Recurrence of postpartum hemorrhage, maternal and paternal contribution, and the effect of offspring birthweight and sex: a population-based cohort study.

PURPOSE: This study examines individual aggregation of postpartum hemorrhage (PPH), paternal contribution and how offspring birthweight and sex influence recurrence of PPH. Further, we wanted to estimate the proportion of PPH cases attributable to a history of PPH or current birthweight. METHODS: We studied all singleton births in Norway from 1967 to 2017 using data from Norwegian medical and administrational registries. Subsequent births in the parents were linked. Multilevel logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CI) for PPH defined as blood loss > 500 ml, blood loss > 1500 ml, or the need for blood transfusion in parous women. Main exposures were previous PPH, high birthweight, and fetal sex. We calculated adjusted population attributable fractions for previous PPH and current high birthweight. RESULTS: Mothers with a history of PPH had three- and sixfold higher risks of PPH in their second and third deliveries, respectively (adjusted OR 2.9; 95% CI 2.9-3.0 and 6.0; 5.5-6.6). Severe PPH (> 1500 ml) had the highest risk of recurrence. The paternal contribution to recurrence of PPH in deliveries with two different mothers was weak, but significant. If the neonate was male, the risk of PPH was reduced. A history of PPH or birthweight ≥ 4000 g each accounted for 15% of the total number of PPH cases. CONCLUSION: A history of PPH and current birthweight exerted strong effects at both the individual and population levels. Recurrence risk was highest for severe PPH. Occurrence and recurrence were lower in male fetuses, and the paternal influence was weak.

Recurrence of postpartum hemorrhage in relatives: A population-based cohort study.

INTRODUCTION: Studies on the family aggregation of postpartum hemorrhage (PPH) are scarce and with inconsistent results, and to what extent current birthweight influences recurrence between relatives remains to be studied. Further, family aggregation of PPH has been studied from an individual, but not from a public heath perspective. We aimed to investigate family aggregation of PPH in Norway, how birthweight influences these effects, and to estimate the proportion of PPH cases attributable to a family history of PPH and current birthweight. MATERIAL AND METHODS: Using data from the Medical Birth Registry of Norway, Statistics Norway, and Central Population Registry of Norway we identified individuals as newborns, parents, grandparents, and full and half-siblings, and studied 1 002 687 mother-offspring, 841 164 father-offspring, and 761 011 both-parents-offspring pairs. We used multilevel logistic regression to calculate odds ratios (OR) with 95% CI. RESULTS: If the birth of the mother but not of the father involved PPH, then the OR of PPH (>500 mL) in the next generation was 1.44 (95% CI 1.39-1.49). If the birth of the father but not of the mother involved PPH, then OR was 1.12 (95% CI 1.08-1.16). These effects were stronger in severe PPH. Recurrence between siblings was highest between full sisters (OR 1.47, 95% CI 1.41-1.52), followed by maternal half-sisters, paternal half-sisters, and partners of full brothers. A family history of PPH or birthweight of 4000 g or more accounted for ≤5% and 15% of the total number of PPH cases, respectively. CONCLUSIONS: A history of PPH in relatives influenced the recurrence risk of PPH in a dose-response pattern consistent with the anticipated proportion of shared genes. The recurrence was highest through the maternal line.

Term Birth Weight and Neurodevelopmental Outcomes.

BACKGROUND: Preterm birth is an important risk factor for neurodevelopmental disabilities. The vast majority of these disabilities occur, however, among term births. The role of fetal growth restriction specifically among term babies has been incompletely described. METHODS: We conducted a population-based study of term birth weight and its link to a range of neurodevelopmental outcomes using Norwegian health registries. To remove the influence of preterm birth, we restricted our analyses to 1.8 million singleton babies born during a narrow range of term gestational age (39-41 weeks). Babies with malformations were excluded. We adjusted analyses simply for year of birth, as further adjustments for sex, parity, maternal age, smoking, marital status, immigrant status, and parental education had trivial influence. An additional sibling analysis controlled for unmeasured family-based confounding. RESULTS: The risk of neurodevelopmental disabilities at term steadily increased at birth weights lower than 3.5 kg. Using the category of 3.5-3.9 kg as the reference, the odds reached 25-fold for cerebral palsy at the smallest weights (95% confidence interval 8.0, 79), 16-fold for vision/hearing disability (4.0, 65), 11-fold for intellectual impairment (6.9, 17), 7-fold for schizophrenia (1.0, 50), 5.4-fold for epilepsy (2.6, 12), and 3.5-fold for autism spectrum (1.3, 9.4) and behavioral disorders including attention-deficit hyperactivity disorder (2.1, 5.4). Associations remained robust with sibling controls. CONCLUSIONS: Reduced fetal growth is a powerful predictor of a wide variety of neurodevelopmental disabilities independent of preterm delivery.

Maternal Chronic Conditions and Risk of Cerebral Palsy in Offspring: A National Cohort Study.

BACKGROUND AND OBJECTIVES: Previous studies suggest that children of mothers with certain chronic conditions may be at increased risk of cerebral palsy (CP). We explored possible associations between 17 maternal chronic conditions and CP in offspring. METHODS: We conducted a prospective cohort study of Norwegian children born in 1990-2012 and surviving to 2 years of age. Information on maternal chronic conditions during pregnancy were extracted from the Medical Birth Registry of Norway (1990-2012). Information on chronic conditions in mothers and fathers recorded in the Norwegian Patient Registry (2008-2014) was available for a subset of children. CP diagnoses were extracted from the National Insurance Scheme (1990-2014) and the Norwegian Patient Registry (2008-2014). We estimated relative risks (RRs) and 95% confidence intervals (CIs) of CP in offspring of parents with chronic conditions compared with the general population using log binominal regression models. RESULTS: A total of 1 360 149 Norwegian children, including 3575 children with CP (2.6 per 1000 live births), fulfilled the inclusion criteria. The highest risk of CP was among offspring of mothers with type 2 diabetes (RR 3.2; 95% CI 1.8-5.4), lupus erythematosus (RR 2.7; 95% CI 0.9-8.3), type 1 diabetes (RR 2.2; 95% CI 1.4-3.4), and Crohn disease (RR 2.1; 95% CI 1.0-4.1) during pregnancy. No increased risks were seen for offspring of fathers with chronic conditions. CONCLUSIONS: Several maternal chronic conditions were associated with increased risk of CP in offspring. Maternal autoimmune disorders carried a particular risk.

Neonatal Morbidity and 1-Year Survival of Extremely Preterm Infants.

OBJECTIVE: To determine 1-year survival and major neonatal morbidities (intracranial hemorrhage grade >2, cystic periventricular leukomalacia, retinopathy of prematurity grade >2, necrotizing enterocolitis, severe bronchopulmonary dysplasia) among extremely preterm infants in Norway in 2013-2014, and to compare the results to the first Norwegian Extreme Prematurity Study 1999-2000 and similar contemporary European population-based studies. METHODS: Population-based study of all infants born at 22 through 26 weeks' gestation in Norway in 2013-2014. Prospectively collected data were obtained by linking data in the Norwegian Neonatal Network to the Medical Birth Registry of Norway. RESULTS: Of 420 infants (incidence 3.5 per 1000 births), 145 were stillborn (34.5%), 275 were live-born (82.3% of the 334 fetuses alive at admission for obstetrical care), and 251 (91.3% of live-born infants) were admitted to a neonatal unit. The survival among live-born infants was 18% at 22 weeks, 29% at 23 weeks, 56% at 24 weeks, 84% at 25 weeks and 90% at 26 weeks (for each week increment in gestational age: odds ratio 3.3; 95% confidence interval, 2.4-4.4). Among infants surviving to 1 year of age, major neonatal morbidity was diagnosed in 55%. Decreasing gestational age was moderately associated with rates of major morbidity (odds ratio 1.6; 95% confidence interval, 1.2-2.2). CONCLUSIONS: Compared to the previous 1999-2000 cohort, the rate of stillbirth before admission to an obstetrical unit increased, whereas the survival rate among live born infants was similar in our 2013-2014 cohort. Neonatal morbidity rates remain high among extremely preterm infants.

Suicide and violent deaths in survivors of cancer in childhood, adolescence and young adulthood-A national cohort study.

Suicide risk in adult cancer patients is found to be elevated, but limited information exists regarding risks of suicide and non-suicidal violent deaths when diagnosed with cancer in young age. We investigate suicide and violent deaths in a national cohort including individuals diagnosed with cancer before age 25. Through the linkage of different national registries (Cancer Registry of Norway, Norwegian Causes of Death Registry and the National Registry) a cohort of all live births in Norway during 1965-1985 was defined and followed up through 2008. Individuals diagnosed with cancer before age 25 and the cancer-free references were compared using an extended Cox proportional hazard regression model. The cohort comprised 1,218,013 individuals, including 5,440 diagnosed with cancer before age 25. We identified 24 suicides and 14 non-suicidal violent deaths in the cancer group. The hazard ratio (HR) of suicide in the cancer group was 2.5 (95% confidence interval (CI) 1.7-3.8), and was increased both when diagnosed with cancer in childhood (0-14 years of age); HR = 2.3 (95% CI: 1.2-4.6), and during adolescence/young adulthood (15-24 years); HR = 2.6 (95% CI: 1.5-4.2). Survivors of bone/soft tissue sarcomas, CNS tumors and testicular cancer were at particular risk. The risk of non-suicidal violent death was not increased in the cancer survivors (HR = 1.0; 95% CI: 0.6-1.7). Although based on small numbers and the absolute risk of suicide being low, these are novel findings with important implications for establishing adequate follow-up including suicide prevention strategies for young cancer survivors.

Premature Adult Death in Individuals Born Preterm: A Sibling Comparison in a Prospective Nationwide Follow-Up Study.

BACKGROUND: Close to one in ten individuals worldwide is born preterm, and it is important to understand patterns of long-term health and mortality in this group. This study assesses the relationship between gestational age at birth and early adult mortality both in a nationwide population and within sibships. The study adds to existing knowledge by addressing selected causes of death and by assessing the role of genetic and environmental factors shared by siblings. METHODS: Study population was all Norwegian men and women born from 1967 to 1997 followed using nation-wide registry linkage for mortality through 2011 when they were between 15 and 45 years of age. Analyses were performed within maternal sibships to reduce variation in unobserved genetic and environmental factors shared by siblings. Specific outcomes were all-cause mortality and mortality from cardiovascular diseases, cancer and external causes including accidents, suicides and drug abuse/overdoses. RESULTS: Compared with a sibling born in week 37-41, preterm siblings born before 34 weeks gestation had 50% increased mortality from all causes (adjusted Hazard Ratio (aHR) 1.54, 95% confidence interval (CI) 1.17, 2.03). The corresponding estimate for the entire population was 1.27 (95% CI 1.09, 1.47). The majority of deaths (65%) were from external causes and the corresponding risk estimates for these deaths were 1.52 (95% CI 1.08, 2.14) in the sibships and 1.20 (95% CI 1.01, 1.43) in the population. CONCLUSION: Preterm birth before week 34 was associated with increased mortality between 15 and 45 years of age. The results suggest that increased premature adult mortality in this group is related to external causes of death and that the increased risks are unlikely to be explained by factors shared by siblings.

Maternal Prepregnancy BMI and Risk of Cerebral Palsy in Offspring.

OBJECTIVES: To investigate the association between maternal pre-pregnancy BMI and risk of cerebral palsy (CP) in offspring. METHODS: The study population consisted of 188 788 children in the Mothers and Babies in Norway and Denmark CP study, using data from 2 population-based, prospective birth cohorts: the Norwegian Mother and Child Cohort Study and the Danish National Birth Cohort. Prepregnancy BMI was classified as underweight (BMI <18.5), lower normal weight (BMI 18.5-22.9), upper normal weight (BMI 23.0-24.9), overweight (BMI 25.0-29.9), and obese (BMI ≥30). CP diagnoses were obtained from the national CP registries. Associations between maternal prepregnancy BMI and CP in offspring were investigated by using log-binomial regression models. RESULTS: The 2 cohorts had 390 eligible cases of CP (2.1 per 1000 live-born children). Compared with mothers in the lower normal weight group, mothers in the upper normal group had a 40% excess risk of having a child with CP (relative risk [RR], 1.35; 95% confidence interval [CI], 1.03-1.78). Excess risk was 60% (RR, 1.56; 95% CI, 1.21-2.01) for overweight mothers and 60% (RR, 1.55; 95% CI 1.11-2.18) for obese mothers. The risk of CP increased ∼4% for each unit increase in BMI (RR, 1.04; 95% CI, 1.02-1.06). Estimates changed little with adjustment for mother's occupational status, age, and smoking habits. CONCLUSIONS: Higher prepregnancy maternal BMI was associated with increased risk of CP in offspring.

Intake of Caffeinated Soft Drinks before and during Pregnancy, but Not Total Caffeine Intake, Is Associated with Increased Cerebral Palsy Risk in the Norwegian Mother and Child Cohort Study.

BACKGROUND: Postnatal administration of caffeine may reduce the risk of cerebral palsy (CP) in vulnerable low-birth-weight neonates. The effect of antenatal caffeine exposure remains unknown. OBJECTIVE: We investigated the association of intake of caffeine by pregnant women and risk of CP in their children. METHODS: The study was based on The Norwegian Mother and Child Cohort Study, comprising >100,000 live-born children, of whom 222 were subsequently diagnosed with CP. Mothers reported their caffeine consumption in questionnaires completed around pregnancy week 17 (102,986 mother-child pairs), week 22 (87,987 mother-child pairs), and week 30 (94,372 mother-child pairs). At week 17, participants were asked about present and prepregnancy consumption. We used Cox regression models to estimate associations between exposure [daily servings (1 serving = 125 mL) of caffeinated coffee, tea, and soft drinks and total caffeine consumption] and CP in children, with nonconsumers as the reference group. Models included adjustment for maternal age and education, medically assisted reproduction, and smoking, and for each source of caffeine, adjustments were made for the other sources. RESULTS: Total daily caffeine intake before and during pregnancy was not associated with CP risk. High consumption (≥6 servings/d) of caffeinated soft drinks before pregnancy was associated with an increased CP risk (HR: 1.9; 95% CI: 1.2, 3.1), and children of women consuming 3-5 daily servings of caffeinated soft drinks during pregnancy weeks 13-30 also had an increased CP risk (HR: 1.7; 95% CI: 1.1, 2.8). A mean daily consumption of 51-100 mg caffeine from soft drinks during the first half of pregnancy was associated with a 1.9-fold increased risk of CP in children (HR: 1.9; 95% CI: 1.1, 3.6). CONCLUSIONS: Maternal total daily caffeine consumption before and during pregnancy was not associated with CP risk in children. The observed increased risk with caffeinated soft drinks warrants further investigation.

Economic independence in survivors of cancer diagnosed at a young age: A Norwegian national cohort study.

BACKGROUND: The impact of cancer on socioeconomic outcomes is attracting attention as the number of survivors of cancer in young age continues to rise. This study examines economic independence in a national cohort of survivors of cancer at a young age in Norway. METHODS: Through the linkage of several national registries, the study cohort comprised 1,212,013 individuals born in Norway during 1965 through 1985, of which 5440 had received a cancer diagnosis before age 25 years. Follow-up was through 2007, and the main outcomes were receipt of governmental financial assistance, employment, income, and occupation. Analytic methods included Cox proportional hazard regression, log-binomial regression, and quantile regression models. RESULTS: Individuals in the cancer survivor group had an increased probability of receiving governmental financial assistance (men: hazard ratio [HR], 1.4; 95% confidence interval [CI], 1.3-1.5; women: HR, 1.5; 95% CI, 1.3-1.6) and of not being employed (men: HR, 1.4; 95% CI, 1.2-1.7; women: HR, 1.4; 95% CI, 1.2-1.6) compared with those in the noncancer group. Income discrepancies were particularly pronounced for survivors of central nervous system tumors. There was no difference in representation in higher skilled occupations. CONCLUSIONS: Survivors of cancer at a young age in Norway had an increased risk of being economically dependent and unemployed. This was evident in several tumor groups and was most pronounced in female survivors. There were only small differences in income or representation in higher skilled occupations for most employed survivors compared with the noncancer group. The current results are important for understanding the impact of a cancer diagnosis at a young age on subsequent job market outcomes. Cancer 2016;122:3873-3882. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Educational attainment among long-term survivors of cancer in childhood and adolescence: a Norwegian population-based cohort study.

PURPOSE: The number of young cancer survivors has increased over the past few decades due to improvement in treatment regimens, and understanding of long-term effects among the survivors has become even more important. Educational achievements and choice of educational fields were explored here. METHODS: Five-year cancer survivors born in Norway during 1965-1985 (diagnosed <19 years) were included in our analysis by linking Norwegian population-based registries. Cox regression was applied to study the educational attainment among survivors of central nervous system (CNS) tumours, those assumed to have received CNS-directed therapy, and other cancer survivors relative to the cancer-free population. Logistic regression was used to compare the choice of educational fields between the cancer survivors at undergraduate and graduate level and the cancer-free population. RESULTS: Overall, a lower proportion of the cancer survivors completed intermediate (67 vs. 70 %), undergraduate (31 vs. 35 %) and graduate education (7 vs. 9 %) compared with the cancer-free population. Deficits in completion of an educational level were mainly observed among survivors of CNS-tumours and those assumed to have received CNS-directed therapy. Choices of educational fields among cancer survivors were in general similar with the cancer-free population at both undergraduate and graduate levels. CONCLUSION: Survivors of CNS-tumours and those assumed to have received CNS-directed therapy were at increased risk for educational impairments compared with the cancer-free population. Choices of educational fields were in general similar. IMPLICATIONS FOR CANCER SURVIVORS: Careful follow-up of the survivors of CNS-tumours and those assumed to have received CNS-directed therapy is important at each level of education.

Cancer in childhood, adolescence, and young adults: a population-based study of changes in risk of cancer death during four decades in Norway.

PURPOSE: Cancer is one of the most common causes of death among young individuals. The purpose of this study was to explore the risk of early death (the first five years after diagnosis) among children (0-14 years), adolescents (15-19 years), and young adults (20-24 years) with cancer in Norway, born during 1965-1985. METHODS: The overall and cancer-specific early deaths were explored by linking population-based national registers (including the Cancer Registry of Norway and the Cause of Death Registry) that include the entire population of Norway (approximately 1.3 million individuals). Hazard and sub-hazard ratios were estimated using Cox regression analyses and competing risk models. RESULTS: A total of 5,828 individuals were diagnosed with cancer (56.3 % males). During follow-up, 1,415 individuals died from cancer (60.2 % males) within five years after diagnosis. The hazard ratio (HR) of overall death of the cancer patients relative to the general population decreased from 1965 (from HR, 385.8 (95 % confidence interval (CI): 335.3, 443.4) in 1965-74 to HR, 19.7 (CI: 9.3, 41.5) in 2005-09). Over all, there were fewer cancer-related deaths among female compared with male patients (sub-hazard ratio (SHR), 0.83 (CI: 0.74, 0.92)). Except for all hematopoietic malignancies, adolescents and young adult patients had lower risk of cancer death than children. CONCLUSION: The difference in risk of cancer and overall deaths between the cancer patients and the general population has been substantially reduced since 1965.

Immediate treatment versus sonographic surveillance for mild hip dysplasia in newborns.

OBJECTIVE: We conducted a blinded, randomized, controlled trial to examine whether mildly dysplastic but stable or instable hips would benefit from early treatment, as compared with watchful waiting. PATIENTS AND METHODS: A total of 128 newborns with mild hip dysplasia (sonographic inclination angle [alpha angle] of 43 degrees -49 degrees ) and stable or instable but not dislocatable hips were randomly assigned to receive either 6 weeks of abduction treatment (immediate-treatment group) or follow-up alone (active-sonographic-surveillance group). The main outcome measurement was the acetabular inclination angle, measured by radiograph, at 1 year of age. RESULTS: Both groups included 64 newborns, and there was no loss to follow-up. With the exception of a small but statistically significant excess of girls in the active-sonographic-surveillance group, there were no statistically significant differences in baseline characteristics between the 2 groups. The mean inclination angle at 12 months was 24.2 degrees for both groups (difference: 0.1 [95% confidence interval (CI): -0.8 to 0.9]), and all children had improved and were without treatment. The mean alpha angle was 59.7 degrees in the treatment group and 57.1 degrees in the active-surveillance group for a difference of 2.6 degrees evaluated after 1.5 and 3 months (95% CI: 1.8 to 3.4; P < .001). At 1.5 months of age, the hips had improved in all treated children but not in 5 children under active surveillance (P = .06). Among the sonographic-surveillance group, 47% received treatment after the initial surveillance period of 1.5 months. CONCLUSIONS: Active-sonographic-surveillance halved the number of children requiring treatment, did not increase the duration of treatment, and yielded similar results at 1-year follow-up. Given a reported prevalence of 1.3% for mildly dysplastic but stable hips, a strategy of active surveillance would reduce the overall treatment rate by 0.6%. Our results may have important implications for families as well as for health care costs.