Neonatal Outcomes After COVID-19 Vaccination in Pregnancy.

Importance: Better knowledge about neonatal adverse events after COVID-19 vaccination during pregnancy could help address concerns about vaccine safety. Objective: To evaluate the risks of neonatal adverse events after exposure to COVID-19 vaccination during pregnancy. Design, Setting, and Participants: Population-based cohort study including all infants in Sweden and Norway born from June 2021 to January 2023. Unique personal identity numbers were used to link individual information from different national registers. Exposure: Administration of any mRNA vaccine against COVID-19 during pregnancy, irrespective of previous vaccination, number of doses during pregnancy, or vaccine manufacturer. Main Outcomes and Measures: Outcomes were neonatal conditions with bleeding/thrombosis or inflammation/infection; disorders of the central nervous system; circulatory, respiratory, or gastrointestinal problems; and neonatal mortality. Statistical methods included logistic regression adjusted for characteristics of the pregnant individuals, with additional restricted and stratified analyses. Results: Of 196 470 newborn infants included (51.3% male, 93.8% born at term, 62.5% born in Sweden), 94 303 (48.0%) were exposed to COVID-19 vaccination during pregnancy. Exposed infants exhibited no increased odds of adverse neonatal outcomes, and they exhibited lower odds for neonatal nontraumatic intracranial hemorrhage (event rate, 1.7 vs 3.2/1000; adjusted odds ratio [aOR], 0.78 [95% CI, 0.61-0.99]), hypoxic-ischemic encephalopathy (1.8 vs 2.7/1000; aOR, 0.73 [95% CI, 0.55-0.96]), and neonatal mortality (0.9 vs 1.8/1000; aOR, 0.68 [95% CI, 0.50-0.91]). Subgroup analyses found a similar association between vaccination during pregnancy and lower neonatal mortality; subgroups were restricted to infants delivered by individuals unvaccinated before pregnancy, individuals vaccinated before pregnancy, individuals vaccinated after a general recommendation of vaccination during pregnancy was issued, and individuals without COVID-19 infection during pregnancy. Analyses restricted to term infants, singleton births, or infants without birth defects yielded similar results. Stratifying the analysis by vaccine manufacturer did not attenuate the association between vaccination and low neonatal mortality. Conclusions and Relevance: In this large population-based study, vaccination of pregnant individuals with mRNA COVID-19 vaccines was not associated with increased risks of neonatal adverse events in their infants.

Polymicrogyria: epidemiology, imaging, and clinical aspects in a population-based cohort.

Polymicrogyria is estimated to be one of the most common brain malformations, accounting for ∼16% of malformations of cortical development. However, the prevalence and incidence of polymicrogyria is unknown. Our aim was to estimate the prevalence, incidence rate, neuroimaging diversity, aetiology, and clinical phenotype of polymicrogyria in a population-based paediatric cohort. We performed a systematic search of MRI scans at neuroradiology department databases in Stockholm using the keyword polymicrogyria. The study population included all children living in the Stockholm region born from January 2004 to June 2021 with polymicrogyria. Information on the number of children living in the region during 2004-21 was collected from records from Statistics Sweden, whereas the number of births for each year during the study period was collected from the Swedish Medical Birth Register. All MRI scans were re-evaluated, and malformations were classified by a senior paediatric neuroradiologist. The prevalence and yearly incidence were estimated. Clinical data were collected from medical records. A total of 109 patients with polymicrogyria were included in the study. The overall polymicrogyria prevalence in Stockholm was 2.3 per 10 000 children, and the overall estimated yearly incidence between 2004 and 2020 was 1.9 per 10 000 person-years. The most common polymicrogyria distribution was in the frontal lobe (71%), followed by the parietal lobe (37%). Polymicrogyria in the peri-sylvian region was observed in 53%. Genetic testing was performed in 90 patients revealing pathogenic variants in 32%. Additionally, 12% had variants of uncertain significance. Five patients had a confirmed congenital infection, and in six individuals, the cause of polymicrogyria was assumed to be vascular. Epilepsy was diagnosed in 54%. Seizure onset during the first year of life was observed in 44%. The most common seizure types were focal seizures with impaired awareness, followed by epileptic spasms. Thirty-three of 59 patients with epilepsy (56%) were treated with more than two anti-seizure medications, indicating that pharmacoresistant epilepsy is common in polymicrogyria patients. Neurodevelopmental symptoms were observed in 94% of the individuals. This is the first population-based study on polymicrogyria prevalence and incidence. Confirmed genetic aetiology was present in one-third of individuals with polymicrogyria. Epilepsy was common in this patient group, and the majority had pharmacoresistant epilepsy. These findings increase our knowledge about polymicrogyria and will help in counselling patients and their families.

Association between SARS-CoV-2 infection and newly diagnosed hypertension during pregnancy: prospective, population based cohort study.

Objective: To study the association between SARS-CoV-2 infection and newly diagnosed hypertension during pregnancy. Design: Prospective, population based cohort study. Setting: All singleton pregnancies after 22 completed gestational weeks registered in the Swedish Pregnancy Register and the Medical Birth Registry of Norway, from 1 March 2020 to 24 May 2022. Participants: 312 456 individuals available for analysis (201 770 in Sweden and 110 686 in Norway), with pregnancies that reached 42 completed gestational weeks by the end of follow-up in the pregnancy registries, excluding individuals with SARS-CoV-2 infection before pregnancy and those with a diagnosis of pre-existing hypertension or onset of hypertension before 20 gestational weeks. Main outcome measures: Newly diagnosed hypertension during pregnancy was defined as a composite outcome of a diagnosis of gestational hypertension, pre-eclampsia, HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome, or eclampsia, from gestational week 20 to one week after delivery. The association between SARS-CoV-2 infection and hypertension during pregnancy was investigated with a stratified Cox proportional hazard model, adjusting for maternal age, body mass index, parity, smoking, region of birth, education, income, coexisting medical conditions, previous hypertension during pregnancy, number of healthcare visits during the past year, and vaccination against SARS-CoV-2. Pre-eclampsia was also analysed as a separate outcome. Results: Of 312 456 individuals available for analysis, 8% (n=24 566) had SARS-CoV-2 infection any time during pregnancy, 6% (n=18 051) had a diagnosis of hypertension during pregnancy, and 3% (9899) had pre-eclampsia. SARS-CoV-2 infection during pregnancy was not associated with an increased risk of hypertension during pregnancy (adjusted hazard ratio 0.99, 95% confidence interval 0.93 to 1.04) or pre-eclampsia (0.98, 0.87 to 1.10). The results were similar for SARS-CoV-2 infection in all gestational trimesters and in different time periods that corresponded to dominance of different variants of the SARS-CoV-2 virus. Conclusions: This population based study did not find any evidence of an association between SARS-CoV-2 infection during pregnancy and an increased risk of hypertension during pregnancy or pre-eclampsia.

Severe COVID-19 during pregnancy in Sweden, Norway, and Denmark.

INTRODUCTION: Pregnancy is a risk factor for severe coronavirus disease 2019 (COVID-19) and adverse pregnancy outcomes. We aimed to explore maternal characteristics, pregnancy outcomes, vaccination status, and virus variants among pregnant women admitted to intensive care units (ICU) with severe COVID-19. MATERIAL AND METHODS: We identified pregnant women admitted to ICU in Sweden (n = 96), Norway (n = 31), and Denmark (n = 16) because of severe COVID-19, from national registers and clinical databases between March 2020 and February 2022 (Denmark), August 2022 (Sweden), or December 2022 (Norway). Their background characteristics, pregnancy outcome, and vaccination status were compared with all birthing women and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test-positive pregnant women during the same time period. We calculated the number admitted to ICU per 10 000 birthing and per 1000 SARS-CoV-2 test-positive women during the Index, Alpha, Delta, and Omicron periods. RESULTS: Women admitted to ICU had a higher mean body mass index, were more often of non-Scandinavian origin, had on average lower education and income levels, had a higher proportion of chronic and pregnancy-related conditions, delivered preterm, had neonates with low Apgar scores, and had more infants admitted to neonatal care, compared with all birthing and test-positive pregnant women. Of those admitted to ICU, only 7% had been vaccinated before admission. Overall, the highest proportion of women admitted to ICU per birthing was during the Delta period (4.1 per 10 000 birthing women). In Norway, the highest proportion admitted to ICU per test-positive pregnant women was during the Delta period (17.8 per 1000 test-positive), whereas the highest proportion of admitted per test-positive in Sweden and Denmark was seen during the Index period (15.4 and 8.9 per 1000 test-positive, respectively). CONCLUSIONS: Admission to ICU because of COVID-19 in pregnancy was a rare event in the Scandinavian countries, but women who were unvaccinated, of non-Scandinavian origin, and with lower socio-economic status were at higher risk of admission to ICU. In addition, women admitted to ICU for COVID-19 had higher risk of adverse pregnancy outcomes.

Fetal death after the introduction of COVID-19 mitigation measures in Sweden, Denmark and Norway: a registry-based study.

It remains unclear whether the rate of fetal death has changed during the COVID-19 pandemic. We assessed the impact of COVID-19 mitigation measures on fetal death in Sweden (449,347 births), Denmark (290,857 pregnancies) and Norway (261,057 pregnancies) using robust population-based registry data. We used Cox regression to assess the impact of the implementation of pandemic mitigation measures on March 12th, 2020, on miscarriage (fetal loss before gestational week 22) and stillbirth (fetal loss after gestational week 22). A total of 11% of 551,914 pregnancies in Denmark and Norway ended in miscarriage, while the proportion of stillbirths among 937,174 births across the three countries was 0.3%. There was no difference in the risk of fetal death during the year following pandemic mitigation measures. For miscarriage, the combined hazard ratio (HR) for Norway and Denmark was 1.01 (95% CI 0.98, 1.03), and for stillbirth, the combined HR for all three countries was 0.99 (95% CI 0.89, 1.09). We observed a slightly decreased risk of miscarriage during the first 4 months, with an HR of 0.94 (95% CI 0.90, 0.99) after lockdown. In conclusion, the risk of fetal death did not change after the implementation of COVID-19 pandemic mitigation measures in the three Scandinavian countries.

Delivery mode and risk of gastrointestinal disease in the offspring.

INTRODUCTION: The global increase of individuals born by cesarean section with reported levels up to 20% of all deliveries, makes it important to study cesarean section and possible associations that can increase risk of subsequent diseases in children. The aim of the study was to evaluate if cesarean section is associated with increased risk of gastrointestinal disease later in life in a large population-based cohort. MATERIAL AND METHODS: In this national population-based cohort study including all full-term individuals registered in the Medical Birth Register in Sweden between 1990 and 2000, type of delivery (exposure) was collected from the Medical Birth Register. The study population was followed until 2017 with regards to the outcomes: inflammatory bowel disease (Crohn's disease or ulcerative colitis), appendicitis, cholecystitis, or diverticulitis registered in the Swedish National Patient Register. Cox proportional-hazards models compared disease-free survival time between exposed and unexposed. RESULTS: The final study population consisted of 1 102 468 individuals of whom 11.6% were delivered by cesarean section and 88.4% were vaginally delivered. In univariate analysis, cesarean section was associated with Crohn's disease (hazard ratio [HR] 1.13, 95% confidence interval [CI] 1.02-1.25), diverticulosis (HR 1.57, 95% CI 1.13-2.18), and cholecystitis (HR 1.16, 95% CI 1.05-1.28). However, the increased risk only remained for Crohn's disease after adjustment for confounders (HR 1.14, 95% CI 1.02-1.27). No associations between delivery mode and appendicitis, ulcerative colitis, cholecystitis, or diverticulosis were found in the multivariate analysis. CONCLUSIONS: Cesarean section is associated with Crohn's disease later in life, but no other association between delivery mode and gastrointestinal disorders later in life could be found.

Challenges imposed by the COVID-19 pandemic on the Obstetrics and Gynecology residency program: a mixed-methods Swedish survey in the COPE Staff cohort study.

BACKGROUND: To outline how the training program and work situation of residents in Obstetrics and Gynecology (OB-GYN) was affected by the pandemic and to illuminate how residents experienced these changes. METHODS: As part of the COVID-19 in Pregnancy and Early Childhood Staff (COPE Staff) cohort study, between January and May 2021, all participating residents were invited to answer a 28-question online Resident Survey focusing on their specialist education, work situation and experiences during the COVID-19 pandemic. Descriptive statistics were given in percentages for categorical variables and means and standard deviations (SD) for continuous variables. Univariate comparative analyses were performed with the use of the Pearson's Chi-2-test for dichotomous data. The association between residents' worry about the quality and length of their specialist training, with extra clinical hours and transfer to other healthcare institutions were assessed by multivariate logistic regression. Free text responses were analyzed by content analysis. RESULTS: Of the 162 participating OB-GYN residents, 69% expressed concern that the pandemic would have a negative impact on their training. Ninety-five (95%) reported cancellation/postponement of educational activities, 70% performed fewer surgeries and 27% had been transferred to other healthcare institutions where about half reported having gained more general knowledge as a physician. Working extra clinical hours was reported by 69% (7.4 ± 5.3 hours per week) and 14% had considered changing their profession due to the pandemic. Senior residents, compared to junior residents, more often experienced cancelled/postponed clinical rotations (30% vs 15%, P=0.02) and reported performing fewer surgeries (P=0.02). The qualitative analysis highlighted the lack of surgical procedural training as a major concern for residents. CONCLUSION: The COVID-19 pandemic has strongly impacted the training program and work situation of OB-GYN residents in Sweden. Residents were concerned over the negative impact of the pandemic on their training program and senior residents reported more missed educational opportunities as compared to junior residents. Program directors, head of institutions and clinical supervisors can use the problem areas pinpointed by this study to support residents and compensate for missed educational opportunities. While hands-on-training and operating time cannot be compensated for, the authors hope that the findings of the study can help develop new strategies to minimize the negative impact of the current and future pandemics on resident education and work situation.

COVID-19 vaccination in pregnant women in Sweden and Norway.

Vaccines against SARS-CoV-2 are highly effective in preventing severe disease and mortality. Although pregnant women are at increased risk of severe COVID-19, vaccination uptake among pregnant women varies. We used the Swedish and Norwegian population-based health registries to identify pregnant women and to investigate background characteristics associated with not being vaccinated. In this study of 164 560 women giving birth between May 2021 and May 2022, 78% in Sweden and 87% in Norway have been vaccinated with at least one dose at delivery. Not being vaccinated while being pregnant was associated with age below 30 years, low education and income level, birth region other than Scandinavia, smoking during pregnancy, not living with a partner, and gestational diabetes. These results can assist health authorities develop targeted vaccination information to diminish vaccination inequality and prevent severe disease in vulnerable groups.

The association between maternal characteristics and SARS-CoV-2 in pregnancy: a population-based registry study in Sweden and Norway.

The objectives of the current study were to identify risk factors for SARS-CoV-2 positivity, and to address how different testing strategies, choice of comparison group, and population background characteristics may influence observed associations. National registries data for 107,627 pregnant women in Sweden and 81,195 in Norway, were used to identify risk factors for SARS-CoV-2, separately for women under non-universal testing (testing by indication) and universal testing (testing of all pregnant women in contact with a delivery ward). We also investigated underlying characteristics associated with testing for SARS-CoV-2. Overall, 2.1% of pregnant women in Sweden and 1.1% in Norway were test-positive during the pandemic's first 18 months. We show that the choice of test strategy for SARS-CoV-2 provided different associations with risk factors for the disease; for instance, women who were overweight, obese or had gestational diabetes had increased odds of being test-positive under non-universal testing, but not under universal testing. Nevertheless, a consistent pattern of association between being born in the Middle East and Africa and test-positivity was found independent of test strategy and in both countries. These women were also less likely to get tested. Our results are useful to consider for surveillance and clinical recommendations for pregnant women during the current and future pandemics.

Chorioamnionitis and risk of long-term neurodevelopmental disorders in offspring: a population-based cohort study.

BACKGROUND: Evidence indicates that in utero exposure to chorioamnionitis might increase the risk of neurodevelopmental disorders in the offspring. However, findings on this topic have been inconsistent. OBJECTIVE: To examine the association between chorioamnionitis and neurodevelopmental disorders in offspring. STUDY DESIGN: This was a retrospective population-based cohort study in Sweden. A total of 2,228,280 singleton live births and stillbirths between 1998 and 2019 were included in our study population. Data on maternal characteristics and neurodevelopmental disorders in offspring were obtained by individual record-linkages of nationwide Swedish registries. Chorioamnionitis was identified using the National Medical Birth Register. Inpatient and outpatient diagnoses were obtained for cerebral palsy, autism, attention deficit hyperactivity disorder, epilepsy, and intellectual disability. Multivariable Cox proportional hazards regression was used to estimate the association between chorioamnionitis and each neurodevelopmental disorder with adjusted hazard ratios and 95% confidence intervals. A causal mediation analysis of the relationship between chorioamnionitis and neurodevelopmental disorders with preterm delivery (<37 weeks) was performed. RESULTS: A total of 5770 (0.26%) offspring were exposed to chorioamnionitis during pregnancy. During the study's follow-up time there were 4752 (0.21%) cases of cerebral palsy, 17,897 (0.80 %) cases of epilepsy, 50,570 (2.27 %) cases of autism, 114,087 (5.12%) cases of attention deficit hyperactivity disorder, and 14,574 (0.65%) cases of intellectual disability. After adjusting for potential confounders, exposure to chorioamnionitis increased the hazard ratios of cerebral palsy (adjusted hazard ratio, 7.43; 95% confidence interval, 5.90-9.37), autism (adjusted hazard ratio, 1.43; 95% confidence interval, 1.21-1.68), attention deficit hyperactivity disorder (adjusted hazard ratio, 1.17; 95% confidence interval, 1.03-1.33), and intellectual disability (adjusted hazard ratio, 1.99; 95% confidence interval, 1.53-2.58), whereas chorioamnionitis was not significantly associated with higher rates of epilepsy in offspring. Mediation analysis revealed that these associations were mainly explained through preterm delivery; however, increased risk was also observed among term infants. CONCLUSION: Chorioamnionitis increases the risk of neurodevelopmental disorders, particularly cerebral palsy, autism, attention deficit hyperactivity disorder, and intellectual disability. These associations were mainly mediated through preterm delivery. Efforts for timely identification and appropriate interventions to treat infections during pregnancy will have sustained benefits in reducing the burden of neurologic complications in children at the population level.

Association of SARS-CoV-2 Vaccination During Pregnancy With Pregnancy Outcomes.

Importance: Data about the safety of vaccines against SARS-CoV-2 during pregnancy are limited. Objective: To examine the risk of adverse pregnancy outcomes after vaccination against SARS-CoV-2 during pregnancy. Design, Setting, and Participants: This registry-based retrospective cohort study included 157 521 singleton pregnancies ending after 22 gestational weeks from January 1, 2021, until January 12, 2022 (Sweden), or January 15, 2022 (Norway). The Pregnancy Register in Sweden and the Medical Birth Registry of Norway were linked to vaccination and other registries for identification of exposure and background characteristics. Exposures: Data on mRNA vaccines-BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)-and 1 viral vector vaccine-AZD1222 (AstraZeneca)-were collected from national vaccination registries. Main Outcomes and Measures: The risk of preterm birth and stillbirth was evaluated using Cox regression models, with gestational day as the time metric and vaccination as a time-dependent exposure variable. The risk of small for gestational age, low Apgar score, and neonatal care admission was evaluated using logistic regression. Random-effects meta-analysis was used to combine results between countries. Results: Among the 157 521 singleton births included in the study (103 409 in Sweden and 54 112 in Norway), the mean maternal age at the time of delivery was 31 years, and 28 506 (18%) were vaccinated against SARS-CoV-2 (12.9% with BNT162b2, 4.8% with mRNA-1273, and 0.3% with AZD1222) while pregnant. A total of 0.7%, 8.3%, and 9.1% of individuals delivering were vaccinated during the first, second, and third trimester, respectively. Vaccination against SARS-CoV-2 was not significantly associated with increased risk of preterm birth (6.2 vs 4.9 per 10 000 pregnancy days; adjusted hazard ratio [aHR], 0.98 [95% CI, 0.91 to 1.05]; I2 = 0%; P for heterogeneity = .60), stillbirth (2.1 vs 2.4 per 100 000 pregnancy days; aHR, 0.86 [95% CI, 0.63 to 1.17]), small for gestational age (7.8% vs 8.5%; difference, -0.6% [95% CI, -1.3% to 0.2%]; adjusted OR [aOR], 0.97 [95% CI, 0.90 to 1.04]), low Apgar score (1.5% vs 1.6%; difference, -0.05% [95% CI, -0.3% to 0.1%]; aOR, 0.97 [95% CI, 0.87 to 1.08]), or neonatal care admission (8.5% vs 8.5%; difference, 0.003% [95% CI, -0.9% to 0.9%]; aOR, 0.97 [95% CI, 0.86 to 1.10]). Conclusions and Relevance: In this population-based study conducted in Sweden and Norway, vaccination against SARS-CoV-2 during pregnancy, compared with no SARS-CoV-2 vaccination during pregnancy, was not significantly associated with an increased risk of adverse pregnancy outcomes. The majority of the vaccinations were with mRNA vaccines during the second and third trimesters of pregnancy, which should be considered in interpreting the findings.

Analysis of Neurodevelopmental Disorders in Offspring of Mothers With Eating Disorders in Sweden.

Importance: Despite indices of impaired neurodevelopment in children of mothers with eating disorders, it remains unclear whether these children are at increased risk of developing neuropsychiatric diseases. Objective: To evaluate the association between maternal eating disorders, whether preexisting or ongoing during pregnancy, and offspring neuropsychiatric disease risk. Design, Setting and Participants: This population-based prospective cohort study used the Swedish Medical Birth Registry and identified singleton births registered between from January 1, 1990, and December 31, 2012. Children of exposed mothers with eating disorders were matched with comparator children of mothers without diagnoses of eating disorders. To adjust for unmeasured shared familial factors, a cluster of exposed children with full maternal cousin comparators was identified. Follow-up was completed on December 31, 2017. Data were analyzed from August 31, 2020, to April 30, 2021. Exposures: Maternal eating disorder diagnosis. Main Outcomes and Measures: All children were followed up from 1 year of age for autism spectrum disorder (ASD) and from 3 years of age for attention-deficit/hyperactivity disorder (ADHD). The relative risk of ASD and ADHD was assessed among exposed children, stratified by eating disorder subtype and ongoing vs previous disease, adjusted for potential confounders, including parental socioeconomic status and comorbidities. Results: Among the 52 878 children included in the analysis, maternal eating disorder exposure (n = 8813) was associated with an increased risk of ADHD (hazard ratio [HR] for anorexia nervosa, 1.42 [95% CI, 1.23-1.63]; HR for bulimia nervosa, 1.91 [95% CI, 1.43-2.54]; and HR for unspecified eating disorder, 2.00 [95% CI, 1.72-2.32]) and ASD (HR for anorexia nervosa, 2.04 [95% CI, 1.58-2.63]; HR for bulimia nervosa, 2.70 [95% CI, 1.68-4.32]; and HR for unspecified eating disorder, 1.95 [95% CI, 1.49-2.54]). After adjustment for parental confounders, the risk of ADHD remained significantly increased, whereas the risk of ASD in children to mothers with bulimia nervosa was no longer significant. Ongoing anorexia nervosa was associated with a significantly higher risk of ADHD (HR, 2.52 [95% CI, 1.86-3.42]) and ASD (HR, 3.98 [95% CI, 2.49-6.27]) compared with previous disease (HRs, 1.26 [95% CI, 1.06-1.48] and 1.81 [95% CI, 1.38-2.38], respectively). Results based on the family cluster were similar to those of the main analysis for maternal exposure to anorexia nervosa and bulimia nervosa. Conclusions and Relevance: These findings suggest that children born to mothers with eating disorders, in particular disorders that were active during pregnancy, were at increased risk of developing ADHD and ASD. The association could not be fully explained by parental psychiatric comorbidities, and among children of mothers with anorexia nervosa and bulimia nervosa, it could not be explained by unmeasured familial confounding.

Preterm birth after the introduction of COVID-19 mitigation measures in Norway, Sweden, and Denmark: a registry-based difference-in-differences study.

BACKGROUND: Although some studies have reported a decrease in preterm birth following the start of the COVID-19 pandemic, the findings are inconsistent. OBJECTIVE: This study aimed to compare the incidences of preterm birth before and after the introduction of COVID-19 mitigation measures in Scandinavian countries using robust population-based registry data. STUDY DESIGN: This was a registry-based difference-in-differences study using births from January 2014 through December 2020 in Norway, Sweden, and Denmark. The changes in the preterm birth (<37 weeks) rates before and after the introduction of COVID-19 mitigation measures (set to March 12, 2020) were compared with the changes in preterm birth before and after March 12 from 2014 to 2019. The differences per 1000 births were calculated for 2-, 4-, 8-, 12-, and 16-week intervals before and after March 12. The secondary analyses included medically indicated preterm birth, spontaneous preterm birth, and very preterm (<32 weeks) birth. RESULTS: A total of 1,519,521 births were included in this study. During the study period, 5.6% of the births were preterm in Norway and Sweden, and 5.7% were preterm in Denmark. There was a seasonal variation in the incidence of preterm birth, with the highest incidence during winter. In all the 3 countries, there was a slight overall decline in preterm births from 2014 to 2020. There was no consistent evidence of a change in the preterm birth rates following the introduction of COVID-19 mitigation measures, with difference-in-differences estimates ranging from 3.7 per 1000 births (95% confidence interval, -3.8 to 11.1) for the first 2 weeks after March 12, 2020, to -1.8 per 1000 births (95% confidence interval, -4.6 to 1.1) in the 16 weeks after March 12, 2020. Similarly, there was no evidence of an impact on medically indicated preterm birth, spontaneous preterm birth, or very preterm birth. CONCLUSION: Using high-quality national data on births in 3 Scandinavian countries, each of which implemented different approaches to address the pandemic, there was no evidence of a decline in preterm births following the introduction of COVID-19 mitigation measures.

Association between travel time to delivery unit and unplanned out-of-hospital birth, infant morbidity and mortality: A population-based cohort study.

INTRODUCTION: Over the last decade, a number of delivery units have been closed in Sweden, justified by both economic incentives and patient safety issues. However, concentrating births to larger delivery units naturally increases travel time for some parturient women, which may lead to unintended negative consequences. We aimed to investigate the association between travel time to delivery unit and unplanned out-of-hospital birth, and subsequent infant morbidity and mortality. MATERIAL AND METHODS: We performed a population-based cohort study including 365 604 women in the Swedish Pregnancy Register, giving birth between 2014 and 2017. Modified Poisson regression was used to investigate the association between travel time from home address to actual delivery unit, based on geographic information system analysis, and risk of an unplanned out-of-hospital birth. Analyses were stratified by parity and urban/rural residence. Lastly, the associations between an unplanned out-of-hospital birth and severe infant morbidity, stillbirth, peripartum, perinatal and neonatal mortality were investigated. RESULTS: Of those with an unplanned out-of-hospital birth (n = 2159), 65% had a travel time up to 30 minutes. A travel time between 31 and 60 minutes was associated with a doubled risk of unplanned out-of-hospital birth (adjusted risk ratio [RR] 1.96, 95% confidence interval [CI] 1.74-2.22) and women with a travel time of more than 1 hour had an adjusted RR of 3.19 (95% CI 2.64-3.86), compared with those with a travel time of <30 minutes. No difference in results was seen when stratified for parity and urban/rural residence. No association was found between unplanned out-of-hospital birth and severe infant morbidity. Significant associations were found in crude analyses for stillbirth (RR 1.85, 95% CI 1.09-3.13), peripartum (RR 1.93, 95% CI 1.18-3.16), perinatal (RR 2.03, 95% CI 1.28-3.23) and neonatal mortality (RR 3.08, 95% CI 1.27-7.46), although neonatal mortality was very rare (2.3/1000 out-of-hospital births). Similar effect estimates were found in the adjusted analyses, though no longer significant. CONCLUSIONS: Although the majority of unplanned out-of-hospital births occurred in the group of women with a travel time of 0-30 minutes, increasing travel time to a delivery unit is associated with unplanned out-of-hospital birth, which may increase the risk of mortality.

Genetic effects of allergen-specific IgE levels on exhaled nitric oxide in schoolchildren with asthma: The STOPPA twin study.

BACKGROUND: Exhaled nitric oxide and blood eosinophils are clinical asthma T-helper type 2 markers in use. Immunoglobulin E (IgE) is often involved in the inflammation associated with atopic asthma. The effect of both blood eosinophils and allergen-specific IgE on exhaled nitric oxide levels is not completely understood. Twin-design studies can improve understanding of the underlying contribution of genetically and/or environmentally driven inflammation markers in asthma. Our aim was to disentangle the covariance between asthma and exhaled nitric oxide into genetic and environmental contributions that can account for inflammation markers in a paediatric population. METHODS: This population-based, cross-sectional twin study enrolled 612 monozygotic (MZ) and same-sex dizygotic (DZ) schoolchildren. Multivariate structural equation modelling was utilized to separate the covariance between asthma and exhaled nitric oxide into genetic and/or environmental effects, taking allergen-specific IgE level and blood eosinophil count into account while controlling for confounding factors. RESULTS: The cross-twin/cross-trait correlations had a higher magnitude in the MZ twins than in the DZ twins, indicating that genes affect the association. The likelihood ratio test for model fitting resulted in the AE model (ie additive genetic effects, A, and non-shared environmental effects, E) as the most parsimonious. A majority, 73%, of the phenotypic correlation between asthma and exhaled nitric oxide, r = .19 (0.05-0.33), was attributable to genetic effects which mainly was due to the allergen-specific IgE level. CONCLUSIONS: This study indicates that the association between asthma and exhaled nitric oxide in children is to a large extent explained by genetics via allergen-specific IgE level and not blood eosinophils. This might partly explain the clinical heterogeneity in this group. A next step could be to include allergen-specific IgE level in multivariate omic studies.

Antibiotic use and the development of inflammatory bowel disease: a national case-control study in Sweden.

BACKGROUND: Use of antibiotics in early life has been linked with childhood inflammatory bowel disease (IBD), but data for adults are mixed, and based on smaller investigations that did not compare risk among siblings with shared genetic or environmental risk factors. We aimed to investigate the association between antibiotic therapy and IBD in a large, population-based study. METHODS: In this prospective case-control study, we identified people living in Sweden aged 16 years or older, with a diagnosis of IBD based on histology and at least one diagnosis code for IBD or its subtypes (ulcerative colitis and Crohn's disease). We identified consecutive patients with incident IBD from the ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) study, cross-referenced with the Swedish Patient Register and the Prescribed Drug Register. We accrued data for cumulative antibiotic dispensations until 1 year before time of matching for patients and up to five general population controls per patient (matched on the basis of age, sex, county, and calendar year). We also included unaffected full siblings as a secondary control group. Conditional logistic regression was used to estimate multivariable-adjusted odds ratios (aORs) and 95% CIs for diagnosis of incident IBD. FINDINGS: We identified 23 982 new patients with IBD (15 951 ulcerative colitis, 7898 Crohn's disease, 133 unclassified IBD) diagnosed between Jan 1, 2007, and Dec 31, 2016. 117 827 matched controls and 28 732 siblings were also identified. After adjusting for several risk factors, aOR in patients who had used antibiotics versus those who had never used antibiotics was 1·88 (95% CI 1·79-1·98) for diagnosis of incident IBD, 1·74 (1·64-1·85) for ulcerative colitis, and 2·27 (2·06-2·49) for Crohn's disease. aOR was higher in patients who had received one antibiotic dispensation (1·11, 1·07-1·15), two antibiotic dispensations (1·38, 1·32-1·44), and three or more antibiotic dispensations (1·55, 1·49-1·61) than patients who had none. Increased risk was noted for ulcerative colitis (aOR with three or more antibiotic dispensations 1·47, 95% CI 1·40-1·54) and Crohn's disease (1·64, 1·53-1·76) with higher estimates corresponding to broad-spectrum antibiotics. Similar but attenuated results were observed when siblings were used as the reference group, with an aOR of 1·35 (95% CI 1·28-1·43) for patients who had received three or more dispensations, compared with general population controls. INTERPRETATION: Higher cumulative exposure to systemic antibiotic therapy, particularly treatments with greater spectrum of microbial coverage, may be associated with a greater risk of new-onset IBD and its subtypes. The association between antimicrobial treatment and IBD did not appear to differ when predisposed siblings were used as the reference controls. Our findings, if substantiated by longer-term prospective studies in humans or mechanistic preclinical investigations, suggest the need to further emphasise antibiotic stewardship to prevent the rise in dysbiosis-related chronic diseases, including IBD. FUNDING: National Institutes of Health. Crohn's and Colitis Foundation.

Fetal and early life antibiotics exposure and very early onset inflammatory bowel disease: a population-based study.

OBJECTIVE: Earlier studies on antibiotics exposure and development of IBD (Crohn's disease (CD) and ulcerative colitis (UC)) may have been biased by familial factors and gastroenteritis. We aimed to estimate the association between antibiotics during pregnancy or infantile age and very early onset (VEO) IBD. DESIGN: In this cohort study of 827 239 children born in Sweden between 2006 and 2013, we examined the link between exposure to systemic antibiotics and VEO-IBD (diagnosis <6 years of age), using Cox proportional hazard regression models. Information on antibiotics and IBD was retrieved from the nationwide population-based Swedish Prescribed Drug Register and the National Patient Register. We specifically examined potential confounding from parental IBD and gastroenteritis. RESULTS: Children exposed to antibiotics during pregnancy were at increased risk of IBD compared with general population controls (adjusted HR (aHR) 1.93; 95% CI 1.06 to 3.50). Corresponding aHRs were 2.48 (95% CI 1.01 to 6.08) for CD and 1.25 (95% CI 0.47 to 3.26) for UC, respectively. For antibiotics in infantile age, the aHR for IBD was 1.11 (95% CI 0.57 to 2.15); for CD 0.72 (95% CI 0.27 to 1.92) and 1.23 (95% CI 0.45 to 3.39) for UC. Excluding children with gastroenteritis 12 months prior to the first IBD diagnosis retained similar aHR for antibiotics during pregnancy and CD, while the association no longer remained significant for IBD. CONCLUSION: We found that exposure to antibiotics during pregnancy, but not in infantile age, is associated with an increased risk of VEO-IBD regardless of gastroenteritis. The risk increase for exposure in pregnancy may be due to changes in the microbiota.

Associations Between Asthma and Sensitization to Pet or Pollen Allergens in Young Swedish Twins - The STOPPA Study.

BACKGROUND: An association between childhood asthma and IgE sensitization has been established, but our understanding of the genetic and environmental contribution to it is incomplete. Our aim was to estimate the associations and dose-response relationship between asthma and sensitization to airborne allergens in Swedish 9- to 14-year-old twins. Additionally, we aimed to explore the importance of familial confounding from shared genes and environment using co-twin controls. METHODS: In the STOPPA cohort, 752 same-sex twin children were screened with Phadiatop® (Thermo Fisher Scientific; Pharmacia, Uppsala, Sweden); if positive further analysis of IgE antibodies to airborne allergens of pets (cat, horse, dog), pollens (birch, timothy, mugwort), mites, and mold were performed. The associations between asthma and airborne allergens were assessed with generalized estimating equations. The co-twin control analysis was performed by conditional logistic regression. RESULTS: Children with positive Phadiatop® had more than doubled odds of asthma (OR 2.53, 95% CI [1.74, 3.70]). Sensitization to pet allergens was associated with increased odds of asthma; for example, cat OR 4.15 (95% CI [2.67, 6.45]), with similar estimates for pollens; for example, birch OR 3.22 (95% CI [2.12, 4.91]). Associations persisted with sensitization as a categorical variable and for trend, indicating a dose-response relationship. Results remained in the co-twin analyses; for example, cat OR 4.75 (95% CI [1.62, 14.0]) and birch OR 5.00 (95% CI [1.45, 17.3]). CONCLUSION: The association between childhood asthma and sensitization to airborne allergens remains in co-twin analyses, indicating they are not due to confounding from shared environmental or genetic factors.

The STOPPA Twin Study Explains the Exhaled Nitric Oxide and Asthma Link by Genetics and Sensitization.

BACKGROUND: The link between asthma and exhaled nitric oxide (FENO) is not completely understood. The aim of this study was to estimate the association between FENO and asthma, taking genetics, sensitization, and inhaled corticosteroids (ICS) into account. METHODS: A total of 681 twins (53% monozygotic [MZ] and 47% dizygotic [DZ]) from the population-based STOPPA study (mean age 12.6 years) were recruited and information on FENO (parts per billion), parental report of current asthma, sensitization to airborne allergens (Phadiatop; IgE ≥0.35 kUA/l), and ICS-treatment was collected. We estimated the association between FENO and asthma, sensitization, and ICS in all twins and within pairs (DZ and MZ) to address shared genetic and environmental factors. Linear regression of log-transformed FENO was used and results presented as exponentiated regression coefficients (exp[ß]), with 95% confidence interval (CI). RESULTS: We found an association between asthma and FENO in all twins, exp(ß) 1.31 [1.11, 1.54]. In within-pairs analysis, the association was stronger within DZ pairs discordant for FENO, exp(ß) 1.50 [1.19, 1.89], compared to MZ pairs, exp(ß) 1.07 [0.84, 1.37], p = .049. There was no difference in FENO in non-sensitized children with asthma, compared to children with neither asthma nor sensitization, exp(ß) 0.89 [0.77, 1.03]. However, increased FENO was associated with sensitization, exp(ß) 1.48 [1.30, 1.69], and with sensitization together with asthma, exp(ß) 1.98 [1.57, 2.51], in all twins and within DZ pairs discordant for FENO, but not in MZ pairs. The FENO asthma association remained in DZ pairs without regular ICS-treatment. CONCLUSIONS: The association between FENO and asthma is explained by genetics and sensitization.