Background and aims: Several studies have indicated that birth cohorts are important in explaining trends in alcohol-related mortality. An earlier study from Sweden with data up to 2002 showed that birth cohorts that grew up under periods of more liberal alcohol policies had higher alcohol-related mortality than those cohorts growing up under more restrictive time periods. In spite of increasing alcohol consumption, predictions in 2002 also indicated lower alcohol-related mortality in the future. The aim of this study is to follow-up whether the effects of birth cohorts and the predictions made for Sweden still holds using data up to 2015. Method: The study comprised an age-period-cohort analysis and predictions based on population predictions from Statistics Sweden. The analysis was based on all alcohol-related deaths in the Swedish population between 1969 and 2015 for the cohorts born in the decades 1920 through 1990. Data were restricted to people 15-84 years of age. In total, the analysis covered 68,341 deaths and more than 284 million person-years. Results: Male and female cohorts born in the 1940s to 1950s exhibited the highest alcohol-related mortality, while those born in the 1970s continued to have the lowest alcohol-related mortality rates. The predicted mortality rates for males are still anticipated to decrease somewhat through 2025. Conclusions: The updated age-period-cohort analysis further supports the importance of focusing on restrictive alcohol policies targeting adolescents.

PurposeCompare analyses of a pooled data set on the individual level with aggregate meta-analysis in a multi-database study.MethodsWe reanalysed data on 2.3 million births in a Nordic register based cohort study. We compared estimated odds ratios (OR) for the effect of selective serotonin reuptake inhibitors (SSRI) and venlafaxine use in pregnancy on any cardiovascular birth defect and the rare outcome right ventricular outflow tract obstructions (RVOTO). Common covariates included maternal age, calendar year, birth order, maternal diabetes, and co-medication. Additional covariates were added in analyses with country-optimized adjustment.ResultsCountry adjusted OR (95%CI) for any cardiovascular birth defect in the individual-based pooled analysis was 1.27 (1.17-1.39), 1.17 (1.07-1.27) adjusted for common covariates and 1.15 (1.05-1.26) adjusted for all covariates. In fixed effects meta-analyses pooled OR was 1.29 (1.19-1.41) based on crude country specific ORs, 1.19 (1.09-1.29) adjusted for common covariates, and 1.16 (1.06-1.27) for country-optimized adjustment. In a random effects model the adjusted OR was 1.07 (0.87-1.32). For RVOTO, OR was 1.48 (1.15-1.89) adjusted for all covariates in the pooled data set, and 1.53 (1.19-1.96) after country-optimized adjustment. Country-specific adjusted analyses at the substance level were not possible for RVOTO.ConclusionResults of fixed effects meta-analysis and individual-based analyses of a pooled dataset were similar in this study on the association of SSRI/venlafaxine and cardiovascular birth defects. Country-optimized adjustment attenuated the estimates more than adjustment for common covariates only. When data are sparse pooled data on the individual level are needed for adjusted analyses. Copyright (c) 2016 John Wiley & Sons, Ltd.

Assessing gestational age by ultrasound can introduce a systematic bias due to sex differences in early growth.

BackgroundUp to one-third of women receive prescriptions for systemic antibacterial medications during pregnancy. This paper looks at the association between maternal use of systemic antibacterial medications during pregnancy and childhood cancer risk in the offspring using the prospective data on medication.MethodsA population-based follow-up study was carried out using Danish and Swedish register data. Exposure was maternal redemption of a prescription for a systemic antibacterial in the 3months prior to pregnancy and during pregnancy (exposure window) documented in the national prescription registers, and offspring were followed up from birth to a cancer diagnosis, death, emigration, day before 15th birthday or end of follow-up, whichever came first. Timing, dosage, specific medication types and types of childhood cancer were also considered.ResultsMothers of 35.1% (n=506194) of the children filled at least one prescription for systemic antibacterials during the exposure window. Exposed children had a hazard ratio of 1.08 (95% confidence interval: 0.97, 1.20) compared with unexposed children. Statistically significant results were found for some specific medications (for example, other antibacterials'/Anatomical Therapeutic Chemical code J01X) and combinations of cancer types and specific medications (leukaemia and other antibacterials, and hepatic cancers and tetracyclines).ConclusionsThe results of this study indicate that most antibacterial drugs used during pregnancy were not related to childhood cancer risk in the offspring. However, some may be associated with the development of some specific types of childhood cancers. Our findings need to be replicated in an independent data source. Copyright (c) 2015 John Wiley & Sons, Ltd.

BACKGROUND:The purpose was to describe utilization of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), including trends in prevalence, characteristics of users, drug switching and changes in prescribed doses in a large group of pregnant women across four Nordic countries.METHODS:A drug utilization study based on linked individual-level data from the nationwide prescription- and medical birth registers in Denmark, Iceland, Norway and Sweden. The study population comprised all pregnancies in these countries, resulting in a live birth or stillbirth after gestational week 22 from January 1st 2008 to December 31st 2012 (N = 1 162 470). In addition to the main study drugs SSRIs and SNRIs, we included (concurrent) use of other antidepressants, antipsychotics, anxiolytics and hypnotics.RESULTS:A total of 38 219 (3.3%) pregnancies were exposed to SSRIs and 5 634 (0.5%) to SNRIs. Prevalence of SSRI and SNRI use varied by country (1.8% in Norway to 7.0% in Iceland). Use and prescribed dosages decreased with each passing trimester of pregnancy; prevalence was 2.7% at conception, and 2.1%, 1.7% and 1.3% respectively in 1st, 2nd and 3rd trimester. In 0.6% of pregnancies women filled a prescription before pregnancy and in every trimester. In one third of exposed pregnancies, women were also dispensed anxiolytics, hypnotics or sedatives.CONCLUSION:Use of SSRI and SNRI use during pregnancy varied between the Nordic countries, but the overall prevalence remained low and relatively stable from 2008 to 2012. The low prevalence of use and high proportion of women who discontinue treatment in pregnancy raise questions about adequate treatment of depression in pregnant women.

Bronchopulmonary dysplasia (BPD) is a frequent chronic lung disease in preterm infants, and we aimed to identify factors associated with this condition in infants with respiratory distress syndrome (RDS). This case–control study, using national Swedish data, included 2255 preterm infants, born before 33 gestational weeks. The 667 BPD cases were oxygen dependent at 36 weeks′ postmenstrual age, and the 1558 controls only had RDS. Comparisons included perinatal conditions and pharmacological treatments. Adjusted odds ratios with 95% confidence intervals were calculated in a conditional logistic regression model, with gestational age as the conditioning term. An increased risk of BPD was associated with prelabour preterm rupture of membranes of more than 1 week (3.35, 2.16–5.19), small for gestational age (2.73, 2.11–3.55), low Apgar score (1.37, 1.05–1.81), patent ductus arteriosus (1.70, 1.33–2.18), persistent pulmonary hypertension (5.80, 3.21–10.50), pulmonary interstitial emphysema (2.78, 1.37–5.64), pneumothorax (2.95, 1.85–4.72), late onset infections (2.69, 1.82–3.98), intubation (1.56, 1.20–2.03), chest compressions (2.05, 1.15–3.66) and mechanical ventilation (2.16, 1.69–2.77), but not antenatal corticosteroids. Growth restriction and inflammation increased the risk of BPD in preterm infants and prelabour preterm rupture of membranes, small for gestational age, low Apgar score or need for resuscitation should raise clinical suspicions.

ObjectiveTo assess whether the use of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, mirtazapine, venlafaxine or other antidepressants is associated with late elective termination of pregnancy.DesignCase-control study using data from national registers.SettingDenmark, Finland, and Norway during the period 1996-2007.PopulationA total of 14902 women were included as cases and 148929 women were included as controls.MethodsCases were women with elective termination of pregnancy at 12-23weeks of gestation. Controls continued their pregnancy and were matched with cases on key factors.Main outcome measuresAssociation between antidepressant use during pregnancy and elective termination of pregnancy at 12-23weeks of gestation for fetal anomalies, or for maternal ill health or socio-economic disadvantage.ResultsAt least one prescription of antidepressants was filled by 3.7% of the cases and 2.2% of the controls. Use of any type of antidepressant was associated with elective termination of pregnancy for maternal ill health or socio-economic disadvantage (odds ratio, OR 2.3; 95% confidence interval, 95% CI 2.0-2.5). Elective termination of pregnancy for fetal anomalies was associated with the use of mirtazapine (OR 2.2, 95% CI 1.1-4.5). There was no association between the use of any of the other antidepressants and elective termination of pregnancy for fetal anomalies.ConclusionThe use of any type of antidepressants was associated with elective termination of pregnancy at 12-23weeks for maternal ill health or socio-economic disadvantage, but not with terminations for fetal anomalies. Further studies need to confirm the findings concerning mirtazapine and termination of pregnancy for fetal anomalies.

OBJECTIVE:To assess whether use of specific selective serotonin reuptake inhibitors (SSRIs) or venlafaxine in early pregnancy is associated with an increased risk of birth defects, with emphasis on cardiovascular birth defects even when accounting for lifestyle or other familial confounding.DESIGN:Multicountry population based cohort study, including sibling controlled design.SETTING:Nordic population (Denmark, Finland, Iceland, Norway, and Sweden) identified from nationwide health registers at different periods in 1996-2010.POPULATION:The full study cohort included women giving birth to 2.3 million live singletons. The sibling cohort included 2288 singleton live births. The sibling controlled analyses included sibling pairs who were discordant for exposure to SSRIs or venlafaxine and birth defects.MAIN OUTCOME MEASURE:Prevalence of birth defects, including subtypes of cardiac defects. Odds ratio of birth defects from logistic and conditional logistic regression.RESULTS:Among 36,772 infants exposed to any SSRI in early pregnancy, 3.7% (n=1357) had a birth defect compared with 3.1% of 2,266,875 unexposed infants, yielding a covariate adjusted odds ratio of 1.13 (95% confidence interval 1.06 to 1.20). In the sibling controlled analysis the adjusted odds ratio decreased to 1.06 (0.91 to 1.24). The odds ratios for any cardiac birth defect with use of any SSRI or venlafaxine were 1.15 (95% confidence interval 1.05 to 1.26) in the covariate adjusted analysis and 0.92 (0.72 to 1.17) in the sibling controlled analysis. For atrial and ventricular septal defects the covariate adjusted odds ratio was 1.17 (1.05 to 1.31). Exposure to any SSRI or venlafaxine increased the prevalence of right ventricular outflow tract obstruction defects, with a covariate adjusted odds ratio of 1.48 (1.15 to 1.89). In the sibling controlled analysis the adjusted odds ratio decreased to 0.56 (0.21 to 1.49) for any exposure to SSRIs or venlafaxine and right ventricular outflow tract obstruction defects.CONCLUSIONS:In this large Nordic study no substantial increase was found in prevalence of overall cardiac birth defects among infants exposed to SSRIs or venlafaxine in utero. Although the prevalence of septal defects and right ventricular outflow tract defects was higher in exposed infants, the lack of an association in the sibling controlled analyses points against a teratogenic effect of these drugs.

In North America, 4% to 10% of pregnant women take selective serotonin reuptake inhibitors (SSRIs) for depression. Some studies have reported an increased risk of congenital cardiovascular defects in the infants delivered to women who used SSRIs during pregnancy, although studies on these and other risks have yielded conflicting results. A previous study also reported that venlafaxine, a serotonin-norepinephrine reuptake inhibitor used as an alternative to SSRIs, was associated with some birth defects, but there are limitations in previous study on both SSRIs and venlafaxine, and further study is needed. The current study aimed to evaluate the association between the use of these drugs and risk of specific birth defects. The study population included women who gave birth to a live singleton in Denmark, Finland, Norway, Iceland, and Sweden between 1996 and 2010. Data came from national registries. Exposure in utero was defined as instances when a woman filed a prescription for SSRI from 30 days before the first day of her last period to 97 days after the last period. Birth defects assessed included a range of cardiovascular defects as well as anal atresia, hypospadias, clubfoot, limb reduction defects, craniosynostosis, omphalocele, gastroschisis, and cystic kidneys. Statistical analyses estimated odds ratios (ORs) for these types of birth defects and were adjusted for confounding factors including maternal age at delivery, maternal smoking during pregnancy, concurrent drug use, maternal diabetes, birth order, and country and year of delivery. A sibling-controlled analysis included 2288 singleton live births. Of a full study cohort of 2,303,647 women, 1.6% (36,772) were exposed to SSRIs or venlafaxine during the first trimester. During the study period, the rate of infants exposed to these drugs increased from 0.6% in 1996-2000 to 1.5% in 2001-2005 and then to 2.2% in 2006-2010. Of the 36,772 exposed, 1357 infants (3.7%) had a diagnosis of a major birth defect as compared with 3.2% (71,374 of 2,226,875) of unexposed infants (adjusted OR, 1.13; 95% confidence interval [CI], 1.06-1.20). In exposed infants, 1.5% had overall cardiac birth defects, whereas 1.2% of unexposed infants had diagnoses of cardiac birth defects (OR, 1.15; 95% CI, 1.05-1.26). The prevalence of birth defects was associated with in utero exposure to each specific SSRI, as well as venlafaxine, but not including escitalopram (adjusted ORs between 1.13 and 1.34). However, in the sibling cohort analysis, adjusted OR was 1.06 (95% CI, 0.91-1.24). The study did not find a substantial teratogenic effect of SSRIs or venlafaxine. Although the prevalence of some defects were higher in the group of exposed infants, the lack of association in the sibling control group suggest no substantial increase in the prevalence of birth defects among infants exposed to SSRIs or venlafaxine.

AIM:Bronchopulmonary dysplasia (BPD) is a frequent chronic lung disease in preterm infants, and we aimed to identify factors associated with this condition in infants with respiratory distress syndrome (RDS).METHODS:This case-control study, using national Swedish data, included 2255 preterm infants, born before 33 gestational weeks. The 667 BPD cases were oxygen dependent at 36 weeks' postmenstrual age, and the 1558 controls only had RDS. Comparisons included perinatal conditions and pharmacological treatments. Adjusted odds ratios with 95% confidence intervals were calculated in a conditional logistic regression model, with gestational age as the conditioning term.RESULTS:An increased risk of BPD was associated with prelabour preterm rupture of membranes of more than 1 week (3.35, 2.16-5.19), small for gestational age (2.73, 2.11-3.55), low Apgar score (1.37, 1.05-1.81), patent ductus arteriosus (1.70, 1.33-2.18), persistent pulmonary hypertension (5.80, 3.21-10.50), pulmonary interstitial emphysema (2.78, 1.37-5.64), pneumothorax (2.95, 1.85-4.72), late onset infections (2.69, 1.82-3.98), intubation (1.56, 1.20-2.03), chest compressions (2.05, 1.15-3.66) and mechanical ventilation (2.16, 1.69-2.77), but not antenatal corticosteroids.CONCLUSION:Growth restriction and inflammation increased the risk of BPD in preterm infants and prelabour preterm rupture of membranes, small for gestational age, low Apgar score or need for resuscitation should raise clinical suspicions.

Bronchopulmonary dysplasia (BPD) is a serious, chronic lung disease affecting preterm infants.

To obtain more accurate calculations of maternal and pregnancy-related mortality ratios in Sweden from 1988 to 2007 by using information from national registers and death certificates. A national register-based study, supplemented by a review of death certificates. Sweden, 1988–2007. The deaths of 27 957 women of reproductive age (15–49 years). The Swedish Cause of Death Register, Medical Birth Register, and National Patient Register were linked. All women with a diagnosis related to pregnancy in at least one of these registers within 1 year prior to death were identified. Death certificates were reviewed to ascertain maternal deaths. Maternal mortality ratio (the number of maternal deaths/100 000 live births, excluding and including suicides), and pregnancy-related mortality ratio (number of deaths within 42 days after termination of pregnancy, irrespective of cause of death/100 000 live births) were calculated. Direct and indirect maternal deaths and pregnancy-related deaths. The maternal mortality ratio in Sweden, based on the current method of identifying maternal deaths, was 3.6. After linking registers and reviewing death certificates, we identified 64% more maternal deaths, resulting in a ratio of 6.0 (or 6.5 if suicides are included). The pregnancy-related mortality ratio was 7.3. A total of 478 women died within a year after being recorded with a diagnosis related to pregnancy. By including the 123 cases of maternal death identified in this study, the mean maternal mortality ratio from 1988 to 2007 was 64% higher than reported to the World Health Organization.

OBJECTIVE:To obtain more accurate calculations of maternal and pregnancy-related mortality ratios in Sweden from 1988 to 2007 by using information from national registers and death certificates.DESIGN:A national register-based study, supplemented by a review of death certificates.SETTING:Sweden, 1988-2007.POPULATION:The deaths of 27 957 women of reproductive age (15-49 years).METHODS:The Swedish Cause of Death Register, Medical Birth Register, and National Patient Register were linked. All women with a diagnosis related to pregnancy in at least one of these registers within 1 year prior to death were identified. Death certificates were reviewed to ascertain maternal deaths. Maternal mortality ratio (the number of maternal deaths/100 000 live births, excluding and including suicides), and pregnancy-related mortality ratio (number of deaths within 42 days after termination of pregnancy, irrespective of cause of death/100 000 live births) were calculated.MAIN OUTCOME MEASURES:Direct and indirect maternal deaths and pregnancy-related deaths.RESULTS:The maternal mortality ratio in Sweden, based on the current method of identifying maternal deaths, was 3.6. After linking registers and reviewing death certificates, we identified 64% more maternal deaths, resulting in a ratio of 6.0 (or 6.5 if suicides are included). The pregnancy-related mortality ratio was 7.3. A total of 478 women died within a year after being recorded with a diagnosis related to pregnancy.CONCLUSIONS:By including the 123 cases of maternal death identified in this study, the mean maternal mortality ratio from 1988 to 2007 was 64% higher than reported to the World Health Organization.

IMPORTANCEMaternal psychiatric disease is associated with adverse pregnancy outcomes. Use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy has been associated with congenital anomalies, neonatal withdrawal syndrome, and persistent pulmonary hypertension of the newborn. However, the risk of stillbirth and infant mortality when accounting for previous maternal psychiatric disease remains unknown.OBJECTIVETo study risk of stillbirth and infant mortality associated with use of SSRIs during pregnancy.DESIGN, SETTING, AND PARTICIPANTSPopulation-based cohort study from all Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) at different periods from 1996 through 2007. The study included women with singleton births. We obtained information on maternal use of SSRIs from prescription registries. Maternal characteristics, pregnancy, and neonatal outcomes were obtained from patient and medical birth registries.MAIN OUTCOME MEASURESWe used logistic regression to estimate relative risks of stillbirth, neonatal death, and postneonatal death associated with SSRI use during pregnancy taking into account maternal characteristics and previous psychiatric hospitalization.RESULTSAmong 1,633,877 singleton births in the study, 6054 were stillbirths; 3609, neonatal deaths; and 1578, postneonatal deaths. A total of 29,228 (1.79%) of mothers had filled a prescription for an SSRI during pregnancy. Women exposed to an SSRI presented with higher rates of stillbirth (4.62 vs 3.69 per 1000, P = .01) and postneonatal death (1.38 vs 0.96 per 1000, P = .03) than those who did not. The rate of neonatal death was similar between groups (2.54 vs 2.21 per 1000, P = .24). Yet in multivariable models, SSRI use was not associated with stillbirth (adjusted odds ratio [OR], 1.17; 95% CI, 0.96-1.41; P = .12), neonatal death (adjusted OR, 1.23; 95% CI, 0.96-1.57; P = .11), or postneonatal death (adjusted OR, 1.34; 95% CI, 0.97-1.86; P = .08). Estimates were further attenuated when stratified by previous hospitalization for psychiatric disease. The adjusted OR for stillbirth in women with a previous hospitalization for psychiatric disease was 0.92 (95% CI, 0.66-1.28; P = .62) and was 1.07 (95% CI, 0.84-1.36; P = .59) for those who had not been previously hospitalized. The corresponding ORs for neonatal death were 0.89 (95% CI, 0.58-1.39; P = .62) for women who were hospitalized and 1.14 (95% CI, 0.84-1.56; P = .39) for women who were not. For postneonatal death, the ORs were 1.02 (95% CI, 0.61-1.69; P = .95) for women who were hospitalized and 1.10 (95% CI, 0.71-1.72; P = .66) for women who were not.CONCLUSIONS AND RELEVANCEAmong women with singleton births in Nordic countries, no significant association was found between use of SSRIs during pregnancy and risk of stillbirth, neonatal mortality, or postneonatal mortality. However, decisions about use of SSRIs during pregnancy must take into account other perinatal outcomes and the risks associated with maternal mental illness.

1National Board of Health and Welfare, Stockholm, Sweden, 2Upper Gastrointestinal Research, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden, 3Equity and Health Policy, Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden, 4Division of Clinical Cancer Epidemiology, Department of Oncology, The Sahlgrenska Academy, Onkologiskt Centrum, Gothenburg, Sweden, 5Division of Clinical Cancer Epidemiology, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden, 6Diabetes Centre, Sahlgrenska University Hospital, Gothenburg, Sweden, 7Nordic School of Public Health, Gothenburg, Sweden and 8National Diabetes Register, Register Center, Västra Götaland Region, Sweden

Objective. To investigate the duration of effects and health consequences of earlier antenatal corticosteroid exposure in infants born late preterm or term. Design. Observational cohort study. Setting. Children born after gestational week 34 in Sweden, 19761997, whose mothers were hospitalized for imminent preterm delivery. The children were followed to their 11th birthday. Sample. The cohort consisted of 11 873 infants, of whom 8620 were exposed. Methods. Exposure was estimated at hospital level. Infants born at a hospital practicing antenatal corticosteroid administration were classified as exposed. Estimation of hospital routines was based on questionnaire data, telephone interviews with physicians and pharmacy sales, validated in a random sample of medical records. Logistic regression was used to assess associations with adjustments for pregnancy length, birth year and hospital level. Main outcome measures. Rates and odds ratios of mortality, respiratory distress syndrome, bronchopulmonary dysplasia, epilepsy, cerebral palsy, childhood diabetes, birthweight, length and head circumference for all infants, and for preterm and term infants, respectively. Results. Exposed infants had reduced risks of respiratory distress syndrome (odds ratio 0.54, 95% confidence interval 0.350.83) and small head circumference (odds ratio 0.47, 95% confidence interval 0.360.61), and an increased risk of low Apgar scores (odds ratio 1.40, 95% confidence interval 1.011.94), most pronounced in infants born after gestational week 37. Conclusions. Infants born after gestational week 34 seem to benefit from earlier antenatal corticosteroid administration, with reduced risks of respiratory distress syndrome. However, the treatment was less beneficial for term infants, because they also had increased risk of low Apgar scores.