1.26).ConclusionThe risk profile of ovarian borderline tumors is similar to that of ovarian carcinomas, and we observed significant etiological differences between serous and mucinous borderline tumors.

Trends in the incidence and mortality of ovarian cancer in Denmark 1978-2002. Comparison with other Nordic countries

Background.  The Nordic countries are well‐known high‐incidence areas of ovarian cancer, but even within the Nordic countries, differences exist.

Trends in incidence of borderline ovarian tumors in Denmark 1978-2006.

Objective. To examine period‐, age‐ and histology‐specific trends in the incidence rate of borderline ovarian tumors in Denmark in 1978–2006. Design. Register‐based cohort study. Setting. Denmark 1978–2006. Population. 5 079 women diagnosed with a borderline ovarian tumor in at least one of two nationwide registries (4 312 epithelial tumors and 767 non‐epithelial/unspecified tumors). Methods. Estimation of overall incidence rates and period‐, age‐ and histology‐specific incidence rates. Age‐adjustment was done using the World Standard Population. To evaluate incidence trends over time, we estimated average annual percentage change and 95% confidence intervals (CI) using log‐linear Poisson models. Main Outcome Measures. Age‐standardized and age‐specific incidence rates and average annual percentage change. Results. The incidence of epithelial borderline ovarian tumors increased from 2.6 to 5.5 per 100 000 women‐years between 1978 and 2006, with an average annual percentage change of 2.6% (95% CI: 2.2–3.0). The median age at diagnosis was 52 years. Women 40 years or older had a higher average annual percentage change than women younger than 40 years. Most tumors were mucinous (49.9%) and serous tumors (44.4%). Women with mucinous tumors were younger at diagnosis (50 years) compared with women with serous tumors (53 years). Women with serous tumors had a higher average annual percentage incidence change than women with mucinous tumors. Conclusions. The incidence rate of borderline ovarian tumors increased significantly in Denmark in 1978–2006. In line with results for ovarian cancer, Denmark had a higher incidence rate of borderline ovarian tumors compared with the other Nordic countries in 1978–2006.

Association of Short Antenatal Corticosteroid Administration-to-Birth Intervals With Survival and Morbidity Among Very Preterm Infants: Results From the EPICE Cohort

Importance Administration-to-birth intervals of antenatal corticosteroids (ANS) vary. The significance of this variation is unclear. Specifically, to our knowledge, the shortest effective administration-to-birth interval is unknown. Objective To explore the associations between ANS administration-to-birth interval and survival and morbidity among very preterm infants. Design, Setting, and Participants The Effective Perinatal Intensive Care in Europe (EPICE) study, a population-based prospective cohort study, gathered data from 19 regions in 11 European countries in 2011 and 2012 on 4594 singleton infants with gestational ages between 24 and 31 weeks, without severe anomalies and unexposed to repeated courses of ANS. Data were analyzed November 2016. Exposure Time from first injection of ANS to delivery in hours and days. Main Outcomes and Measures Three outcomes were studied: in-hospital mortality; a composite of mortality or severe neonatal morbidity, defined as an intraventricular hemorrhage grade of 3 or greater, cystic periventricular leukomalacia, surgical necrotizing enterocolitis, or stage 3 or greater retinopathy of prematurity; and severe neonatal brain injury, defined as an intraventricular hemorrhage grade of 3 or greater or cystic periventricular leukomalacia. Results Of the 4594 infants included in the cohort, 2496 infants (54.3%) were boys, and the mean (SD) gestational age was 28.5 (2.2) weeks and mean (SD) birth weight was 1213 (400) g. Mortality for the 662 infants (14.4%) unexposed to ANS was 20.6% (136 of 661). Administration of ANS was associated with an immediate and rapid decline in mortality, reaching a plateau with more than 50% risk reduction after an administration-to-birth interval of 18 to 36 hours. A similar pattern for timing was seen for the composite mortality or morbidity outcome, whereas a significant risk reduction of severe neonatal brain injury was associated with longer administration-to-birth intervals (greater than 48 hours). For all outcomes, the risk reduction associated with ANS was transient, with increasing mortality and risk for severe neonatal brain injury associated with administration-to-birth intervals exceeding 1 week. Under the assumption of a causal relationship between timing of ANS and mortality, a simulation of ANS administered 3 hours before delivery to infants who did not receive ANS showed that their estimated decline in mortality would be 26%. Conclusions and Relevance Antenatal corticosteroids may be effective even if given only hours before delivery. Therefore, the infants of pregnant women at risk of imminent preterm delivery may benefit from its use.

Long-term follow-up of the risk for cervical intraepithelial neoplasia grade 2 or worse in HPV-negative women after conization

Little research has been conducted on the long‐term value of human papillomavirus (HPV) testing after conization. We investigated whether cytology adds to the value of a negative HPV test for long‐term prediction of cervical intraepithelial neoplasia grade 2 or worse (CIN2+). In addition, we compared risk of CIN2+ following a negative HPV test in women after conization with that in women from the general population. During 2002–2005, 667 women treated for CIN2+ were tested for HPV and cytology 46 months after conization. Only HPV‐negative women were included. Women participating in routine screening were age‐matched with post‐conization HPV‐negative women, leaving 13,230 and 477 women, respectively, for analysis. By linkage to the Pathology Data Bank, we identified all cases of CIN2+ by December 2013. The 3‐, 5‐, 8‐ and 10‐year risks for CIN2+ were 0.7, 0.9, 2.8 and 5.7% after a negative HPV test and 0.5, 0.8, 2.9 and 6.1% in HPV and cytology‐negative women. HPV‐negative women in the general population had similar 3‐year and 5‐year risks of 0.4 and 1.0%; thereafter, they had lower risks of 1.9% at 8 years and 2.7% at 10 years. Our results indicate that HPV testing may be used as a test of cure after conization. In the first 5 years after testing, the risk for CIN2+ of women who were HPV‐negative at 34 months after conization was similar to that of HPV‐negative women in the general population. After 67 years, however, women who have undergone conization may be at higher risk for CIN2+.

Role of human papillomavirus testing and cytology in follow‐up after conization

Adequate follow‐up of women who have undergone conization for high‐grade cervical lesions is crucial in cervical cancer screening programs. We evaluated the performance of testing for high‐risk human papillomavirus (HPV) types, cytology alone, and combined testing in predicting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) after conization.

Persistence and reappearance of high-risk human papillomavirus after conization

OBJECTIVE Women with early cervical cancer or intraepithelial neoplasia grades 2 and 3 (CIN2+) are treated by conization; however, they still have a higher risk for subsequent CIN2+ than the general female population. Persistence of high-risk (HR) human papillomavirus (HPV) is a key factor in the development of CIN2+. We investigated persistence and reappearance of type-specific HR HPV infection after conization and evaluated possible co-factors. METHODS During 2002-2006, cervical swabs from 604 women were collected before conization, at 4-6 months and at 8-12 months after conization. HPV was detected by HC2 and genotyped by LiPAv2. Information on co-factors was collected through a questionnaire. Associations were assessed by multivariate logistic regression analysis. RESULTS HR HPV persistence rate was 9.5%. The α5/6 species were more likely to persist than α9 species (OR, 2.28; 95% CI, 1.11-4.70). For single infections, a doubling in viral load at enrolment increased the risk for persistence by 36% (95% CI, 1.13-1.63). In addition, margin status was associated with risk of persistence. Smoking, oral contraceptive use and severity of the cervical lesion did not significantly affect persistence. Among the HPV infections that had cleared, 2.2% reappeared. CONCLUSION Our study indicates that viral load is important in predicting HPV persistence. The α5/6 species were most likely to persist. However, most of these HPV types have a lower carcinogenic potential than the α7/α9 species and may be by-standers. Further studies are needed to assess whether pre-conization viral load can also predict subsequent CIN2+.

Conclusive meta‐analyses on antenatal magnesium may be inconclusive! Are we underestimating the risk of random error?

Results from meta‐analyses significantly influence clinical practice. Both simulation and empirical studies have demonstrated that the risk of random error (i.e. spurious chance findings) in meta‐analyses is much higher than previously anticipated. Hence, authors and users of systematic reviews and meta‐analyses have a responsibility to carefully consider the risk of random errors to avoid misleading conclusions. Trial sequential analysis is a useful meta‐analytic method for gauging the risk of random error in meta‐analysis and the amount of additional evidence required to reach firm conclusions about the investigated intervention effect(s). We outline the rationale for conducting trial sequential analysis including some examples of the meta‐analysis on antenatal magnesium for women at risk of preterm birth.