[Swedish Medical Birth Register 50 years - a source for scientific publications]. / Medicinska födelseregistret 50 år.

The nationwide Swedish Medical Birth Register (MBR) includes more than 98% of all births in Sweden since 1973. The MBR is updated annually, and is based on information from antenatal, obstetric, and neonatal records. Maternal information includes self-reported medical history, socio-demographic factors, smoking and snuff use, medication use, height and measured weight. Birth and neonatal/postpartal data include birth date, 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. The overall quality of the MBR is very high, partly due to the semi-automated data extraction from the standardized regional electronic health records. The MBR can be linked to other health registers through the unique personal identity numbers of mothers and live-born offspring. More than 1000 scientific publications have used MBR as a data source.

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.

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.

Pre-pregnancy and pregnancy disorders, pre-term birth and the risk of cerebral palsy: a population-based study.

BACKGROUND: Cerebral palsy (CP) is the most common cause of childhood physical disability whose aetiology remains unclear in most cases. Maternal pre-existing and pregnancy complications are recognized risk factors of CP but the extent to which their effects are mediated by pre-term birth is unknown. METHODS: Population-based cohort study in Sweden including 2 055 378 singleton infants without congenital abnormalities, born between 1999 and 2019. Data on maternal and pregnancy characteristics and diagnoses of CP were obtained by individual record linkages of nationwide Swedish registries. Exposure was defined as maternal pre-pregnancy and pregnancy disorders. Inpatient and outpatient diagnoses were obtained for CP after 27 days of age. Adjusted rate ratios (aRRs) were calculated, along with 95% CIs. RESULTS: A total of 515 771 (25%) offspring were exposed to maternal pre-existing chronic disorders and 3472 children with CP were identified for a cumulative incidence of 1.7 per 1000 live births. After adjusting for potential confounders, maternal chronic cardiovascular or metabolic disorders, other chronic diseases, mental health disorders and early-pregnancy obesity were associated with 1.89-, 1.24-, 1.26- and 1.35-times higher risk (aRRs) of CP, respectively. Most notably, offspring exposed to maternal antepartum haemorrhage had a 6-fold elevated risk of CP (aRR 5.78, 95% CI, 5.00-6.68). Mediation analysis revealed that ∼50% of the effect of these associations was mediated by pre-term delivery; however, increased risks were also observed among term infants. CONCLUSIONS: Exposure to pre-existing maternal chronic disorders and pregnancy-related complications increases the risk of CP in offspring. Although most infants with CP were born at term, pre-term delivery explained 50% of the overall effect of pre-pregnancy and pregnancy disorders on CP.

Pregnancy-Induced Hypertensive Disorder and Risks of Future Ischemic and Nonischemic Heart Failure.

BACKGROUND: Although adverse pregnancy outcomes are associated with an increased risk of cardiovascular disease, studies on timing and subtypes of heart failure after a hypertensive pregnancy are lacking. OBJECTIVES: The goal of this study was to assess the association between pregnancy-induced hypertensive disorder and risk of heart failure, according to ischemic and nonischemic subtypes, and the impact of disease characteristics and the timing of heart failure risks. METHODS: This was a population-based matched cohort study, comprising all primiparous women without a history of cardiovascular disease included in the Swedish Medical Birth Register between 1988 and 2019. Women with pregnancy-induced hypertensive disorder were matched with women with normotensive pregnancies. Through linkage with health care registers, all women were followed up for incident heart failure, classified as ischemic or nonischemic. RESULTS: In total, 79,334 women with pregnancy-induced hypertensive disorder were matched with 396,531 women with normotensive pregnancies. During a median follow-up of 13 years, rates of all heart failure subtypes were more common among women with pregnancy-induced hypertensive disorder. Compared with women with normotensive pregnancies, adjusted HRs (aHRs) with 95% CIs were as follows: heart failure overall, aHR: 1.70 (95% CI: 1.51-1.91); ischemic heart failure, aHR: 2.28 (95% CI: 1.74-2.98); and nonischemic heart failure, aHR: 1.60 (95% CI: 1.40-1.83). Disease characteristics indicating severe hypertensive disorder were associated with higher heart failure rates, and rates were highest within the first years after the hypertensive pregnancy but remained significantly increased thereafter. CONCLUSIONS: Pregnancy-induced hypertensive disorder is associated with an increased short-term and long-term risk of incident ischemic and nonischemic heart failure. Disease characteristics indicating more severe forms of pregnancy-induced hypertensive disorder amplify the heart failure risks.

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.

Preterm Birth, Small for Gestational Age, and Large for Gestational Age and the Risk of Atrial Fibrillation Up to Middle Age.

Importance: Adverse birth outcomes, including preterm birth, small for gestational age (SGA), and large for gestational age (LGA) are associated with increased risks of hypertension, ischemic heart disease, stroke, and heart failure, but knowledge regarding their associations with atrial fibrillation (AF) is limited and inconsistent. Objective: To investigate whether preterm birth, SGA, or LGA are associated with increased risks of AF later in life. Design, Setting, and Participants: This multinational cohort study included Danish, Swedish, and Finnish national health registries. Live singleton births in Denmark from 1978 through 2016, in Sweden from 1973 through 2014, and in Finland from 1987 through 2014, who were followed up until December 31, 2016, in Denmark, December 31, 2021, in Sweden, and December 31, 2014, in Finland were included. Data analyses were performed between January 2021 and August 2022. Exposures: Preterm birth (less than 37 gestational weeks), SGA (less than 10th percentile birth weight for gestational age), and LGA (more than 90th percentile birth weight for gestational age) identified from medical birth registers. Main Outcomes and Measures: Diagnosis of AF obtained from nationwide inpatient and outpatient registers. The study team ran multivariable Cox proportional hazard models and flexible parametric survival models to estimate hazard ratios (HRs) and 95% CIs for AF according to preterm birth, SGA, and LGA. Sibling analyses were conducted to control for unmeasured familial factors. Results: The cohort included 8 012 433 study participants (maximum age, 49 years; median age, 21 years; male, 51.3%). In 174.4 million person-years of follow-up, 11 464 participants had a diagnosis of AF (0.14%; median age, 29.3 years). Preterm birth and LGA were associated with increased AF risk in both the full population cohort and in the sibling analyses; the multivariate HRs from the cohort analyses were 1.30 (95% CI, 1.18-1.42) and 1.55 (95% CI, 1.46-1.63), respectively. Preterm birth was more strongly associated with AF in childhood than in adulthood. Children born SGA had an increased risk of AF in the first 18 years of life but not afterwards. Conclusions and Relevance: Preterm births and LGA births were associated with increased risks of AF up to middle age independently of familial confounding factors. Individuals born SGA had an increased AF risk only during childhood.

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 asphyxia complications at birth and risk of longer-term cardiovascular disease: a nationwide population-based study of term infants.

Background: Most follow-up studies have focused on the long-term consequences of asphyxia at birth on the brain. The aim of this study was to investigate associations between low Apgar score and asphyxia-related complications and subsequent risks of cardiovascular diseases (CVD) in childhood and early adulthood. Methods: This population-based cohort study included 2,826,424 non-malformed singleton births, born at term (≥37 weeks' gestation) between 1988 and 2018 in Sweden. Primary exposure was a composite of asphyxia-related complications, defined as a) Apgar score 0-3 at 1-min; or b) Apgar score 0-3 at 5-min; or c) neonatal seizures (including hypoxic ischemic encephalopathy). Using Cox regression, we estimated the risk of CVD after 1 year of age, defined as stroke, coronary heart disease, heart failure, and atrial fibrillation. Results: Overall, there were 4165 cases with cardiovascular diseases. Individuals with asphyxia-related complications had adjusted hazard ratios (95% confidence intervals) of 1.90 (1.54 to 2.34) for cardiovascular disease, 2.29 (1.74 to 3.03) for stroke, 2.17 (1.37 to 3.42) for heart failure, and 1.38 (0.87 to 2.17) for atrial fibrillation. Hazard ratios for CVD were elevated among individuals with Apgar score 0-3 at 1 and 5 min, and those with neonatal seizures. Compared with unexposed individuals, neonatal seizures were associated with 5 times higher rates of stroke and heart failure, respectively. Interpretation: Asphyxia-related complications and its neonatal complications, especially low Apgar score and neonatal seizures, are associated with increased risks of CVD in childhood and early adulthood, although the absolute risk of CVD is low in young age. Funding: Swedish Research Council and the Swedish Heart-Lung Foundation.

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.

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.

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.

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.

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.

Cardiovascular outcomes in transgender individuals in Sweden after initiation of gender-affirming hormone therapy.

AIMS: We compared the incidence of cardiovascular disease (CVD) in transgender participants with a diagnosis of gender dysphoria (GD) with and without gender-affirming hormone therapy (GAHT) to the incidence observed in the general population. METHODS AND RESULTS: The population-based cohort included all individuals >10 years in Sweden linked to Swedish nationwide healthcare Registers (2006-16). Two comparator groups without GD/GAHT were matched (1:10) on age, county of residence, and on male and female birth-assigned sex, respectively. Cox proportional models provided hazard ratios (HRs) and 95% confidence intervals (CI) for CVD outcomes. Among 1779 transgender individuals [48% birth-assigned males (AMAB), 52% birth-assigned females (AFAB)], 18 developed CVD, most of which were conduction disorders. The incidence of CVD for AFAB individuals with GD was 3.7 per 1000 person-years (95% CI: 1.4-10.0). Assigned male at birth individuals with GD had an incidence of CVD event of 7.1 per 1000 person-years (95% CI: 4.2-12.0). The risk of CVD event was 2.4 times higher in AMAB individuals (HR: 2.4, 95% CI: 1.3-4.2) compared with cisgender women, and 1.7 higher compared with cisgender men (HR: 1.7, 95% CI: 1.0-2.9). Analysis limited to transgender individuals without GAHT yielded similar results to those with GAHT treatment. CONCLUSION: The incidence of CVD among GD/GAHT individuals was low, although increased compared with matched individuals without GD and similar to the incidence among GD/no GAHT individuals, thus not lending support for a causal relationship between treatment and CVD outcomes. Larger studies with longer follow-up are needed to verify these findings, as well as possible effect modification by comorbidity.

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.

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.

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.

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.