Kari Klungsøyr

Cardiovascular mortality after pre-eclampsia in one child mothers: prospective, population based cohort study

Objective To assess the association of pre-eclampsia with later cardiovascular death in mothers according to their lifetime number of pregnancies, and particularly after only one child. Design Prospective, population based cohort study. Setting Medical Birth Registry of Norway. Participants We followed 836 147 Norwegian women with a first singleton birth between 1967 and 2002 for cardiovascular mortality through linkage to the national Cause of Death Registry. About 23 000 women died by 2009, of whom 3891 died from cardiovascular causes. Associations between pre-eclampsia and cardiovascular death were assessed by hazard ratios, estimated by Cox regression analyses. Hazard ratios were adjusted for maternal education (three categories), maternal age at first birth, and year of first birth Results The rate of cardiovascular mortality among women with preterm pre-eclampsia was 9.2% after having only one child, falling to 1.1% for those with two or more children. With term pre-eclampsia, the rates were 2.8% and 1.1%, respectively. Women with pre-eclampsia in their first pregnancy had higher rates of cardiovascular death than those who did not have the condition at first birth (adjusted hazard ratio 1.6 (95% confidence interval 1.4 to 2.0) after term pre-eclampsia; 3.7 (2.7 to 4.8) after preterm pre-eclampsia). Among women with only one lifetime pregnancy, the increase in risk of cardiovascular death was higher than for those with two or more children (3.4 (2.6 to 4.6) after term pre-eclampsia; 9.4 (6.5 to 13.7) after preterm pre-eclampsia). The risk of cardiovascular death was only moderately elevated among women with pre-eclamptic first pregnancies who went on to have additional children (1.5 (1.2 to 2.0) after term pre-eclampsia; 2.4 (1.5 to 3.9) after preterm pre-eclampsia). There was little evidence of additional risk after recurrent pre-eclampsia. All cause mortality for women with two or more lifetime births, who had pre-eclampsia in first pregnancy, was not elevated, even with preterm pre-eclampsia in first pregnancy (1.1 (0.87 to 1.14)). Conclusions Cardiovascular death in women with pre-eclampsia in their first pregnancy is concentrated mainly in women with no additional births. This association might be due to health problems that discourage or prevent further pregnancies rather than to pre-eclampsia itself. As a screening criterion for cardiovascular disease risk, pre-eclampsia is a strong predictor primarily among women with only one child—particularly with preterm pre-eclampsia.

Pre- and Perinatal Risk Factors in Adults with Attention-Deficit/Hyperactivity Disorder

BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) is a prevalent and disabling lifespan disorder, but little is yet known about risk factors for ADHD persisting beyond adolescence. The present study investigates the association between pregnancy and birth complications and ADHD in adulthood. METHODS We used data from the Medical Birth Registry of Norway to compare pre-and perinatal risk factors among 2323 adults approved for medical treatment for ADHD, with the remaining population born during the same years, 1967-1987, and surviving into adulthood (n = 1,170,073). Relative risks (RR) adjusted for potential confounders were calculated. RESULTS Preterm (< 37 weeks of gestation) and extremely preterm birth (< 28 weeks of gestation) were associated with 1.3- and 5-fold increased risks of ADHD, respectively. Birth weights <2500 g and <1500 g also increased the risk of ADHD (RR: 1.5, 95% confidence interval [CI]: 1.2-1.8, and RR: 2.1, 95% CI: 1.3-3.6, respectively). Five-minute Apgar scores <4 and <7 were associated with 2.8- and 1.5-fold increased risks of persisting ADHD, respectively. Maternal epilepsy (RR: 1.7, 95% CI: 1.1-2.7) and offspring oral cleft (RR: 2.8, 95% CI: 1.6-4.9) occurred more frequently among adult ADHD patients. CONCLUSIONS This is the first population-based study of pre-and perinatal risk factors in adults with ADHD. We show that low birth weight, preterm birth, and low Apgar scores increase the risk of ADHD, persisting up to 40 years after birth. The increased risk of ADHD related to oral cleft and to maternal epilepsy warrants further investigation to explore possible causal mechanisms.

Long term trends in prevalence of neural tube defects in Europe : population based study

Study question What are the long term trends in the total (live births, fetal deaths, and terminations of pregnancy for fetal anomaly) and live birth prevalence of neural tube defects (NTD) in Europe, where many countries have issued recommendations for folic acid supplementation but a policy for mandatory folic acid fortification of food does not exist? Methods This was a population based, observational study using data on 11 353 cases of NTD not associated with chromosomal anomalies, including 4162 cases of anencephaly and 5776 cases of spina bifida from 28 EUROCAT (European Surveillance of Congenital Anomalies) registries covering approximately 12.5 million births in 19 countries between 1991 and 2011. The main outcome measures were total and live birth prevalence of NTD, as well as anencephaly and spina bifida, with time trends analysed using random effects Poisson regression models to account for heterogeneities across registries and splines to model non-linear time trends. Summary answer and limitations Overall, the pooled total prevalence of NTD during the study period was 9.1 per 10 000 births. Prevalence of NTD fluctuated slightly but without an obvious downward trend, with the final estimate of the pooled total prevalence of NTD in 2011 similar to that in 1991. Estimates from Poisson models that took registry heterogeneities into account showed an annual increase of 4% (prevalence ratio 1.04, 95% confidence interval 1.01 to 1.07) in 1995-99 and a decrease of 3% per year in 1999-2003 (0.97, 0.95 to 0.99), with stable rates thereafter. The trend patterns for anencephaly and spina bifida were similar, but neither anomaly decreased substantially over time. The live birth prevalence of NTD generally decreased, especially for anencephaly. Registration problems or other data artefacts cannot be excluded as a partial explanation of the observed trends (or lack thereof) in the prevalence of NTD. What this study adds In the absence of mandatory fortification, the prevalence of NTD has not decreased in Europe despite longstanding recommendations aimed at promoting peri-conceptional folic acid supplementation and existence of voluntary folic acid fortification. Funding, competing interests, data sharing The study was funded by the European Public Health Commission, EUROCAT Joint Action 2011-2013. HD and ML received support from the European Commission DG Sanco during the conduct of this study. No additional data available.

Epidemiology of congenital diaphragmatic hernia in Europe: a register-based study

Introduction Published prevalence rates of congenital diaphragmatic hernia (CDH) vary. This study aims to describe the epidemiology of CDH using data from high-quality, population-based registers belonging to the European Surveillance of Congenital Anomalies (EUROCAT). Methods Cases of CDH delivered between 1980 and 2009 notified to 31 EUROCAT registers formed the population-based case series. Prevalence over time was estimated using multilevel Poisson regression, and heterogeneity between registers was evaluated from the random component of the intercept. Results There were 3373 CDH cases reported among 12 155 491 registered births. Of 3131 singleton cases, 353 (10.4%) were associated with a chromosomal anomaly, genetic syndrome or microdeletion, 784 (28.2%) were associated with other major structural anomalies. The male to female ratio of CDH cases overall was 1:0.69. Total prevalence was 2.3 (95% CI 2.2 to 2.4) per 10 000 births and 1.6 (95% CI 1.6 to 1.7) for isolated CDH cases. There was a small but significant increase (relative risk (per year)=1.01, 95% credible interval 1.00–1.01; p=0.030) in the prevalence of total CDH over time but there was no significant increase for isolated cases (ie, CDH cases that did not occur with any other congenital anomaly). There was significant variation in total and isolated CDH prevalence between registers. The proportion of cases that survived to 1 week was 69.3% (1392 cases) for total CDH cases and 72.7% (1107) for isolated cases. Conclusions This large population-based study found an increase in total CDH prevalence over time. CDH prevalence also varied significantly according to geographical location. No significant association was found with maternal age.

Secular trends in the epidemiology of pre-eclampsia throughout 40 years in Norway: prevalence, risk factors and perinatal survival

Pre-eclampsia is a leading complication of pregnancy, associated with maternal and neonatal morbidity. The present study describes the epidemiology of pre-eclampsia in Norway, with data from the Medical Birth Registry of Norway, covering 40 years. We aimed at describing time trends in prevalence, selected risk factors and perinatal mortality. We also analysed time trends in recurrence risk of total pre-eclampsia and pre-eclampsia with preterm delivery. A total of 2,416,501 women giving birth during 1967-2008 were included. Prevalence of pre-eclampsia increased from 1967 to 1999 and decreased thereafter, with an overall prevalence of 3%. Rates increased more over time among younger than older women, resulting in a significantly lower excess risk of pre-eclampsia associated with high maternal age in later years. For example, relative risk (RR) of pre-eclampsia among primiparae aged ≥35 relative to <25 years changed from 2.4 [95% confidence interval (CI) 2.1, 2.7] in 1967-1976 to 1.2 [95% CI 1.1, 1.3] in 1999-2008. For recurrence risk, subsequent pregnancies to a mother were linked, with the mother being the unit of analysis. Recurrence risk of pre-eclampsia was high, particularly recurrence of preterm pre-eclampsia, with overall RR close to 50 of a second pregnancy with pre-eclampsia and preterm birth compared with women without pre-eclampsia in first pregnancies. Finally, stillbirth associated with pre-eclampsia decreased more than neonatal mortality over time, and in the last 5 years only a moderate excess risk of stillbirth and neonatal death was observed.

Validity of the diagnosis of pre‐eclampsia in the Medical Birth Registry of Norway

Evaluating the validity of pre‐eclampsia registration in the Medical Birth Registry of Norway (MBRN) according to both broader and restricted disease definitions.

Prevalence, prenatal diagnosis and clinical features of oculo-auriculo-vertebral spectrum: a registry-based study in Europe

Oculo-auriculo-vertebral spectrum is a complex developmental disorder characterised mainly by anomalies of the ear, hemifacial microsomia, epibulbar dermoids and vertebral anomalies. The aetiology is largely unknown, and the epidemiological data are limited and inconsistent. We present the largest population-based epidemiological study to date, using data provided by the large network of congenital anomalies registries in Europe. The study population included infants diagnosed with oculo-auriculo-vertebral spectrum during the 1990–2009 period from 34 registries active in 16 European countries. Of the 355 infants diagnosed with oculo-auriculo-vertebral spectrum, there were 95.8% (340/355) live born, 0.8% (3/355) fetal deaths, 3.4% (12/355) terminations of pregnancy for fetal anomaly and 1.5% (5/340) neonatal deaths. In 18.9%, there was prenatal detection of anomaly/anomalies associated with oculo-auriculo-vertebral spectrum, 69.7% were diagnosed at birth, 3.9% in the first week of life and 6.1% within 1 year of life. Microtia (88.8%), hemifacial microsomia (49.0%) and ear tags (44.4%) were the most frequent anomalies, followed by atresia/stenosis of external auditory canal (25.1%), diverse vertebral (24.3%) and eye (24.3%) anomalies. There was a high rate (69.5%) of associated anomalies of other organs/systems. The most common were congenital heart defects present in 27.8% of patients. The prevalence of oculo-auriculo-vertebral spectrum, defined as microtia/ear anomalies and at least one major characteristic anomaly, was 3.8 per 100 000 births. Twinning, assisted reproductive techniques and maternal pre-pregnancy diabetes were confirmed as risk factors. The high rate of different associated anomalies points to the need of performing an early ultrasound screening in all infants born with this disorder.

The Nordic medical birth registers – a potential goldmine for clinical research

The Nordic medical birth registers have long been used for valuable clinical research. Their collection of data for more than four decades offers unusual possibilities for research across generations. At the same time, serum and blotting paper blood samples have been stored from most neonates. Two large cohorts (approximately 100 000 births) in Denmark and Norway have been described by questionnaires, interviews and collection of biological samples (blood, urine and milk teeth), as well as a systematic prospective follow‐up of the offspring. National patient registers provide information on preceding, underlying and present health problems of the parents and their offspring. Researchers may, with permission from the national authorities, obtain access to individualized or anonymized data from the registers and tissue‐banks. These data allow for multivariate analyses but their usefulness depends on knowledge of the specific registers and biological sample banks and on proper validation of the registers.

Validity of Pre-Eclampsia Registration in the Medical Birth Registry of Norway for Women Participating in the Norwegian Mother and Child Cohort Study, 1999–2010

BACKGROUND The Norwegian Mother and Child Cohort Study (MoBa), a prospective population-based pregnancy cohort, is a valuable database for studying causes of pre-eclampsia. Pre-eclampsia data in MoBa come from the Medical Birth Registry of Norway (MBRN); thus, we wanted to study the validity of MBRN pre-eclampsia registration for MoBa women. METHODS We selected all MoBa pregnancies with pre-eclampsia registered in the MBRN (n = 4081) and a random control group (n = 2000) without pre-eclampsia registrations. After excluding two delivery units not participating in MoBa and one no longer operating, units were asked to provide copies of antenatal charts with blood pressure and urinary measurements from all antenatal visits during pregnancy, and hospital discharge codes from the delivery stay. We received data for 5340 pregnancies delivered 1999-2010 (87% of all eligible). We calculated positive predictive value (PPV), and sensitivity and specificity of MBRN registration, using hypertension and proteinuria on the antenatal charts and/or hospital discharge codes indicating pre-eclampsia as gold standard. RESULTS Overall PPV was 83.9% [95% CI 82.7, 85.1] and was higher when women were primiparous, or delivered preterm or low birthweight infants. Severe pre-eclampsia in the MBRN was found to be a true severe pre-eclampsia in 70% of cases. Extrapolating to the total MoBa population, the estimated sensitivity was low - 43.0% (38.7, 48.2) - while specificity was high - 99.2% (99.2, 99.3). False negative cases seemed to have mild forms of pre-eclampsia. CONCLUSIONS PPV and specificity of pre-eclampsia registration in the MBRN during 1999-2010 was satisfactory, while sensitivity was low.

Abnormally invasive placenta-prevalence, risk factors and antenatal suspicion: results from a large population-based pregnancy cohort study in the Nordic countries.

The objective was to investigate prevalence, estimate risk factors, and antenatal suspicion of abnormally invasive placenta (AIP) associated with laparotomy in women in the Nordic countries.