[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.

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.

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.

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 smoking during pregnancy and fractures in offspring: national register based sibling comparison study.

OBJECTIVE: To study the impact of maternal smoking during pregnancy on fractures in offspring during different developmental stages of life. DESIGN: National register based birth cohort study with a sibling comparison design. SETTING: Sweden. PARTICIPANTS: 1 680 307 people born in Sweden between 1983 and 2000 to women who smoked (n=377 367, 22.5%) and did not smoke (n=1 302 940) in early pregnancy. Follow-up was until 31 December 2014. MAIN OUTCOME MEASURE: Fractures by attained age up to 32 years. RESULTS: During a median follow-up of 21.1 years, 377 970 fractures were observed (the overall incidence rate for fracture standardised by calendar year of birth was 11.8 per 1000 person years). The association between maternal smoking during pregnancy and risk of fracture in offspring differed by attained age. Maternal smoking was associated with a higher rate of fractures in offspring before 1 year of age in the entire cohort (birth year standardised fracture rates in those exposed and unexposed to maternal smoking were 1.59 and 1.28 per 1000 person years, respectively). After adjustment for potential confounders the hazard ratio for maternal smoking compared with no smoking was 1.27 (95% confidence interval 1.12 to 1.45). This association followed a dose dependent pattern (compared with no smoking, hazard ratios for 1-9 cigarettes/day and ≥10 cigarettes/day were 1.20 (95% confidence interval 1.03 to 1.39) and 1.41 (1.18 to 1.69), respectively) and persisted in within-sibship comparisons although with wider confidence intervals (compared with no smoking, 1.58 (1.01 to 2.46)). Maternal smoking during pregnancy was also associated with an increased fracture incidence in offspring from age 5 to 32 years in whole cohort analyses, but these associations did not follow a dose dependent gradient. In within-sibship analyses, which controls for confounding by measured and unmeasured shared familial factors, corresponding point estimates were all close to null. Maternal smoking was not associated with risk of fracture in offspring between the ages of 1 and 5 years in any of the models. CONCLUSION: Prenatal exposure to maternal smoking is associated with an increased rate of fracture during the first year of life but does not seem to have a long lasting biological influence on fractures later in childhood and up to early adulthood.

Maternal diabetes during pregnancy and early onset of cardiovascular disease in offspring: population based cohort study with 40 years of follow-up.

OBJECTIVE: To evaluate the associations between maternal diabetes diagnosed before or during pregnancy and early onset cardiovascular disease (CVD) in offspring during their first four decades of life. DESIGN: Population based cohort study. SETTING: Danish national health registries. PARTICIPANTS: All 2 432 000 liveborn children without congenital heart disease in Denmark during 1977-2016. Follow-up began at birth and continued until first time diagnosis of CVD, death, emigration, or 31 December 2016, whichever came first. EXPOSURES FOR OBSERVATIONAL STUDIES: Pregestational diabetes, including type 1 diabetes (n=22 055) and type 2 diabetes (n=6537), and gestational diabetes (n=26 272). MAIN OUTCOME MEASURES: The primary outcome was early onset CVD (excluding congenital heart diseases) defined by hospital diagnosis. Associations between maternal diabetes and risks of early onset CVD in offspring were studied. Cox regression was used to assess whether a maternal history of CVD or maternal diabetic complications affected these associations. Adjustments were made for calendar year, sex, singleton status, maternal factors (parity, age, smoking, education, cohabitation, residence at childbirth, history of CVD before childbirth), and paternal history of CVD before childbirth. The cumulative incidence was averaged across all individuals, and factors were adjusted while treating deaths from causes other than CVD as competing events. RESULTS: During up to 40 years of follow-up, 1153 offspring of mothers with diabetes and 91 311 offspring of mothers who did not have diabetes were diagnosed with CVD. Offspring of mothers with diabetes had a 29% increased overall rate of early onset CVD (hazard ratio 1.29 (95% confidence interval 1.21 to 1.37); cumulative incidence among offspring unexposed to maternal diabetes at 40 years of age 13.07% (12.92% to 13.21%), difference in cumulative incidence between exposed and unexposed offspring 4.72% (2.37% to 7.06%)). The sibship design yielded results similar to those of the unpaired design based on the whole cohort. Both pregestational diabetes (1.34 (1.25 to 1.43)) and gestational diabetes (1.19 (1.07 to 1.32)) were associated with increased rates of CVD in offspring. We also observed varied increased rates of specific early onset CVDs, particularly heart failure (1.45 (0.89 to 2.35)), hypertensive disease (1.78 (1.50 to 2.11)), deep vein thrombosis (1.82 (1.38 to 2.41)), and pulmonary embolism (1.91 (1.31 to 2.80)). Increased rates of CVD were seen in different age groups from childhood to early adulthood until age 40 years. The increased rates were more pronounced among offspring of mothers with diabetic complications (1.60 (1.25 to 2.05)). A higher incidence of early onset CVD in offspring of mothers with diabetes and comorbid CVD (1.73 (1.36 to 2.20)) was associated with the added influence of comorbid CVD but not due to the interaction between diabetes and CVD on the multiplicative scale (P value for interaction 0.94). CONCLUSIONS: Children of mothers with diabetes, especially those mothers with a history of CVD or diabetic complications, have increased rates of early onset CVD from childhood to early adulthood. If maternal diabetes does have a causal association with increased CVD rate in offspring, the prevention, screening, and treatment of diabetes in women of childbearing age could help to reduce the risk of CVD in the next generation.

Opium use during pregnancy and infant size at birth: a cohort study.

BACKGROUND: The reported positive association between opiatic drug use during pregnancy and adverse pregnancy outcomes might be confounded by other factors related to high-risk behaviors, including the use of other harmful substances. In rural areas of Iran, opium use during pregnancy is relatively common among women who otherwise do not have a hazardous lifestyle, which reduces the risk of residual confounding and increasing the possibility to identify its effects. We aimed to examine the association of antenatal exposure to opium with risks of small for gestational age, short birth length, and small head circumference at birth. METHOD: In this cohort study in the rural area of the Golestan province, Iran, we randomly selected 920 women who were exposed to opium during pregnancy and 920 unexposed women during 2008-2010. Log-binomial regression was used to estimate risk ratios (RR) and 95% confidence intervals (CI) for the associations between prenatal exposure to opium and risks of small for gestational age, short birth length, and small head circumference at birth. RESULTS: Compared with non-use of opium and tobacco during pregnancy, using opium only and dual use of opium and tobacco were associated with increased risks of small for gestational age at births (RR = 1.71; 95% CI 1.34-2.18 and RR = 1.62; 95% CI 1.13-2.30, respectively). Compared with non-use of opium and tobacco, exposure to only opium or dual use of opium and tobacco were also associated with more than doubled increased risks of short birth length, and small head circumference in term infants. CONCLUSION: Maternal opium use during pregnancy is associated with increased risks of giving birth to a small for gestational age infant, as well as a term infant with short birth length or small head circumference.

Maternal snuff use and cotinine in late pregnancy-A validation study.

INTRODUCTION: Oral moist snuff is widely used in Sweden including during pregnancy. Maternal snuff use has been associated with increased risks of adverse pregnancy outcomes in epidemiological studies. Self-reported maternal snuff use has not been validated previously. The main objective of this study was to validate self-reported snuff use in pregnancy in a prospective cohort study and in the Medical Birth Register. MATERIAL AND METHODS: A prospective Swedish cohort study, 2005-2011, in which 572 women were asked to participate. Of 474 recruited women, 381 non-smokers (263 snuff users and 118 non-tobacco users) were included in the main analyses. Participants prospectively reported snuff use through questionnaires. Medical Birth Register data on the participants was obtained. Maternal urine cotinine was collected in late pregnancy and was used as a biomarker. RESULTS: Cotinine levels in maternal urine confirmed a high validity of self-reported snuff use through questionnaires in late pregnancy; sensitivity and specificity values were 98% and 96%, respectively. In the Medical Birth Register, 45% of the snuff users were misclassified as nonusers in late pregnancy. There were significant differences in median cotinine levels between users of mini pouches and users of standard pouches, but there was a great difference of cotinine levels among users with similar number of pouches used daily. CONCLUSIONS: Self-reported snuff use through questionnaires has high validity. In the Medical Birth Register, in late pregnancy, many snuff users were misclassified as nonusers. As a consequence, there is a risk of underestimating the harmful effects of snuff use when using late pregnancy Medical Birth Register data.

Prenatal exposure to preeclampsia is associated with accelerated height gain in early childhood.

BACKGROUND: Preeclampsia is associated with low birth weight, both because of increased risks of preterm and of small-for-gestational-age (SGA) births. Low birth weight is associated with accelerated childhood height gain and cardiovascular diseases later in life. The aim was to investigate if prenatal exposure to preeclampsia is associated with accelerated childhood height gain, also after adjustments for SGA-status and gestational age at birth. METHODS: In a cohort of children prenatally exposed to preeclampsia (n = 865) or unexposed (n = 22,898) we estimated height gain between birth and five years of age. The mean difference in height gain between exposed and unexposed children was calculated and adjustments were done with linear regression models. RESULTS: Children exposed to preeclampsia were on average born shorter than unexposed. Exposed children grew on average two cm more than unexposed from birth to five years of age. After adjustments for maternal characteristics including socioeconomic factors, height, body mass index (BMI) and diabetes, as well as for parents smoking habits, infant's breastfeeding and childhood obesity, the difference was 1.6 cm (95% CI 1.3-1.9 cm). Further adjustment for SGA birth only slightly attenuated this estimate, but adjustment for gestational age at birth decreased the estimate to 0.5 cm (95% CI 0.1-0.7 cm). CONCLUSION: Prenatal exposure to preeclampsia is associated with accelerated height gain in early childhood. The association seemed independent on SGA-status, but partly related to shorter gestational age at birth.

Tumor characteristics and prognosis in women with pregnancy-associated breast cancer.

There is evidence of poor prognosis in women with pregnancy-associated breast cancer (PABC) diagnosed during pregnancy or within 2 years of delivery. Using a large, population-based cohort, we examined clinicopathologic features and survival in women with PABC. A cohort of women diagnosed with invasive breast cancer between 1992 and 2009 at ages 15-44 years was identified in the Swedish Cancer Register and the Breast Cancer Quality Registers. Dates of childbirths for each woman were retrieved from the Swedish Multi-Generation Register. Age-standardized distributions of tumor stage (tumor size, nodal status, metastasis), Elston grade and ER/PR/HER2 status were compared between nulliparous women and women with breast cancer during pregnancy and up to 10 years postdelivery. Adjusted hazard ratios for all-cause mortality rates among patients were estimated using Cox regression. We identified 1,661 nulliparous women with breast cancer, 778 women with PABC (97 during pregnancy, 270 within first and 411 within second year postdelivery) and 3,598 during 2-10 years postdelivery. Compared to nulliparous women, women with PABC, and especially women diagnosed 0-12 months after delivery, had more advanced T and N stage, and higher proportions of ER/PR negative, HER2 positive and triple-negative tumors. Increased hazard ratios were observed in women diagnosed within 5 years of delivery after adjustment for age, year, education and region. Following additional adjustment for tumor characteristics, the hazard ratios were attenuated and nonsignificant. The poorer prognosis observed in women with PABC appears to be largely explained by more adverse tumor characteristics at diagnosis.

A prospective investigation of perceived stress, infertility-related stress, and cortisol levels in women undergoing in vitro fertilization: influence on embryo quality and clinical pregnancy rate.

INTRODUCTION: Women undergoing fertility treatment experience high levels of stress. However, it remains uncertain if and how stress influences in vitro fertilization (IVF) cycle outcome. This study aimed to investigate whether self-reported perceived and infertility-related stress and cortisol levels were associated with IVF cycle outcomes. MATERIAL AND METHODS: A prospective cohort of 485 women receiving fertility treatment was recruited from September 2011 to December 2013 and followed until December 2014. Data were collected by online questionnaire prior to IVF start and from clinical charts. Salivary cortisol levels were measured. Associations between stress and cycle outcomes (clinical pregnancy and indicators of oocyte and embryo quality) were measured by logistic or linear regression, adjusted for age, body mass index, education, smoking, alcohol and caffeine consumption, shiftwork and night work. RESULTS: Ultrasound verified pregnancy rate was 26.6% overall per cycle started and 32.9% per embryo transfer. Stress measures were not associated with clinical pregnancy: when compared with the lowest categories, the adjusted odds ratio (OR) and 95% confidence interval (CI) for the highest categories of the perceived stress score was 1.04 (95% CI 0.58-1.87), infertility-related stress score was OR = 1.18 (95% CI 0.56-2.47), morning and evening cortisol was OR = 1.18 (95% CI 0.60-2.29) and OR = 0.66 (95% CI 0.34-1.30), respectively. CONCLUSIONS: Perceived stress, infertility-related stress, and cortisol levels were not associated with IVF cycle outcomes. These findings are potentially reassuring to women undergoing fertility treatment with concerns about the influence of stress on their treatment outcome.

Surge of immune cell formation at birth differs by mode of delivery and infant characteristics-A population-based cohort study.

BACKGROUND: Birth by cesarean section is associated with increased risks of immune disorders. We tested whether establishment of immune function at birth relates to mode of delivery, taking other maternal and infant characteristics into account. METHODS AND FINDINGS: Using a prospectively collected database, we retrieved information on maternal and infant characteristics of 6,014 singleton infants delivered from February to April 2014 in Stockholm, Sweden, with gestational age ≥35 weeks, Apgar scores ≥7, and without congenital malformations or any neonatal morbidity. We linked our data to blood levels of T-cell receptor excision circles (TREC) and κ-deleting recombination excision circles (KREC), determined as part of a neonatal screening program for immune-deficiencies, and representing quantities of newly formed T- and B-lymphocytes. Multivariate logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI) for participants having TREC and KREC levels in the lowest quintile. Multivariate models were adjusted for postnatal age at blood sampling, and included perinatal (mode of delivery, infant sex, gestational age, and birth weight for gestational age), and maternal characteristics (age, parity, BMI, smoking, diabetes, and hypertensive disease). Low TREC was associated with cesarean section before labor (adjusted OR:1.32 [95% CI 1.08-1.62]), male infant sex (aOR:1.60 [1.41-1.83]), preterm birth at 35-36 weeks of gestation (aOR:1.89 [1.21-2.96]) and small for gestational age (aOR:1.67 [1.00-2.79]). Low KREC was associated with male sex (aOR:1.32 [1.15-1.50]), postterm birth at ≥42 weeks (aOR:1.43 [1.13-1.82]) and small for gestational age (aOR:2.89 [1.78-4.69]). Maternal characteristics showed no consistent associations with neonatal levels of either TREC or KREC. CONCLUSION: Cesarean section before labor was associated with lower T-lymphocyte formation, irrespective of maternal characteristics, pregnancy, and neonatal risk factors. The significance of a reduced birth-related surge in lymphocyte formation for future immune function and health remains to be investigated.

Association Between Pregnancy and Perinatal Outcomes Among Women With Epilepsy.

Importance: To date, few attempts have been made to examine associations between exposure to maternal epilepsy with or without antiepileptic drug (AED) therapy and pregnancy and perinatal outcomes. Objectives: To investigate associations between epilepsy in pregnancy and risks of pregnancy and perinatal outcomes as well as whether use of AEDs influenced risks. Design, Setting, and Participants: A population-based cohort study was conducted on all singleton births at 22 or more completed gestational weeks in Sweden from 1997 through 2011; of these, 1 424 279 were included in the sample. Information on AED exposure was available in the subset of offspring from July 1, 2005, to December 31, 2011. Data analysis was performed from October 1, 2016, to February 15, 2017. Main Outcomes and Measures: Pregnancy, delivery, and perinatal outcomes. Multivariable Poisson log-linear regression was used to estimate adjusted risk ratios (aRRs) and 95% CIs, after adjusting for maternal age, country of origin, educational level, cohabitation with a partner, height, early pregnancy body mass index, smoking, year of delivery, maternal pregestational diabetes, hypertension, and psychiatric disorders. Results: Of the 1 429 652 births included in the sample, 5373 births were in 3586 women with epilepsy; mean (SD) age at first delivery of the epilepsy cohort was 30.54 (5.18) years. Compared with pregnancies of women without epilepsy, women with epilepsy were at increased risks of adverse pregnancy and delivery outcomes, including preeclampsia (aRR 1.24; 95% CI, 1.07-1.43), infection (aRR, 1.85; 95% CI, 1.43-2.29), placental abruption (aRR, 1.68; 95% CI, 1.18-2.38), induction (aRR, 1.31; 95% CI, 1.21-1.40), elective cesarean section (aRR, 1.58; 95% CI, 1.45-1.71), and emergency cesarean section (aRR, 1.09; 95% CI, 1.00-1.20). Infants of mothers with epilepsy were at increased risks of stillbirth (aRR, 1.55; 95% CI, 1.05-2.30), having both medically indicated (aRR, 1.24; 95% CI, 1.08-1.43) and spontaneous (aRR, 1.34; 95% CI, 1.20-1.53) preterm birth, being small for gestational age at birth (aRR, 1.25; 95% CI, 1.13-1.30), and having neonatal infections (aRR, 1.42; 95% CI, 1.17-1.73), any congenital malformation (aRR, 1.48; 95% CI, 1.35-1.62), major malformations (aRR, 1.61; 95% CI, 1.43-1.81), asphyxia-related complications (aRR, 1.75; 95% CI, 1.26-2.42), Apgar score of 4 to 6 at 5 minutes (aRR, 1.34; 95% CI, 1.03-1.76), Apgar score of 0 to 3 at 5 minutes (aRR, 2.42; 95% CI, 1.62-3.61), neonatal hypoglycemia (aRR, 1.53; 95% CI, 1.34-1.75), and respiratory distress syndrome (aRR, 1.48; 95% CI, 1.30-1.68) compared with infants of unaffected women. In women with epilepsy, using AEDs during pregnancy did not increase the risks of pregnancy and perinatal complications, except for a higher rate of induction of labor (aRR, 1.30; 95% CI, 1.10-1.55). Conclusions and Relevance: Epilepsy during pregnancy is associated with increased risks of adverse pregnancy and perinatal outcomes. However, AED use during pregnancy is generally not associated with adverse outcomes.

Maternal Overweight and Obesity and Genital Anomalies in Male Offspring: A Population-Based Swedish Cohort Study.

BACKGROUND: Overweight and obese pregnant women face higher risk of several critical birth outcomes, including an overall increased risk of congenital abnormalities. Only few studies have focused on associations between maternal overweight and the genital anomalies in boys, cryptorchidism and hypospadias, and results are inconclusive. METHODS: We performed a population-based cohort study and assessed the associations between maternal body mass index (BMI) in early pregnancy and occurrence of cryptorchidism and hypospadias. All live-born singleton boys born in Sweden from 1992 to 2012 were included. From the Swedish Patient Register, information on cryptorchidism and hypospadias was available. Data were analysed using Cox proportional hazards regression adjusted for potential confounders. Mediation analyses were performed to estimate how much of the association between BMI and genital anomalies were mediated through obesity-related diseases. RESULTS: Of the 1 055 705 live-born singleton boys born from 1992 to 2012, 6807 (6.4 per 1000) were diagnosed with hypospadias and 16 469 (15.6 per 1000) were diagnosed with cryptorchidism, of which 9768 (9.3 per 1000) underwent corrective surgery for cryptorchidism. We observed dose-response associations between maternal BMI and hypospadias and cryptorchidism. Boys of mothers with BMI ≥40.0 kg/m2 had the highest adjusted hazard ratios for hypospadias (HR 1.35, 95% confidence interval [CI] 1.04, 1.76) and cryptorchidism (HR 1.25, 95% CI 1.00, 1.58). A substantial proportion of the associations between BMI and the genital anomalies were mediated through preeclampsia. CONCLUSION: This large register-based study adds to the current literature and indicates that the occurrence of hypospadias and cryptorchidism increase with maternal overweight and obesity severity.

Opium use during pregnancy and risk of preterm delivery: A population-based cohort study.

BACKGROUND: Use of narcotic or "recreational" drugs has been associated with adverse pregnancy outcomes such as preterm delivery. However, the associations might be confounded by other factors related to high-risk behaviours. This is the first study to investigate the association between traditional opium use during pregnancy and risk of preterm delivery. METHOD AND FINDINGS: We performed a population-based cohort study in the rural areas of the Golestan province, Iran between 2008 and 2010. We randomly selected 920 women who used (usually smoked) opium during pregnancy and 920 women who did not. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations between the opium use during pregnancy and preterm delivery and adjustment was made for potential confounding factors. This study shows compared with non-use of opium and tobacco, use of only opium during pregnancy was associated with an increased risk of preterm delivery (OR = 1.56; 95% CI 1.05-2.32), and the risk was more than two-fold increased among dual users of opium and tobacco (OR = 2.31; 95% CI 1.37-3.90). We observed that opium use only was associated with a doubled risk for preterm caesarean delivery (OR = 2.05; 95% CI 1.10-3.82) but not for preterm vaginal delivery (OR = 1.25; 95% CI 0.75-2.07). Dual use of opium and tobacco was associated with a substantially increased risk of vaginal preterm delivery (OR = 2.58; 95% CI 1.41-4.71). CONCLUSIONS: Opium use during pregnancy among non-tobacco smokers is associated with an increased risk of preterm caesarean delivery, indicating an increased risk of a compromised foetus before or during labour. Women who use both opium and smoked during pregnancy have an increased risk of preterm vaginal delivery, indicating an increased risk of spontaneous preterm delivery.

Maternal Cancer During Pregnancy and Risks of Stillbirth and Infant Mortality.

Purpose To examine whether maternal cancer during pregnancy is associated with increased risks of stillbirth and infant mortality. Methods On the basis of nationwide health registers, we conducted a study of 3,947,215 singleton births in Sweden from 1973 through 2012. Exposure was defined as maternal cancer diagnosed during pregnancy (number of births = 984) or during the year after pregnancy (number of births = 2,723). We calculated incidence rate ratios (IRRs) for stillbirth and infant mortality, comparing exposed births to unexposed births. Small-for-gestational-age (SGA) and preterm births were examined as secondary outcomes. Results Maternal cancer diagnosed during pregnancy was positively associated with stillbirth (IRR, 2.5; 95% CI, 1.2 to 5.0), mainly stillbirths assessed as SGA (IRR, 4.9; 95% CI, 2.2 to 11.0), and with preterm SGA births (relative risk 3.0; 95% CI, 2.1 to 4.4). Positive associations of maternal cancer diagnosed during pregnancy or the year after pregnancy were noted for both neonatal mortality (deaths within 0 to 27 days; IRR, 2.7; 95% CI, 1.3 to 5.6 and IRR, 2.0; 95% CI, 1.2 to 3.2, respectively) and preterm birth (IRR, 5.8; 95% CI, 5.3 to 6.5 and IRR, 1.6; 95% CI, 1.4 to 1.8, respectively). The positive association with preterm birth was due to iatrogenic instead of spontaneous preterm birth. Preterm birth explained 89% of the association of maternal cancer during pregnancy with neonatal mortality. Conclusion Maternal cancer during pregnancy is associated with increased risks of rare but fatal outcomes, including stillbirth and neonatal mortality. This may be due to conditions associated with fetal growth restriction and iatrogenic preterm birth. Careful monitoring of fetal growth and cautious decision making on preterm delivery should therefore be reinforced.

Maternal Body Mass Index in Early Pregnancy and Risk of Epilepsy in Offspring.

Importance: There is growing concern about the long-term neurologic effects of prenatal exposure to maternal overweight and obesity. The causes of epilepsy are poorly understood and, in more than 60% of the patients, no definitive cause can be determined. Objectives: To investigate the association between early pregnancy body mass index (BMI) and the risk of childhood epilepsy and examine associations between obesity-related pregnancy and neonatal complications and risks of childhood epilepsy. Design, Setting, and Participants: A population-based cohort study of 1 441 623 live single births at 22 or more completed gestational weeks in Sweden from January 1, 1997, to December 31, 2011, was conducted. The diagnosis of epilepsy as well as obesity-related pregnancy and neonatal complications were based on information from the Sweden Medical Birth Register and National Patient Register. Multivariate Cox proportional hazards regression models were used to estimate adjusted hazard ratios (HRs) and 95% CIs after adjusting for maternal age, country of origin, educational level, cohabitation with partner, height, smoking, maternal epilepsy, and year of delivery. Data analysis was conducted from June 1 to December 15, 2016. Main Outcomes and Measures: Risk of childhood epilepsy. Results: Of the 1 421 551 children born between January 1, 1997, and December 31, 2011, with covariate information available, 7592 (0.5%) were diagnosed with epilepsy through December 31, 2012. Of these 3530 (46.5%) were female. The overall incidence of epilepsy in children aged 28 days to 16 years was 6.79 per 10 000 child-years. Compared with offspring of normal-weight mothers (BMI 18.5 to <25.0), adjusted HRs of epilepsy by maternal BMI categories were as follows: overweight (BMI 25.0 to <30.0), 1.11 (95% CI, 1.04-1.17); obesity grade I (BMI 30.0 to <35.0), 1.20 (95% CI, 1.10-1.31); obesity grade II (BMI 35.0 to <40.0), 1.30 (95% CI, 1.12-1.50); and obesity grade III (BMI≥40.0), 1.82 (95% CI, 1.46-2.26). The rates of epilepsy were considerably increased for children with malformations of the nervous system (adjusted HR, 46.4; 95% CI, 42.2-51.0), hypoxic ischemic encephalopathy (adjusted HR, 23.6; 95% CI, 20.6-27.1), and neonatal convulsions (adjusted HR, 33.5; 95% CI, 30.1-37.4). The rates of epilepsy were doubled among children with neonatal hypoglycemia (adjusted HR, 2.10; 95% CI, 1.90-2.33) and respiratory distress syndrome (adjusted HR, 2.43; 2.21-2.66), and neonatal jaundice was associated with more than a 50% increased risk of epilepsy (adjusted HR, 1.47; 95% CI, 1.33-1.63). The elevated risk of epilepsy in children of overweight or obese mothers was not explained by obesity-related pregnancy or neonatal complications. Conclusions and Relevance: The rates of childhood epilepsy increased with maternal overweight or obesity in a dose-response manner. Given that overweight and obesity are modifiable, prevention of obesity may be an important public health strategy to reduce the incidence of childhood epilepsy.

Association Between Maternal Body Mass Index in Early Pregnancy and Incidence of Cerebral Palsy.

Importance: Maternal overweight and obesity are associated with increased risks of preterm delivery, asphyxia-related neonatal complications, and congenital malformations, which in turn are associated with increased risks of cerebral palsy. It is uncertain whether risk of cerebral palsy in offspring increases with maternal overweight and obesity severity and what could be possible mechanisms. Objective: To study the associations between early pregnancy body mass index (BMI) and rates of cerebral palsy by gestational age and to identify potential mediators of these associations. Design, Setting, and Participants: Population-based retrospective cohort study of women with singleton children born in Sweden from 1997 through 2011. Using national registries, children were followed for a cerebral palsy diagnosis through 2012. Exposures: Early pregnancy BMI. Main Outcomes and Measures: Incidence rates of cerebral palsy and hazard ratios (HRs) with 95% CIs, adjusted for maternal age, country of origin, education level, cohabitation with a partner, height, smoking during pregnancy, and year of delivery. Results: Of 1 423 929 children included (mean gestational age, 39.8 weeks [SD, 1.8]; 51.4% male), 3029 were diagnosed with cerebral palsy over a median 7.8 years of follow-up (risk, 2.13 per 1000 live births; rate, 2.63/10 000 child-years). The percentages of mothers in BMI categories were 2.4% at BMI less than 18.5 (underweight), 61.8% at BMI of 18.5 to 24.9 (normal weight), 24.8% at BMI of 25 to 29.9 (overweight), 7.8% at BMI of 30 to 34.9 (obesity grade 1), 2.4% at BMI of 35 to 39.9 (obesity grade 2), and 0.8% at BMI 40 or greater (obesity grade 3). The number of cerebral palsy cases in each BMI category was 64, 1487, 728, 239, 88, and 38; and the rates per 10 000 child-years were 2.58, 2.35, 2.92, 3.15, 4.00, and 5.19, respectively. Compared with children of normal-weight mothers, adjusted HR of cerebral palsy were 1.22 (95% CI, 1.11-1.33) for overweight, 1.28 (95% CI, 1.11-1.47) for obesity grade 1, 1.54 (95% CI, 1.24, 1.93) for obesity grade 2, and 2.02 (95% CI, 1.46-2.79) for obesity grade 3. Results were statistically significant for children born at full term, who comprised 71% of all children with cerebral palsy, but not for preterm infants. An estimated 45% of the association between maternal BMI and rates of cerebral palsy in full-term children was mediated through asphyxia-related neonatal morbidity. Conclusions and Relevance: Among Swedish women with singleton children, maternal overweight and obesity were significantly associated with the rate of cerebral palsy. The association was limited to children born at full term and was partly mediated through asphyxia-related neonatal complications.

Chronic Hypertension in Women after Perinatal Exposure to Preeclampsia, Being Born Small for Gestational Age or Preterm.

BACKGROUND: There is an established association between adverse events during perinatal life and chronic hypertension in adult life. However, disadvantageous conditions often co-exist in the same pregnancy. We investigated single and joint perinatal exposure to preeclampsia, being born small for gestational age (SGA) or preterm and subsequent risk of chronic hypertension. METHODS: The study population consisted of 731 008 primiparous women from Norway and Sweden registered in the Medical Birth Registers, both as infants and as first time mothers between 1967-2009 (Norway) and 1973-2010 (Sweden). Risk of chronic hypertension in early pregnancy was calculated in women with perinatal exposures to preeclampsia, born SGA or preterm by log-binominal regression analysis, and adjusted for maternal age and level of education in the first generation. RESULTS: The rate of chronic hypertension was 0.4%. Risk of chronic hypertension was associated with single perinatal exposure to preeclampsia, being born SGA or preterm with adjusted relative risk (95% confidence interval, CI) of 2.2 (95% CI 1.8, 2.7), 1.1 (95% CI 1.0, 1.3), and 1.3 (95% CI 1.0, 1.5) respectively. The risks increased after joint exposures, with an almost fourfold risk increase after perinatal exposure to preeclampsia and preterm birth. Additional adjustment for BMI and smoking in the second generation in a subset of the cohort only had a minor impact on the results. CONCLUSIONS: Perinatal exposure to preeclampsia, being born SGA or preterm is independently associated with increased risk of chronic hypertension. The highest risk was seen after exposure to preeclampsia, especially if combined with SGA or preterm birth.

The Impact of Small for Gestational Age Births in Early and Late Preeclamptic Pregnancies for Preeclampsia Recurrence: a Cohort Study of Successive Pregnancies in Sweden.

BACKGROUND: Results from uterine artery Doppler investigations suggest that the aetiology of late preeclampsia with fetal growth restriction may be more similar to the aetiology of early preeclampsia than with late preeclampsia without fetal growth restriction. We hypothesised that a small-for-gestational-age (SGA) birth in a late preeclamptic pregnancy may be associated with increased subsequent risk of early preeclampsia. We also studied effects of maternal factors on risks of preeclampsia recurrence. METHODS: In a nation-wide Swedish cohort study of first and second consecutive single births between 1992 and 2012, we identified 22 473 mothers with preeclampsia in their first pregnancy. We calculated relative risks (RR), and 95% confidence intervals (CI), to investigate associations between subtypes of preeclampsia in the first pregnancy and risks of early (<34 weeks) and late (≥34 weeks) preeclampsia in the second pregnancy. RESULTS: In women with a previous late preeclampsia, a co-occurring SGA birth was associated with an increased risk of subsequent early preeclampsia (adjusted RR 2.85, 95% CI 1.93, 4.20), but not of subsequent late preeclampsia. Among women with a previous early preeclampsia, a co-occurring SGA birth was not associated with increased subsequent risks of early or late preeclampsia. Interpregnancy weight gain was associated with increased risks of early and late preeclampsia in the second pregnancy. CONCLUSIONS: Late preeclampsia combined with fetal growth restriction may be regarded as an ischaemic placental disease. Given the high absolute risk of preeclampsia recurrence, preventing weight gain may be especially important in women with previous preeclampsia.