Processing Speed Partially Mediates Executive Function Impairments in Adolescents with Congenital Heart Disease: Results from a Prospective Cohort Study.

OBJECTIVE: To assess processing speed, fine motor function, attention, and executive function (EF) impairments in adolescents with complex congenital heart disease (CHD) who underwent open-heart surgery during infancy. STUDY DESIGN: We administered a comprehensive neuropsychological test battery evaluating 5 EF domains: working memory, inhibition, cognitive flexibility, fluency, and planning and primary neurodevelopmental processes (PNPs): processing speed, fine motor function, and attention. The sample included 100 adolescents with complex CHD from a previous University Children's Hospital Zurich study, with 104 healthy controls for comparison. We generated scores for each EF domain and computed an EF summary score. Group comparisons and associations were analyzed with multiple regressions accounting for parental education. Mediation analysis explored how PNPs mediate the effect between a CHD diagnosis and EF. RESULTS: In adolescents with complex CHD, all EF domains and the EF summary score were impaired (ß = 0.20 to 0.37, all P < .05). Furthermore, they exhibited slower processing speed (ß = 0.27, P < .01) than healthy controls, with no differences in attention (ß = -0.07, P = .34) and fine motor function (ß = 0.08, P = .34). Processing speed showed a strong association with the EF summary score (ß = 0.60, P < .001) and partially mediated the relationship between CHD diagnosis and the EF summary score (ß = 0.37, 95% CI [0.24, 0.50], P < .001). CONCLUSION: Adolescents with complex CHD show difficulties in EFs and processing speed. Notably, processing speed is strongly associated with EFs and partly accounts for EFs disparities between patients and healthy controls. Early detection and interventions for processing speed difficulties may improve EF outcomes in these patients.

Reference values for plasma and urine trace elements in a Swiss population-based cohort.

OBJECTIVES: Trace elements (TEs) are ubiquitous. TE concentrations vary among individuals and countries, depending on factors such as living area, workplaces and diet. Deficit or excessive TEs concentrations have consequences on the proper functioning of human organism so their biomonitoring is important. The aim of this project was to provide reference values for TEs concentrations in the Swiss population. METHODS: The 1,078 participants to the SKiPOGH cohort included in this study were aged 18-90 years. Their 24-h urine and/or plasma samples were analyzed by inductively coupled plasma mass spectrometry (ICP-MS) to determine 24 TEs concentrations: Ag, Al, As, Be, Bi, Cd, Co, Cr, Cu, Hg, I, Li, Mn, Mo, Ni, Pb, Pd, Pt, Sb, Se, Sn, Tl, V and Zn. Statistical tests were performed to evaluate the influence of covariates (sex, age, BMI, smoking) on these results. Reference intervals for the Swiss adult population were also defined. RESULTS: TEs concentrations were obtained for respectively 994 and 903 persons in plasma and urine matrices. It was possible to define percentiles of interest (P50 and P95) for almost all the TEs. Differences in TEs distribution between men and women were noticed in both matrices; age was also a cofactor. CONCLUSIONS: This first Swiss biomonitoring of a large TEs-panel offers reference values in plasma and in urine for the Swiss population. The results obtained in this study were generally in line with clinical recommendations and comparable to levels reported in other population-based surveys.

Years of Life Lost to COVID-19 and Related Mortality Indicators: An Illustration in 30 Countries.

The concept of (potential) years of life lost is a measure of premature mortality that can be used to compare the impacts of different specific causes of death. However, interpreting a given number of years of life lost at face value is more problematic because of the lack of a sensible reference value. In this paper, we propose three denominators to divide an excess years of life lost, thus obtaining three indicators, called average life lost, increase of life lost, and proportion of life lost, which should facilitate interpretation and comparisons. We study the links between these three indicators and classical mortality indicators, such as life expectancy and standardized mortality rate, introduce the concept of weighted standardized mortality rate, and calculate them in 30 countries to assess the impact of COVID-19 on mortality in the year 2020. Using any of the three indicators, a significant excess loss is found for both genders in 18 of the 30 countries.

[Is mortality an objective indicator for measuring the impact of an epidemic?: The example of Covid-19 in Switzerland]. / La mortalité est-elle un indicateur objectif pour mesurer l'impact d'une épidémie ?. L'exemple du Covid-19 en Suisse.

Measuring the health impact of an epidemic using appropriate indicators is necessarily complex. Mortality does not sum up all the issues, but at least it seems to be an objective indicator. There are, however, a number of different mortality indicators, which do not all convey the same message. During the Covid-19 epidemic in Switzerland, the mortality rate rose by 10.2% in 2020, while life expectancy fell by "only" 0.8%, or 8.3 months, a decline described as "modest" or "complete freefall" depending on when it was published. In reality, the population living in Switzerland in 2020 lost an average of "only" 2.4 days, as the epidemic did not last their entire lives. The use of such an indicator, in comparison with losses due to other factors, would enable us to better estimate the real impact of an epidemic.

Mesurer l'impact sanitaire d'une épidémie à l'aide d'indicateurs appropriés est forcément complexe. La mortalité ne résume pas tous les enjeux mais semble au moins être un indicateur objectif. Il existe cependant différents indicateurs de mortalité ne donnant pas tous le même message. Lors de l'épidémie de Covid-19 en Suisse, le taux de mortalité a augmenté de 10,2 % en 2020, alors que l'espérance de vie n'a diminué « que ¼ de 0,8 %, ou 8,3 mois, recul par ailleurs qualifié de « modeste ¼ ou de « chute libre ¼ selon quand il a été publié. En réalité, la population vivant en Suisse en 2020 n'a perdu en moyenne « que ¼ 2,4 jours car l'épidémie n'a pas duré toute sa vie. L'utilisation d'un tel indicateur, en comparaison avec les pertes dues à d'autres facteurs, permettrait une meilleure estimation de l'impact réel d'une épidémie.

Reproductive Safety of Trazodone After Maternal Exposure in Early Pregnancy: A Comparative ENTIS Cohort Study.

PURPOSE/BACKGROUND: Trazodone is indicated for the treatment of major depressive disorder, but more frequently prescribed off-label at lower doses for insomnia in women of childbearing age. The aim of this study was to assess the risks linked to trazodone exposure during pregnancy for which limited safety data are available. METHODS/PROCEDURES: This multicenter, observational prospective cohort study compared pregnancy outcomes in women exposed to trazodone in early pregnancy against those in a reference group of women exposed to a selective serotonin reuptake inhibitors (SSRIs) between 1996 and 2021. FINDINGS/RESULTS: The sample included 221 trazodone and 869 SSRI-exposed pregnancies. Exposure to trazodone in the first trimester was not associated with a significant difference in the risk of major congenital anomalies (trazodone [1/169, 0.6%]; SSRI [19/730, 2.6%]; adjusted odds ratio, 0.2; 95% confidence interval, 0.03-1.77). The cumulative incidences of live birth were 61% and 73% in the trazodone and reference group, respectively (25% vs 18% for pregnancy loss and 14% vs 10% for pregnancy termination). Trazodone exposure was not associated with a significantly increased risk of pregnancy termination and pregnancy loss. The rate of small for gestational age infants did not differ between the groups. IMPLICATIONS/CONCLUSIONS: This study did not reveal a significant difference in the risk of major congenital anomalies after first trimester exposure to trazodone, compared with SSRI exposure. Although this study is the largest so far, these results call for confirmation through further studies.

Organizational interventions and occupational burnout: a meta-analysis with focus on exhaustion.

PURPOSE: To assess whether organizational interventions are effective to prevent or reduce exhaustion, the core dimension of occupational burnout. METHODS: We searched in PubMed, EMBASE, PsycINFO, and Cochrane Library databases randomized and non-randomized controlled trials conducted among active workers and reporting the outcome as exhaustion score. We calculated the effect sizes using the pre-test-post-test control group design's estimate. We used the random effects model in meta-analysis and Cochrane collaboration's tool for interventions to assess the risk of bias. Overall quality of evidence was appraised using the GRADE. RESULTS: From the 2425 identified records, we assessed 228 full texts for eligibility and included 11 original articles describing 13 studies, 11 on organizational interventions, and 2 on combined inventions. The interventions were participatory (n = 9), focused on workload (n = 2), or on work schedule (n = 2). The overall effect size was - 0.30 ((95% CI = - 0.42; - 0.18), I2 = 62.28%), corresponding to a small reduction in exhaustion with a very low quality of evidence. Combined interventions had a larger effect (- 0.54 (95% CI = - 0.76; - 0.32)) than organizational interventions. When split by type of intervention, both participatory interventions and interventions focused on workload had a benefic effect of exhaustion reduction, with an estimated effect size of - 0.34 (95% CI = - 0.47; - 0.20) and - 0.44 (95% CI = - 0.68, - 0.20), respectively. CONCLUSION: Interventions at combined level in workplaces could be helpful in preventing exhaustion. However, the evidence is still limited, due to a high heterogeneity between studies, bias potential, and small number of eligible studies. This calls for further research, using workload interventions at organizational level, especially in sectors with high risk of job stress and exhaustion.

Comparison of statistical models to predict age-standardized cancer incidence in Switzerland.

This study compares the performance of statistical methods for predicting age-standardized cancer incidence, including Poisson generalized linear models, age-period-cohort (APC) and Bayesian age-period-cohort (BAPC) models, autoregressive integrated moving average (ARIMA) time series, and simple linear models. The methods are evaluated via leave-future-out cross-validation, and performance is assessed using the normalized root mean square error, interval score, and coverage of prediction intervals. Methods were applied to cancer incidence from the three Swiss cancer registries of Geneva, Neuchatel, and Vaud combined, considering the five most frequent cancer sites: breast, colorectal, lung, prostate, and skin melanoma and bringing all other sites together in a final group. Best overall performance was achieved by ARIMA models, followed by linear regression models. Prediction methods based on model selection using the Akaike information criterion resulted in overfitting. The widely used APC and BAPC models were found to be suboptimal for prediction, particularly in the case of a trend reversal in incidence, as it was observed for prostate cancer. In general, we do not recommend predicting cancer incidence for periods far into the future but rather updating predictions regularly.

Association of growth with neurodevelopment in extremely low gestational age infants: a population-based analysis.

To assess the association between postnatal growth and neurodevelopment at the age of 2 years in extremely low gestational age newborns (ELGAN, < 28 weeks' gestation). Retrospective population-based cohort study including all live born ELGAN in 2006-2012 in Switzerland. Growth parameters (weight, length, head circumference, body mass index) were assessed at birth, at hospital discharge home, and 2-year follow-up (FU2). Unadjusted and adjusted regression models assessed associations between growth (birth to hospital discharge and birth to FU2) and neurodevelopment at FU2. A total of 1244 infants (mean GA 26.5 ± 1.0 weeks, birth weight 853 ± 189 g) survived to hospital discharge and were included in the analyses. FU2 was documented for 1049 (84.3%) infants. The mean (± SD) mental and a psychomotor development index at 2FU were 88.9 (± 18.0) and 86.9 (± 17.7), respectively. Moderate or severe neurodevelopmental impairment was documented in 23.2% of patients. Changes of z-scores between birth and discharge and between birth and FU2 for weight were - 1.06 (± 0.85) and - 0.140 (± 1.15), for length - 1.36 (± 1.34), and - 0.40 (± 1.33), for head circumference - 0.61 (± 1.04) and - 0.76 (± 1.32) as well as for BMI 0.22 (± 3.36) and - 0.006 (± 1.45). Unadjusted and adjusted analyses showed that none of the four growth parameters was significantly associated with any of the three outcome parameters of neurodevelopment. This was consistent for both time intervals. CONCLUSION: In the present population-based cohort of ELGAN, neither growth between birth and hospital discharge nor between birth and FU2 were significantly associated with neurodevelopment at age of 2 years. WHAT IS KNOWN: • Studies assessing the association between growth and neurodevelopment in extremely low gestational age newborns (28 weeks' gestation) show conflicting results. WHAT IS NEW: • Neither growth between birth and hospital discharge nor between birth and corrected age of 2 years were significantly associated with neurodevelopment at age of 2 years. • The role of postnatal growth as a predictor of neurodevelopmental outcome during infancy might be smaller than previously assumed.

Integration of Speed and Quality in Measuring Graphomotor Skills: The Zurich Graphomotor Test.

IMPORTANCE: In educational settings, children are under pressure to finish their work successfully within required time frames. Existing tools for assessing graphomotor skills measure either quality or speed of performance, and the speed-accuracy trade-off (SAT) in such tools has never been investigated. OBJECTIVE: We aimed to evaluate a newly developed tool for measuring graphomotor skills, the Zurich Graphomotor Test (ZGT), that assesses both speed and quality of performance. We also explored whether graphomotor tests are affected by the SAT and, if so, the effects it has on graphomotor test results. DESIGN: Cross-sectional study. SETTING: Educational institutions in Switzerland. PARTICIPANTS: Children, adolescents, and young adults (N = 547) ages 4-22 yr (50.3% female). OUTCOMES AND MEASURES: Graphomotor performance was measured with the ZGT and the Developmental Test of Visual Perception, Second Edition (DVTP-2). Standard deviation scores were used to quantify performance. We combined ZGT speed and quality measurements into a performance score adjusted for age and sex. RESULTS: ZGT results indicated a marked developmental trend in graphomotor performance; older children were faster than younger children. Girls showed higher overall performance than boys. The pattern of making more mistakes when being faster and making fewer mistakes when being slower was observed for both graphomotor tests, regardless of time pressure, indicating that the SAT affected the children's scores on both tests. CONCLUSIONS AND RELEVANCE: SAT is influential in graphomotor assessment. The ZGT captures this trade-off by combining accuracy and speed measurements into one score that provides a realistic assessment of graphomotor skills. What This Article Adds: The newly developed ZGT provides occupational therapy practitioners with more precise information on graphomotor skills in children, adolescents, and young adults than currently available tools.

Pregnancy outcome following first-trimester exposure to fingolimod: A collaborative ENTIS study.

This prospective multicentre cohort study investigated pregnancy outcomes after fingolimod use for multiple sclerosis during pregnancy. Pregnancy outcomes of 63 fingolimod and 62 interferon-ß-exposed pregnancies were compared. Rates of major congenital anomalies (MCA) were 4.8% (2/42) in the fingolimod group versus 2.3% (1/44) in the interferon-ß group (odds ratio, 2.2; 95% confidence interval, 0.2-24.6). The adjusted hazard ratio for spontaneous abortion in fingolimod versus interferon-ß-exposed pregnancies was 0.6 (95% confidence interval, 0.2-1.8). Further studies are needed to definitely rule out a moderately increased MCA risk after fingolimod exposure during pregnancy.

A comparison of statistical methods for allocating disease costs in the presence of interactions.

We consider the non-trivial problem of estimating a health cost repartition among diseases from patients' hospital stays' global costs in the presence of multimorbidity, that is, when the patients may suffer from more than one disease. The problem is even harder in the presence of interactions among the disease costs, that is, when the costs of having, for example, two diseases simultaneously do not match the sum of the basic costs of having each disease alone, generating an extra cost which might be either positive or negative. In such a situation, there might be no "true solution" and the choice of the method to be used to solve the problem will depend on how one wishes to allocate the extra costs among the diseases. In this article, we study mathematically how different methods proceed in this regard, namely ordinary least squares (OLS), generalized linear models (GLM), and an iterative proportional repartition (IPR) algorithm, in a simple case with only two diseases. It turned out that only IPR allowed to retrieve the total costs and the unambiguous solution that one would have in a setting without interaction, that is, when no extra cost has to be allocated, while OLS and GLM may produce some negative health costs. Also, contrary to OLS, IPR is taking into account the basic costs of the diseases for the allocation of the extra cost. We conclude that IPR seems to be the most natural method to solve the problem, at least among those considered.

Impact of body mass index and socio-economic status on motor development in children and adolescents.

This study assessed the impact of body mass index (BMI) and socioeconomic status (SES) on the Zurich Neuromotor Assessment, second version (ZNA-2), a battery of tests of motor development in typically developing children between 3 and 18 years of age. BMI measurements and international socio-economic index data were taken from the normative sample of the ZNA-2 for 321 children (158 boys, 163 girls) with a median age of 9.3 years. The age- and gender-adjusted motor performance of these children was quantified and grouped into five components: fine, pure, and gross motor tasks, static balance, and contralateral associated movements. A total score was also calculated. The associations of BMI and SES with the motor scores contribute to less than 5.1% of the total variance.Conclusion: The ZNA-2 for motor development is suitable for measuring motor abilities' development as it is largely independent of the BMI of the child and the SES of the family. What is Known: • Typical motor development, as measured with the Zurich Neuromotor Assessment, second edition (ZNA-2), is strongly dependent on age and gender. • The ZNA-2 focusses on motor performance, motor quality and simple motor skills. What is New: • Higher socio-economic status (SES) is associated with slightly better motor performance as measured by the ZNA-2 total score. • In the ZNA-2 less than 5.1% of the variability in motor performance is attributable to the combined effect of body mass index and SES.

[Analysis of Excess Mortality in Switzerland in 2020 before the 2nd Wave of COVID-19]. / Analyse de la surmortalité en Suisse en 2020 avant la 2e vague de Covid-19.

An analysis of excess mortality in Switzerland in 2020 before the 2nd wave of COVID-19 is proposed by comparing the number of deaths observed in 2020 with those of the last five years, while taking into account population growth. Three periods are identified : before, during and after the 1st wave of COVID-19. Over all these periods, a sub-mortality of -3.3 % is obtained at the national level. However, if we restrict the analysis to the period during the first wave and to the cantons most affected by the virus, we obtain an important excess mortality, up to more than 80 % in Ticino, showing that these calculations depend crucially on when, where and for whom the deaths are counted. Such an analysis will have to be repeated once the 2nd wave is over in order to estimate the overall impact of the epidemic on excess mortality in Switzerland.

Une analyse de la surmortalité en Suisse en 2020 avant la 2e vague de Covid-19 est proposée en comparant le nombre de décès observé en 2020 avec ceux des 5 dernières années, tout en tenant compte de l'augmentation de la population. Trois périodes sont identifiées : avant, pendant et après la 1re vague de Covid-19. Sur l'ensemble de ces périodes, on obtient au niveau national une sous-mortalité de -3,3 %. Si l'on se restreint à la période pendant la 1re vague et aux cantons les plus touchés par le virus, on obtient par contre une surmortalité importante, jusqu'à plus de 80 % au Tessin, montrant que ces calculs dépendent crucialement de quand, où, et pour qui on comptabilise les décès. Une telle analyse sera à répéter une fois la 2e vague terminée afin d'estimer l'impact global de l'épidémie sur la surmortalité en Suisse.

Cognitive outcome of early school-aged children born very preterm is not predicted by early short-term amplitude-integrated electroencephalography.

AIM: We investigated the association between early amplitude-integrated electroencephalography (aEEG) and cognitive outcome in very preterm infants at early school-age. METHODS: This prospective cohort study, conducted in the Department of Neonatology, University Hospital Zurich, Switzerland, from 2009 to 2012, comprised of infants born at <32 weeks of gestation, who underwent continuous aEEG recording during the first 4 days of life. Cognitive outcome was assessed with the Kaufman-Assessment Battery for Children at 5 years. Univariate and multivariate logistic regressions were calculated between aEEG parameters and normal cognitive outcome, defined as an intelligence quotient (IQ) of at least 85. RESULTS: The 118 (52.5% male) infants were born at a mean gestational age of 29.9 weeks and a mean birth weight of 1235 ± 363 g. We followed up 89 children at the age of five, and they had a mean IQ of 97.8 ± 12.7 with 21.3% under 85-and 2.2% had cerebral palsy. Univariate analyses found associations between aEEG measures and normal cognitive outcome, but these were no longer significant after adjustment for confounders. Socioeconomic status and neonatal morbidity were independent predictors of cognitive outcome. CONCLUSION: Early short-term aEEG did not predict later cognitive outcome in our cohort of very preterm infants.

Cohort and Individual Neurodevelopmental Stability between 1 and 6 Years of Age in Children with Congenital Heart Disease.

OBJECTIVE: To assess cohort and individual neurodevelopmental stability in children with congenital heart disease across childhood. STUDY DESIGN: The Reachout Study is a cohort study at the University Children's Hospital Zurich. Data from 148 children with congenital heart disease who underwent cardiopulmonary bypass surgery and 1-, 4-, and 6-year neurodevelopmental assessment were analyzed using mixed models. RESULTS: Cognitive and motor functions of the total cohort improved over time (cognitive: P = .01; motor: P <.001). The prevalence of children with cognitive impairment at age 6 years was 22.3%. Socioeconomic status showed a significant interaction with age on cognitive and motor development (cognitive: P <.001; motor: P = .001): higher socioeconomic status was associated with better neurodevelopmental outcome over time. Weight and head circumference at birth showed a significant interaction with age on motor development (weight: P = .048; head: P = .006). The correlation between test scores at different ages was weak to moderate (cognition: age 1-6 years: rho = 0.20, age 4-6 years: rho = 0.56, motor: age 1-6 years: rho = 0.23, age 4-6 years: rho = 0.50). CONCLUSIONS: Children with congenital heart disease show a mild improvement in cognitive and motor functions within the first 6 years of life, particularly those with higher socioeconomic status and larger head circumference and weight at birth. However, individual stability is moderate at best. Therefore, follow-up assessments are crucial to target therapeutic intervention effectively.

Growth and Intellectual Abilities of Six-Year-Old Children with Congenital Heart Disease.

OBJECTIVE: To determine growth and its relationship to IQ in children with congenital heart disease (CHD) undergoing cardiopulmonary bypass surgery within the first year of life. STUDY DESIGN: Prospective single-center cohort study on 143 children (91 males) with different types of CHD (29 univentricular). Children with recognized genetic disorders were excluded. Growth (weight, height, and head circumference [HC]) was assessed at birth, before surgery, and at 1, 4, and 6 years and compared with Swiss growth charts. IQ was assessed at 6 years using standardized tests. Univariate and multivariable linear regressions were performed to determine predictors of HC and IQ at 6 years. RESULTS: HC at birth was in the low average range (33rd percentile, P = .03), and weight (49th percentile, P = .23) and length (47th percentile, P = .06) were normal. All growth measures declined until the first surgery, with a catch-up growth until 6 years for height (44th percentile, P = .07) but not for weight (39th percentile, P = .003) or for HC (23rd percentile, P < .001). Children undergoing univentricular palliation showed poorer height growth than other types of CHD (P = .01). Median IQ at 6 years was 95 (range 50-135). Lower IQ at 6 years was independently predicted by lower HC at birth, lower socioeconomic status, older age at first bypass surgery, and longer length of intensive care unit stay. CONCLUSIONS: Smaller HC at birth and postnatal factors are predictive of impaired intellectual abilities at school age. Early identification should alert clinicians to provide early childhood interventions to optimize developmental potential.

A quick and qualitative assessment of gross motor development in preschool children.

There is a need for a quick, qualitative, reliable, and easy tool to assess gross motor development for practitioners. The aim of this cross-sectional study is to present the Zurich Neuromotor Assessment-Q (ZNA-Q), which assesses static and dynamic balance in children between 3 and 6 years of age in less than 5 min. A total of 216 children (103 boys; 113 girls; median age 4 years, 4 months; interquartile range 1 year, 3 months) were enrolled from day-care centers, kindergartens, and schools, and were tested with 5 different gross motor tasks: standing on one leg, tandem stance, hopping on one leg, walking on a straight line, and jumping sideways. All ordinal measures (consisting of qualitative measures and scales) featured a marked developmental trend and substantial inter-individual variability. Test-retest reliability was assessed on 37 children. It varied from .17 for tandem stance to .43 for jumping sideways for the individual tasks, and it was .41 and .67 for the static and dynamic balance components, respectively. For the whole ZNA-Q, test-retest reliability was .7.Conclusion: Ordinal scales enable practitioners to gather data on children's gross motor development in a fast and uncomplicated way. It offers the practitioner with an instrument for the exploration of the current developmental motor status of the child. What is Known: • Measurement of gross motor skills in the transitional period between motor mile stones and quantitative assessments is difficult. • Assessment of gross motor skills is relatively easy. What is New: • Supplementary and quick gross motor test battery for children for practitioners. • Normative values of five gross motor skills measured with ordinal scales.

Stabilizing cumulative incidence estimation of pregnancy outcome with delayed entries.

A pregnancy may end up with (at least) three possible events: live birth, spontaneous abortion, or elective termination, yielding a competing risks issue when studying an association between a risk factor and a pregnancy outcome. Cumulative incidences (probabilities to end up with the different outcomes depending on gestational age) can be estimated via the Aalen-Johansen estimate. Another issue is that women are usually not entering such an observational study from the first day of pregnancy, resulting in delayed entries. As in traditional survival analysis, this can be solved by considering "at risk" at a given gestational age only for those women who entered the study before that age. However, the number of women at risk at an early gestational age might be extremely low, such that the estimates of cumulative incidence may increase exaggeratedly at that age because of a single event. One solution to reduce the problem has been recently proposed in the literature, which is to ignore simply those early events, creating a small mean bias but enhancing stability of estimates. In the present paper, we propose an alternative computationally simple approach to tackle this problem that consists to postpone to later gestational ages (rather than to ignore) those early events. The two approaches are compared with respect to bias, stability, and sensitivity on the smoothing parameter via simulations reproducing realistic pregnancy scenarios, and are illustrated with data from a study on the effects of statins on pregnancy outcomes. We also outline that all three approaches are asymptotically equivalent.

Pregnancy outcomes in women on metformin for diabetes or other indications among those seeking teratology information services.

AIMS: Metformin is used to treat type 2 diabetes, polycystic ovary syndrome associated infertility, and gestational diabetes. This study aims to evaluate the safety of metformin in early pregnancy. METHOD: We evaluated the risk of major birth defects and pregnancy losses in a cohort of pregnant women exposed to metformin during the first trimester for different indications relative to a matched unexposed reference group. RESULTS: The risk of major birth defects was 5.1% (20/392) in pregnancies exposed to metformin during the first trimester and 2.1% (9/431) in the reference group [adjusted odds ratio (OR) 1.70; 95% CI 0.70-4.38]. Among metformin users, this risk was 7.8% (17/219) in patients with pre-gestational diabetes and 1.7% (3/173) in those without this diagnosis. Compared to the unexposed reference, the OR for metformin user with diabetes was 3.95 (95% CI 1.77-9.41) and for metformin with other indications it was 0.83 (95% CI 0.18-2.81). The risk of pregnancy losses (spontaneous abortions and stillbirths) was 20.8% in women on metformin during the first trimester and 10.8% in the reference group [adjusted hazard ratio (HR) 1.57; 95% CI 0.90-2.74]. The risks for women on metformin with and without pre-gestational diabetes were 24.0% and 16.8% respectively, with adjusted HR of 2.51 (95% CI 1.44-4.36) and 1.38 (95% CI 0.74-2.59) when compared to the reference. CONCLUSION: Pregnant women with pre-gestational diabetes on metformin are at a higher risk for adverse pregnancy outcomes than the general population. This appears to be due to the underlying diabetes since women on metformin for other indications do not present meaningfully increased risks.