Changes in the prevalence of maternal chronic conditions during pregnancy: A nationwide age-period-cohort analysis.

OBJECTIVE: To estimate temporal changes in the prevalence of pre-existing chronic conditions among pregnant women in Sweden and evaluate the extent to which secular changes in maternal age, birth cohorts and obesity are associated with these trends. DESIGN: Population-based cross-sectional study. SETTING: Sweden, 2002-2019. POPULATION: All women (aged 15-49 years) who delivered in Sweden (2002-2019). METHODS: An age-period-cohort analysis was used to evaluate the effects of age, calendar periods, and birth cohorts on the observed temporal trends. MAIN OUTCOME MEASURES: Pre-existing chronic conditions, including 17 disease categories of physical and psychiatric health conditions recorded within 5 years before childbirth, presented as prevalence rates and rate ratios (RRs) with 95% confidence intervals (CIs). Temporal trends were also adjusted for pre-pregnancy body mass index (BMI) and the mother's country of birth. RESULTS: The overall prevalence of at least one pre-existing chronic condition was 8.7% (147 458 of 1 703 731 women). The rates of pre-existing chronic conditions in pregnancy increased threefold between 2002-2006 and 2016-2019 (RR 2.82, 95% CI 2.77-2.87). Rates of psychiatric (RR 3.80, 95% CI 3.71-3.89), circulatory/metabolic (RR 1.62, 95% CI 1.55-1.71), autoimmune/neurological (RR 1.69, 95% CI 1.61-1.78) and other (RR 2.10, 95% CI 1.99-2.22) conditions increased substantially from 2002-2006 to 2016-2019. However, these increasing rates were less pronounced between 2012-2015 and 2016-2019. No birth cohort effect was evident for any of the pre-existing chronic conditions. Adjusting for secular changes in obesity and the mother's country of birth did not affect these associations. CONCLUSIONS: The burden of pre-existing chronic conditions in pregnancy in Sweden increased from 2002 to 2019. This increase may be associated with the improved reporting of diagnoses and advancements in chronic condition treatment among women, potentially enhancing their fecundity.

Grandmaternal body mass index in early pregnancy and risk of grandoffspring stillbirth: A nationwide, three-generation cohort study.

We investigated the association between maternal grandmaternal early pregnancy body mass index (BMI) and grandoffspring stillbirth risk in a Swedish population-based three-generation cohort of 176,908 grandmothers (F0), 197,579 mothers (F1), and 316,459 grandoffspring (F2) born 1997-2016. There were 998 stillbirths (risk, 3.2 per 1000 births). Compared with grandmaternal BMI 18.5-24.9, adjusted relative risks [RR (95% CI)] of grandoffspring stillbirth for BMI 25.0-29.9 and ≥30 were, respectively, 1.41 (1.15, 1.72) and 1.62 (1.14, 2.30). RR (95% CI) for corresponding maternal (F1) BMI categories were, respectively, 1.32 (1.06, 1.65) and 1.77 (1.39, 2.25). Maternal BMI mediated only 19% of this relation. Grandmaternal preeclampsia and maternal small-for-gestational age (SGA) birth were related to increased F2 stillbirth risk but did not mediate the association between grandmaternal BMI and grandoffspring stillbirth risk. To explore whether this association was explained by factors shared within families, we studied the relation of maternal full sisters' BMI and stillbirth risk in 101,368 pregnancies. Stillbirth RR (95% CI) for full sisters' BMI 25.0-29.9 and ≥30 compared with 18.5-24.9 were, respectively, 0.76 (0.51, 1.13) and 0.88 (0.55, 1.40). In conclusion, grandmaternal overweight and obesity are associated with grandoffspring stillbirth. This association is not fully explained by shared familial factors.

Birth Weight, Gestational Age, and Risk of Cardiovascular Disease in Early Adulthood: Influence of Familial Factors.

The association between intrauterine growth restriction and cardiovascular disease (CVD) later in life might be confounded by familial factors. We conducted a binational register-based cohort study to assess associations of birth weight for gestational age (GA), a proxy for intrauterine growth restriction, and GA with CVD risk in early adulthood, before and after addressing familial factors via sibling comparison. We included 3,410,334 live nonmalformed singleton births from Sweden (1973-1996) and Denmark (1978-1998). During a median follow-up period of 10 years from age 18 years onwards, 29,742 individuals developed incident CVD (hypertension, ischemic heart disease, or cerebrovascular disease). Compared with individuals born with appropriate birth weight for GA (AGA; 10th-90th percentiles) or full term (39-40 gestational weeks), individuals born severely small for GA (SGA; ≤3rd percentile) or preterm (22-36 weeks) were at increased risk of CVD (hazard ratio (HR) = 1.38 (95% confidence interval (CI): 1.32, 1.45) and HR = 1.31 (95% CI: 1.25, 1.38), respectively). The association was attenuated when comparing individuals born SGA with their AGA siblings (HR = 1.11, 95% CI: 0.99, 1.25) but remained robust when comparing individuals born preterm with their term siblings (HR = 1.21, 95% CI: 1.07, 1.37). Our findings suggest that both SGA and preterm birth are associated with CVD risk in early adulthood, with greater familial confounding noted for SGA birth.

Apgar Score and Risk of Neonatal Death among Preterm Infants.

BACKGROUND: Gestational age is the major determinant of neonatal death (death within the first 28 days of life) in preterm infants. The joint effect of gestational age and Apgar score on the risk of neonatal death is unknown. METHODS: Using data from the Swedish Medical Birth Register, we identified 113,300 preterm infants (22 weeks 0 days to 36 weeks 6 days of gestation) born from 1992 through 2016. In analyses stratified according to gestational age (22 to 24 weeks, 25 to 27 weeks, 28 to 31 weeks, 32 to 34 weeks, and 35 or 36 weeks), we estimated adjusted relative risks of neonatal death and absolute rate differences in neonatal mortality (i.e., the excess number of neonatal deaths per 100 births) according to the Apgar scores at 5 and 10 minutes and according to the change in the Apgar score between 5 minutes and 10 minutes. Scores range from 0 to 10, with higher scores indicating a better physical condition of the newborn. RESULTS: There were 1986 neonatal deaths (1.8%). The incidence of neonatal death ranged from 0.2% (at 36 weeks of gestation) to 76.5% (at 22 weeks of gestation). Lower Apgar scores were associated with higher relative risks of neonatal death and greater absolute rate differences in neonatal mortality in all gestational-age strata. For example, among infants born at 28 to 31 weeks, the adjusted absolute rate differences according to the 5-minute Apgar score, with those who had a score of 9 or 10 serving as the reference group, were 51.7 (95% confidence interval [CI], 38.1 to 65.4) for a score of 0 or 1, 25.5 (95% CI, 18.3 to 32.8) for a score of 2 or 3, 7.1 (95% CI, 5.1 to 9.1) for a score of 4 to 6, and 1.2 (95% CI, 0.5 to 1.9) for a score of 7 or 8. An increase in the Apgar score between 5 minutes and 10 minutes was associated with lower neonatal mortality than a stable Apgar score. CONCLUSIONS: In this study, Apgar scores at 5 and 10 minutes provided prognostic information about neonatal survival among preterm infants across gestational-age strata. (Funded by the Swedish Research Council for Health, Working Life, and Welfare and Karolinska Institutet.).

Associations of parental and perinatal factors with subsequent risk of stress-related disorders: a nationwide cohort study with sibling comparison.

Little is known about the contribution of pregnancy-related parental and perinatal factors to the development of stress-related disorders. We aimed to investigate whether parental/perinatal adversities entail higher risks of stress-related disorders in the offspring, later in life, by accounting for genetic and early environmental factors. Based on the nationwide Swedish registers, we conducted a population-based cohort study of 3,435,747 singleton births (of which 2,554,235 were full siblings), born 1973-2008 and survived through the age of 5 years. Using both population- and sibling designs, we employed Cox regression to assess the association between parental and perinatal factors with subsequent risk of stress-related disorders. We identified 55,511 individuals diagnosed with stress-related disorders in the population analysis and 37,433 in the sibling analysis. In the population-based analysis we observed increased risks of stress-related disorders among offspring of maternal/paternal age <25, single mothers, parity ≥4, mothers with BMI ≥ 25 or maternal smoking in early pregnancy, gestational diabetes, and offspring born moderately preterm (GA 32-36 weeks), or small-for-gestational-age. These associations were significantly attenuated toward null in the sibling analysis. Cesarean-section was weakly associated with offspring stress-related disorders in population [hazard ratio (HR) 1.09, 95% confidence interval (CI) 1.06-1.12] and sibling analyses (HR 1.10, 95% CI 1.02-1.20). Our findings suggest that most of the observed associations between parental and perinatal factors and risk of stress-related disorders in the population analysis are driven by shared familial environment or genetics, and underscore the importance of family designs in epidemiological studies on the etiology of psychiatric disorders.

Associations of pregnancy complications and neonatal characteristics with bipolar disorder in the offspring: Nationwide cohort and sibling-controlled studies.

OBJECTIVES: To investigate associations of neonatal characteristics and pregnancy complications with bipolar disorder (BPD) in offspring. METHODS: We conducted a nationwide cohort study among 2,059,578 non-malformed singleton live-births in Sweden born 1983-2004. Using national registries with prospectively recorded information, we followed participants for a BPD diagnosis from 13 up to 34 years of age. We compared BPD risks between exposure categories using hazard ratios (HR) with 95% confidence intervals (CI) from adjusted Cox models. We also conducted sibling-controlled analyses among 1,467,819 full siblings. RESULTS: There were 14,998 BPD diagnoses. Risk of BPD was 0.74% through 25 years of age. Very/extremely preterm birth (22 to 31 weeks) was related to increased BPD HRs in sibling-controlled analyses; compared with a gestational age of 37 weeks, adjusted HR (95% CI) for 31, 28, and 22 weeks were, respectively, 1.31 (0.99, 1.74), 2.09 (1.15, 3.79), and 5.74 (1.15, 28.63). Spontaneous but not medically indicated very/extremely preterm birth was associated with increased risk. Compared with vaginal birth, caesarean section birth was associated with 1.20 (1.08, 1.33) and 1.58 (1.06, 2.36) times higher BPD risk in general and sibling cohorts, respectively. Small-for-gestational age (SGA) birth was related to increased BPD HRs in general cohort and sibling analyses (HRs [95% CI] were 1.22 [1.06, 1.39] and 1.68 [1.13, 2.50], respectively); only term SGA was associated with increased risk. Head circumference-for-gestational age, gestational diabetes, preeclampsia, and placental abruption were not associated with BPD. CONCLUSIONS: Very/extremely preterm birth, caesarean birth, and SGA are related to BPD incidence.

Maternal early pregnancy body mass index and bipolar disorder in the offspring.

OBJECTIVES: To investigate the association between maternal early pregnancy body mass index (BMI) and offspring bipolar disorder (BPD). METHODS: We conducted a nationwide cohort study among 1,507,056 non-malformed singleton live-births in Sweden born 1983-2004. Using national registries with prospectively recorded information, we followed participants for a BPD diagnosis from ages 13 to up to 35 years. We compared BPD risks by early pregnancy BMI using hazard ratios (HR) with 95% confidence intervals (CI) from adjusted Cox models. We also conducted sibling-controlled analyses among 874,047 full siblings. RESULTS: There were 9970 BPD diagnoses. Risk of BPD was 0.72% through 25 years of age. Maternal early pregnancy BMI was positively associated with offspring BPD risk. Compared with normal BMI (18.5-24.9), adjusted HR (95% CI) for overweight (BMI 25-29.9), obesity grade 1 (BMI 30-34.9), and obesity grades 2-3 (BMI ≥35) were 1.08 (1.02, 1.15), 1.26 (1.14, 1.40), and 1.31 (1.07, 1.60), respectively. Adjusted HR per unit BMI was 1.015 (95% CI 1.009, 1.021). A similar trend was observed among siblings. Pregnancy and neonatal complications did not substantially mediate the association between maternal obesity (BMI ≥30) and offspring BPD. CONCLUSIONS: Maternal BMI ≥25 is associated with offspring BPD risk in a dose-response manner.

Severity of preterm birth and the risk of pulmonary hypertension in childhood: A population-based cohort study in Sweden.

BACKGROUND: Preterm birth (<37 completed gestational weeks) has been linked to pulmonary hypertension (PH), but the relationship to severity of preterm birth has not been studied. OBJECTIVES: We investigated associations between extremely (<28 weeks), very (28-31 weeks), moderately (32-36 weeks) preterm birth, early-term birth (37-38 weeks) and later PH. Additionally, we explored associations between birthweight for gestational age and PH. METHODS: This registry-based cohort study followed 3.1 million individuals born in Sweden (1987-2016) from 1 up to a maximum of 30 years of age. The outcome was diagnosis or death from PH in national health registers. Adjusted hazard ratios (HR) were estimated using Cox regression analysis. Unadjusted and confounder-adjusted incidence rate differences were also calculated. RESULTS: Of 3,142,812 individuals, there were 543 cases of PH (1.2 per 100,000 person-years), 153 of which in individuals without malformations. Compared with individuals born at 39 weeks, adjusted HRs with 95% confidence interval (CI) for PH for extremely, moderately, and very preterm birth were 68.78 (95% CI 49.49, 95.57), 13.86 (95% CI 9.27, 20.72) and 3.42 (95% CI 2.46, 4.74), respectively, and for early-term birth 1.74 (1.31, 2.32). HRs were higher in subjects without malformations. There were 90 additional cases of PH per 100,000 person-years in the extremely preterm group (50 after excluding malformations). Very small for gestational age (below 2 SD from estimated birthweight for gestational age and sex) was also associated with increased risk of PH (adjusted HR 2.02, 95% CI 1.14, 3.57). CONCLUSIONS: We found an inverse association between gestational age and later PH, but the incidence and absolute risks are low. The severity of preterm birth adds clinically relevant information to the assessment of cardiovascular risks in childhood.

The Stockholm-Gotland perinatal cohort-A population-based cohort including longitudinal data throughout pregnancy and the postpartum period.

BACKGROUND: Register-based reproductive and perinatal databases rarely contain detailed information from medical records or repeated measurements throughout pregnancy and delivery. This lack of enriched pregnancy and birth data led to the initiation of the Swedish Stockholm-Gotland Perinatal Cohort (SGPC). OBJECTIVES: To describe the strengths of the SGPC, as well as the unique research questions that can be addressed using this cohort. POPULATION: The SGPC is a prospectively collected, population-based cohort that includes all births (from 22 completed gestational weeks onwards) between 1 January 2008 and 15 June 2020 in the Stockholm and Gotland regions of Sweden (335,153 singleton and 11,025 multiple pregnancies). DESIGN: Descriptive study. METHODS: The SGPC is based on the electronic medical records of women and their infants. The medical record system is used for all antenatal clinic visits and admissions, delivery and neonatal admissions, as well as postpartum clinical visits. SGPC has been further enriched with data linkages to 10 Swedish National Health Care and Quality Registers. PRELIMINARY RESULTS: In contrast to other reproductive and perinatal databases available in Sweden, including the Medical Birth Register and the Pregnancy Register, SGPC contains highly detailed medical record data, including time-varying serial measurements for physiological parameters throughout pregnancy, delivery, and postpartum, for both mother and infant. These strengths have enabled studies that were previously inconceivable; the effects of serial measurements of pregnancy weight gain, changes in haemoglobin counts and blood pressure during pregnancy, fetal weight estimations by ultrasound, duration of stages and phases of labour, cervical dilatation and oxytocin use during delivery, and constructing reference curves for umbilical cord pH. CONCLUSIONS: The SGPC-with its rich content, repeated measurements and linkages to numerous health care and quality registers-is a unique cohort that enables high-quality perinatal studies that would otherwise not be possible.

The Swedish medical birth register during five decades: documentation of the content and quality of the register.

Pregnancy-related factors are important for short- and long-term health in mothers and offspring. The nationwide population-based Swedish Medical Birth Register (MBR) was established in 1973. The present study describes the content and quality of the MBR, using original MBR data, Swedish-language and international publications based on the MBR.The MBR includes around 98% of all births in Sweden. From 1982 onwards, the MBR is based on prospectively recorded information in standardized antenatal, obstetric, and neonatal records. When the mother and infant are discharged from hospital, this information is forwarded to the MBR, which is updated annually. Maternal data include information from first antenatal visit on self-reported obstetric history, infertility, diseases, medication use, cohabitation status, smoking and snuff use, self-reported height and measured weight, allowing calculation of body mass index. Birth and neonatal data include date and time of birth, mode of delivery, singleton or multiple birth, gestational age, stillbirth, birth weight, birth length, head circumference, infant sex, Apgar scores, and maternal and infant diagnoses/procedures, including neonatal care. The overall quality of the MBR is very high, owing to the semi-automated data extraction from the standardized regional electronic health records, Sweden's universal access to antenatal care, and the possibility to compare mothers and offspring to the Total Population Register in order to identify missing records. Through the unique personal identity numbers of mothers and live-born offspring, the MBR can be linked to other health registers. The Swedish MBR contains high-quality pregnancy-related information on more than 5 million births during five decades.

Accuracy and precision of sonographic fetal weight estimation in Sweden.

INTRODUCTION: Fetal growth assessment by ultrasound is an essential part of modern obstetric care. The formula by Persson and Weldner for estimated fetal weight (EFW), used in Sweden since decades, has not yet been evaluated. The objective of this study was to evaluate accuracy and precision of the formula by Persson and Weldner, and to compare it to two other formulae using biparietal diameter instead of head circumference. MATERIAL AND METHODS: The study population consisted of 31 521 singleton pregnancies delivered at 22+0 gestational weeks or later, with an ultrasound EFW performed within 2 days before delivery, registered in the Swedish Pregnancy Register between 2014 and 2021. Fetal biometric ultrasound measurements were used to calculate EFW according to the formulae by Persson and Weldner, Hadlock 2 and Shepard. Bland-Altman analysis, systematic error (mean percentage error), random error (standard deviation [SD] of mean percentage error), proportion of weight estimates within ±10% of birthweight, and proportion with underestimated and overestimated weight was calculated. Moreover, calculations were made after stratification into small, appropriate, and large for gestational age (SGA, AGA and LGA), respectively, and gestational age at examination. RESULTS: For the formula by Persson and Weldner, MPE was -2.7 (SD 8.9) and the proportion of EFW within ±10% from actual birthweight was 76.0%. MPE was largest for fetuses estimated as severe SGA (<3rd percentile, -5.4) and for the most preterm fetuses (<24 weeks, -5.4). For Hadlock 2 and Shepard's formulae, MPE were 3.9 (SD 8.9) and 3.4 (SD 9.7), respectively, and the proportions of EFW within ±10% from actual birthweight were 69.4% and 67.1%, respectively. MPE was largest for fetuses estimated as severe LGA (>97th percentile), 7.6 and 9.4, respectively. CONCLUSIONS: The recommended Swedish formula by Persson and Weldner is generally accurate for fetal weight estimation. The systematic underestimation of EFW and random error is largest in extreme preterm and estimated SGA-fetuses, which is of importance in clinical decision making. The accuracy of EFW with the formula by Persson and Weldner is as good as or better than Hadlock 2 and Shepard's formulae.

Low Apgar score and need for resuscitation increased the probability of receiving therapeutic hypothermia more strongly than acidosis at birth.

AIM: The aim of this study was to investigate how individual markers for birth asphyxia, so-called A criteria, were associated with the probability of receiving therapeutic hypothermia. METHODS: This population-based cohort study included 1336 live-born singleton term infants with any A criterion in the Stockholm-Gotland Region, Sweden during 2008 to 2014. The Swedish Neonatal Quality Register and National Patient Register were used for data collection. Results were presented as adjusted odds ratios (aORs) with 95% confidence intervals (CIs). RESULTS: There were 89 infants, 44 boys and 45 girls with mean gestational age 40.5 weeks, who received therapeutic hypothermia. Low Apgar score, aOR 12.44 (95% CI 5.99-25.86), and resuscitation, aOR 9.18 (95% CI 3.77-22.34), were strongly associated with therapeutic hypothermia. A pH <7.0 was less associated with the outcome, aOR 2.02 (95% CI 1.02-4.0). No infant who received therapeutic hypothermia fulfilled the criteria of base deficit ≥16 mmol/L only. CONCLUSION: A low Apgar score of and/or a need for resuscitation is more relevant for identifying infants eligible for therapeutic hypothermia, compared to other A criteria. This knowledge could be used clinically to identify cases for review and avoid unnecessary monitoring of infants.

Defective Placentation Syndromes and Intellectual Disability in the Offspring: Nationwide Cohort and Sibling-Controlled Studies.

We investigated the relationships between syndromic manifestations of defective placentation and the incidence of intellectual disability (ID) in offspring by conducting a population-based cohort study of 1,581,200 nonmalformed, live singleton infants born in Sweden between 1998 and 2014. Exposures were: 1) placental abruption, 2) preterm preeclampsia (<34 weeks of gestation), 3) preeclampsia combined with infant being small for gestational age (SGA) at birth, and 4) spontaneous preterm birth. The outcome was an ID diagnosis after 3 years of age. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for each syndrome using Cox regression and robust variances. There were 9,451 children with ID (5.5 per 10,000 child-years). ID incidence rates increased with placental abruption (HR = 2.8, 95% CI: 2.3, 3.5), preterm preeclampsia (HR = 3.7, 95% CI: 2.9, 4.7), preeclampsia combined with SGA (HR = 3.3, 95% CI: 2.6, 4.1), and spontaneous preterm birth (for 32-36 and 22-31 weeks, respectively, HR = 1.6 (95% CI: 1.4, 1.8) and 5.2 (95% CI: 4.3, 6.2)). The same pattern of results was evident in sibling-controlled analyses among 1,043,158 full siblings. The strength of associations increased with ID severity. Preterm birth only partly explained the associations of placental abruption, preeclampsia, or SGA with ID. We conclude that defective placentation is related to increased incidence of ID in the offspring.

Time of delivery among low-risk women at 37-42 weeks of gestation and risks of stillbirth and infant mortality, and long-term neurological morbidity.

BACKGROUND: The most important knowledge gap in connection with obstetric management for time of delivery in term low-risk pregnancies relates to the absence of information on long-term neurodevelopmental outcomes. OBJECTIVES: We examined risks of stillbirth, infant mortality, cerebral palsy (CP) and epilepsy among low-risk pregnancies. METHODS: In this population-based Swedish study, we identified, from 1998 to 2019, 1,773,269 singleton infants born between 37 and 42 completed weeks in women with low-risk pregnancies. Poisson log-linear regression models were used to examine the association between gestational age at delivery and stillbirth, infant mortality, CP and epilepsy. Adjusted rate ratios (RR) and 95% confidence intervals expressing the effect of birth at a particular gestational week compared with birth at a later gestational week were estimated. RESULTS: Compared with those born at a later gestation, RRs for stillbirth and infant mortality were higher among births at 37 weeks' and 38 weeks' gestation. The RRs for infant mortality were approximately 20% and 25% lower among births at 40 or 41 weeks compared with those born at later gestation, respectively. Infants born at 37 and 38 weeks also had higher RRs for CP (vs infants born at ≥38 and ≥39 weeks, respectively), while those born at 39 gestation had similar RRs (vs infants born at ≥40 weeks); infants born at 40 and 41 weeks had lower RRs of CP (vs those born at ≥41 and 42 weeks, respectively). The RRs for epilepsy were higher in those born at 37 and 38 weeks compared with those born at later gestation. CONCLUSIONS: Among low-risk pregnancies, birth at 37 or 38 completed weeks' gestation is associated with increased risks of stillbirth, infant mortality and neurological morbidity, while birth at 39-40 completed weeks is associated with reduced risks compared with births at later gestation.

Defective placentation syndromes and autism spectrum disorder in the offspring: population-based cohort and sibling-controlled studies.

Defective placentation underlies diverse syndromic manifestations that could affect brain development including: (1) placental abruption, (2) term preeclampsia with a small-for-gestational age (SGA) infant, (3) preterm preeclampsia, and (4) spontaneous preterm birth. We investigated the relations between these defective placentation syndromes and the incidence of Autism Spectrum Disorder (ASD) in offspring. We conducted a population-based cohort study of 1,645,455 non-malformed singleton infants born in Sweden 2000-2016 who were followed for up to 17 years using national registers. We compared ASD rates for children prenatally exposed and unexposed to defective placentation syndromes with use of adjusted hazard ratios (HR) with 95% confidence intervals (CI) from Cox regression. We also conducted sibling-controlled analyses among 1,092,132 full siblings. The association of the syndromes with ASD independent of preterm birth was estimated in mediation analyses. There were 23,810 cases of ASD. In both general cohort and sibling analyses, adjusted HRs (95% CI) of ASD were increased in children of mothers with term preeclampsia combined with SGA [1.5 (1.3, 1.9) and 1.9 (1.1, 3.3), respectively], preterm preeclampsia < 34 weeks [1.8 (1.4, 2.2) and 4.2 (2.1, 8.5), respectively], and spontaneous very or extremely preterm birth (≤ 31 weeks) [2.6 (2.2, 3.0) and 2.4 (1.5, 3.8), respectively]. Placental abruption was associated with increased HR of ASD in general cohort analysis only. The association between preeclampsia and ASD was not fully explained by preterm birth. In conclusion, syndromes linked to defective placentation are associated with increased incidence of ASD in the offspring.

Risk of gestational diabetes mellitus in relation to early pregnancy and gestational weight gain before diagnosis: A population-based cohort study.

INTRODUCTION: Gestational diabetes mellitus (GDM) is a common pregnancy complication associated with adverse consequences for the mother and offspring in both short and long term. The aim of this study was to investigate associations between risk of GDM and gestational weight gain in early pregnancy and before diagnosis. MATERIAL AND METHODS: Our population-based cohort study included 131 164 singleton pregnancies in the Stockholm-Gotland region in Sweden from 2008 through 2013. The exposures were weight gain in early pregnancy (<22 weeks) and weight gain before diagnosis, standardized into gestational age-specific z scores. The outcome was GDM. We used logistic regression models with a generalized estimating equations method to estimate odds ratios with 95% confidence intervals for GDM, stratified by early-pregnancy body mass index (BMI) category. RESULTS: Above average weight gain before diagnosis (z score >0) was associated with increased risk of GDM among all BMI groups except for obese III. Early gestational weight gain above average was associated with increased risk for GDM in overweight women. Below average weight gain before diagnosis (z score <0) was only associated with decreased risk of GDM in obese III. Early gestational weight gain below average was associated with reduced risks of GDM in obese class I, II, and III women. CONCLUSIONS: The risk of GDM increased with higher weight gain before diagnosis in all BMI groups except obese class III, whereas the risk was reduced with lower weight gain before diagnosis in obese III women only. The risk of GDM increased with higher early gestational weight gain in overweight women, while the risk was reduced with lower early gestational weight gain among obese women. Obese women may benefit from lower weight gain, especially in early pregnancy.

Associations of preterm birth, small-for-gestational age, preeclampsia and placental abruption with attention-deficit/hyperactivity disorder in the offspring: Nationwide cohort and sibling-controlled studies.

AIM: The aim of this study was to investigate preterm birth, small-for-gestational age (SGA), preeclampsia and placental abruption in relation to attention-deficit/hyperactivity disorder (ADHD) in offspring. METHODS: We conducted a population-based cohort study among non-malformed live-born singleton children in Sweden born during 2002-2014. Using national registries with recorded information, we followed 1,212,201 children for an ADHD diagnosis from 3 to 15 years. We compared ADHD rates between exposure categories using adjusted hazard ratios (HR) with 95% confidence intervals (CI) from Cox proportional hazards models. We also conducted sibling-controlled analyses among 751,464 full siblings. RESULTS: There were 27,665 ADHD diagnoses in the cohort. Compared with term birth (≥37 weeks), adjusted HR (95% CI) for ADHD increased with decreasing gestational age: 1.18 (1.11, 1.25), 1.61 (1.37, 1.89) and 2.79 (2.23, 3.49) for 32-36 weeks, 28-31 weeks and 22-27 weeks. Both spontaneous and medically indicated preterm birth were associated with ADHD. SGA was related to 1.62 (1.49, 1.77) times higher ADHD incidence. Preeclampsia, but not placental abruption, was associated with ADHD. Sibling-controlled analyses showed similar results. Preterm birth did not fully explain the associations of SGA or preeclampsia with ADHD. CONCLUSION: Preterm birth, SGA and preeclampsia are related to ADHD incidence in offspring.

Maternal Obesity and Risk of Early-onset Neonatal Bacterial Sepsis: Nationwide Cohort and Sibling-controlled Studies.

BACKGROUND: Maternal overweight and obesity are related to risks of pregnancy and delivery complications that, in turn, are associated with newborn infections. We examined the associations between early pregnancy body mass index (BMI; kg/m2) and risk of early-onset neonatal bacterial sepsis (EOS). METHODS: We conducted a nationwide population-based retrospective cohort study of 1 971 346 live singleton infants born in Sweden between 1997 and 2016. Outcome was a culture-confirmed EOS diagnosis. We estimated hazard ratios (HR) of EOS according to BMI using proportional hazard models, and identified potential mediators. Among term infants, we conducted sibling-controlled analyses. RESULTS: EOS risk per 1000 live births was 1.48; 0.76 in term and 15.52 in preterm infants. Compared with infants of normal-weight mothers (BMI, 18.5-24.9), the adjusted HR (95% confidence interval [CI]) of EOS for BMI categories <18.5, 25.0-29.9, 30.0-34.9, 35.0-39.9, and ≥40.0 were, respectively, 1.07 (.83-1.40), 1.19 (1.08-1.32), 1.70 (1.49-1.94), 2.11 (1.73-2.58), and 2.50 (1.86-3.38). Maternal overweight and obesity increased the risk of EOS by group B Streptococcus, Staphylococcus aureus, and Escherichia coli. Half of the association was mediated through preeclampsia, cesarean section delivery, and preterm delivery. A dose-response association was consistently apparent in term infants only. In sibling-controlled analyses, every kilogram per meter squared interpregnancy BMI change was associated with a mean 8.3% increase in EOS risk (95% CI, 1.7%-15.3%; P = .01). CONCLUSIONS: Risk of EOS increases with maternal overweight and obesity severity, particularly in term infants.

Gestational weight gain and delivery outcomes: A population-based cohort study.

BACKGROUND: Gestational weight gain is a modifiable factor that could impact maternal and infant health. However, its effect on delivery outcomes is not well established. OBJECTIVES: To investigate the associations between gestational weight gain and delivery outcomes stratified by early-pregnancy body mass index (BMI). METHODS: The study population included singleton livebirths in the Stockholm-Gotland obstetric cohort (January 2008 to October 2014; n = 174 953). The exposure was total gestational weight gain standardised into gestational-age-specific z-scores by using previously defined Swedish pregnancy weight gain-for-gestational age charts. The outcomes included caesarean delivery (overall, elective, and emergency), instrumental vaginal delivery, induction of labour, and postpartum haemorrhage. Confounders included maternal age, maternal height, parity, smoking status, cohabitation status, chronic hypertension, and pre-pregnancy diabetes. Logistic regression models with marginal standardisation were used to estimate risk ratios (RR) with 95% confidence intervals (CI) for each delivery outcome stratified by early-pregnancy BMI. RESULTS: Above average weight gain (z-score ≥ 0.50 SD) increased risks of caesarean delivery (from RR 1.08, 95% CI 1.00, 1.15 to RR 1.45, 95% CI 1.35, 1.55 across BMI groups), induction of labour (from RR 1.14, 95% CI 1.04, 1.23 to RR 1.38, 95% CI 1.25, 1.51 across BMI groups except underweight), and postpartum haemorrhage (from RR 1.13, 95% CI 1.07, 1.19 to RR 1.25, 95% CI 1.09, 1.41 among normal and overweight). Below average weight gain (z-score <-0.50 SD) decreased caesarean delivery risk (from RR 0.77, 95% CI 0.61, 0.93 to RR 0.89, 95% CI 0.84, 0.95 across BMI groups except underweight). CONCLUSIONS: In normal and overweight women, the risks of caesarean delivery, induction of labour, and postpartum haemorrhage increased with gestational weight gain. In obese women, higher gestational weight gain increased risks of caesarean delivery and induction of labour. Low gestational weight gain reduced risk of caesarean delivery in all BMI groups except underweight.

Maternal Influenza A(H1N1) Immunization During Pregnancy and Risk for Autism Spectrum Disorder in Offspring : A Cohort Study.

BACKGROUND: There are concerns that influenza vaccine exposure during pregnancy may be associated with increased risk for autism spectrum disorder (ASD). OBJECTIVE: To examine the risk for ASD in offspring of mothers who were vaccinated against influenza A(H1N1)pdm09 ("swine flu") during pregnancy. DESIGN: Population-based cohort study using nationwide registers. SETTING: Seven health care regions in Sweden. PARTICIPANTS: Live births between October 2009 and September 2010, with follow-up through December 2016. In total, 39 726 infants were prenatally exposed to H1N1 vaccine (13 845 during the first trimester) and 29 293 infants were unexposed. MEASUREMENTS: Cox regression was used to estimate hazard ratios (HRs) for the primary outcome, ASD, before and after adjustment for potential confounders. The secondary outcome was autistic disorder (AD). RESULTS: Mean follow-up was 6.7 years in both unexposed and exposed children. During follow-up, 394 (1.0%) vaccine-exposed and 330 (1.1%) unexposed children had a diagnosis of ASD. In adjusted analyses, prenatal exposure to H1N1 vaccination was not associated with a later diagnosis of ASD (adjusted HR [aHR], 0.95 [95% CI, 0.81 to 1.12]) or AD (aHR, 0.96 [CI, 0.80 to 1.16]). The 6-year standardized cumulative incidence difference between the unexposed and exposed children was 0.04% (CI, -0.09% to 0.17%) for ASD and 0.02% (CI, -0.09% to 0.14%) for AD. Restricting the analysis to vaccination in the first trimester of pregnancy did not influence risk estimates (aHR, 0.92 [CI, 0.74 to 1.16] for ASD and 0.91 [CI, 0.70 to 1.18] for AD). LIMITATION: Data on H1N1 influenza infection are lacking. CONCLUSION: This large cohort study found no association between maternal H1N1 vaccination during pregnancy and risk for ASD in the offspring. PRIMARY FUNDING SOURCE: Swedish Research Council.