A Population-Based Study of Effects of Genetic Loci on Orofacial Clefts.

Prior genome-wide association studies for oral clefts have focused on clinic-based samples with unclear generalizability. Prior samples were also small for investigating effects by cleft type and exclusively studied isolated clefts (those occurring without other birth defects). We estimated the effects of 17 top loci on cleft types in both isolated and nonisolated cases in the largest consortium to date of European-descent population-based studies. Our analytic approach focused on a mother-child dyad case-control design, but it also allowed analyzing mother-only or child-only genotypes to maximize power. Our total sample included 1,875 cases with isolated clefts, 459 cases with nonisolated clefts, and 3,749 controls. After correcting for multiple testing, we observed significant associations between fetal single-nucleotide polymorphisms (SNPs) at IRF6, PAX7, 8q21.3, 8q24, KIAA1598-VAX1, and MAFB and isolated cleft lip only (CLO) and cleft lip and palate (CLP). Significant associations were observed between isolated CLO and fetal SNPs near TPM1 and NOG1 and between CLP and fetal SNPs at ABCA4-ARHGAP29, THADA, FOXE1, and SPRY2. Overall, effects were similar for isolated CLO and CLP, except for ABCA4-ARHGAP29. A protective effect was observed for the fetal NOG1 SNP on cleft palate only, opposite in direction to the effect on CLO. For most fetal SNPs, a dose-response allelic effect was observed. No evidence of parent-of-origin or maternal genome effects was observed. Overall, effect direction and magnitude were similar between isolated and nonisolated clefts, suggesting that several loci are modifiers of cleft risk in both isolated and nonisolated forms. Our results provide reliable estimates of the effects of top loci on risks of oral clefts in a population of European descent.

Reproduction and marriage among male survivors of cancer in childhood, adolescence and young adulthood: a national cohort study.

BACKGROUND: Increased survival after cancer in young age has made long-term follow-up studies of high external validity important. In this national cohort study, we explored the impact of cancer in young age on reproduction and marital status in male survivors. METHODS: Hazard ratios (HRs) and relative risks (RRs) of reproductive and marital outcomes were studied for male survivors of cancer in young age (<25 years) and cancer-free male comparisons, born during 1965-1985, by linking compulsory national registries in Norway. RESULTS: Male cancer survivors (n=2687) had reduced paternity (HR: 0.72, 95% confidence interval (CI): 0.68-0.76). This was most apparent in survivors of testicular cancer, brain tumours, lymphoma, leukemia and bone tumours, and when diagnosed with cancer before 15 years of age. Male cancer survivors were more likely to avail of assisted reproduction (RR: 3.32, 95% CI: 2.68-4.11). There was no increased risk of perinatal death, congenital malformations, being small for gestational age, of low birth weight or preterm birth in their first offspring. Male cancer survivors were less likely to marry (HR: 0.93, 95% CI: 0.86-1.00), in particular brain tumour survivors. CONCLUSIONS: In this national cohort study, we demonstrated reduced paternity and increased use of assisted reproduction among male cancer survivors, but no adverse outcome for their first offspring at birth.

Pleural effusion decreases left ventricular pre-load and causes haemodynamic compromise: an experimental porcine study.

BACKGROUND: Although pleural effusion is a common complication in critically ill patients, detailed knowledge is missing about the haemodynamic impact and the underlining mechanisms. The aim of this study was to evaluate the haemodynamic effect of incremental pleural effusion by means of invasive haemodynamic parameters and transthoracic echocardiography. METHODS: This experimental interventional study was conducted using 22 female piglets (17.5-21.5 kg) randomized for right-side (n = 9) and left-side (n = 9) pleural effusion, or sham operation (n = 4). Pleural effusion was induced by infusing incremental volumes of saline into the pleural cavity. Invasive haemodynamic measurements and echocardiographical images were obtained at baseline, a volume of 45 ml/kg, a volume of 75 ml/kg and 45 min after drainage. RESULTS: No difference (all P > 0.147) was found between right- and left-side pleural effusion, and the groups were thus pooled. At 45 ml/kg cardiac output, mean arterial pressure, stroke volume and mixed venous saturation decreased (all P < 0.003); central venous pressure and pulmonary arterial pressure increased (both P > 0.003) at this point. The changes accelerated at 75 ml/kg. At 45 ml/kg left ventricular pre-load in terms of end-diastolic area decreased significantly (P < 0.001). The effect on haemodynamics and cardiac dimensions changed dramatically at 75 ml/kg. Cardiac output, mean arterial pressure, central venous pressure and left ventricular end-diastolic area returned to normal during a recovery period of 45 min (all P > 0.061). CONCLUSION: Incremental volumes of unilateral pleural effusion induced a significant haemodynamic impact fully reversible after drainage. Pleural effusion causes a significant decrease of left ventricular pre-load in a diverse picture of haemodynamic compromise.

Association between inhibited binding of folic acid to folate receptor alpha in maternal serum and folate-related birth defects in Norway.

BACKGROUND: Folic acid intake during pregnancy can reduce the risk of neural tube defects (NTDs) and perhaps also oral facial clefts. Maternal autoantibodies to folate receptors can impair folic acid binding. We explored the relationship of these birth defects to inhibition of folic acid binding to folate receptor α (FRα), as well as possible effects of parental demographics or prenatal exposures. METHODS: We conducted a nested case-control study within the Norwegian Mother and Child Cohort Study. The study included mothers of children with an NTD (n = 11), cleft lip with or without cleft palate (CL/P, n= 72), or cleft palate only (CPO, n= 27), and randomly selected mothers of controls (n = 221). The inhibition of folic acid binding to FRα was measured in maternal plasma collected around 17 weeks of gestation. On the basis of prior literature, the maternal age, gravidity, education, smoking, periconception folic acid supplement use and milk consumption were considered as potential confounding factors. RESULTS: There was an increased risk of NTDs with increased binding inhibition [adjusted odds ratio (aOR) = 1.4, 95% confidence interval (CI) 1.0-1.8]. There was no increased risk of oral facial clefts from inhibited folic acid binding to FRα (CL/P aOR = 0.7, 95% CI 0.6-1.0; CPO aOR = 1.1, 95% CI 0.8-1.4). No association was seen between smoking, folate supplementation or other cofactors and inhibition of folic acid binding to FRα. CONCLUSIONS: Inhibition of folic acid binding to FRα in maternal plasma collected during pregnancy was associated with increased risk of NTDs but not oral facial clefts.

Post-conditioning with cyclosporine A fails to reduce the infarct size in an in vivo porcine model.

BACKGROUND: Cyclosporine A has generated intense interest in the field of cardioprotection due to its ability to protect the mitochondria at reperfusion by blocking the opening of the mitochondrial permeability transition pore. The aim of our study was to examine the cardioprotective effect of Sandimmun, a clinically available formulation of cyclosporine A, in an in vivo large mammal model. METHODS: Forty-eight pigs were randomly allocated to one of three groups: (i) Control group (Con, n=19), (ii) Cyclosporine group, (Cyclo, n=19) Sandimmun 10 mg/kg i.v. bolus 5 min before reperfusion and (iii) Pre-conditioning group (Precon, n=10) two cycles of 10 min ischemia interspersed with 30-min reperfusion. The study was further sub-divided into a metabolic protocol, evaluating myocardial metabolism by measuring changes in the interstitial lactate concentration, and a coronary flow protocol. All animals were subjected to 40 min of left anterior descending coronary artery occlusion, followed by 180 min of reperfusion before histochemical staining and assessment of infarct size by planimetry. RESULTS: Infarct sizes were measured as: Con 51.4 +/- 16.5%, Cyclo 47.3 +/- 15.7% and Precon 2.4 +/- 3.6%, with no significant difference between the Con and Cyclo groups but a highly significant difference between the Precon and Cyclo and Con groups (P<0.0001 for both comparisons). In the Cyclo group, the interstitial lactate concentration was significantly increased compared with the Con group at 6-min reperfusion, although significantly lower at 14 min presumably due to accelerated washout. CONCLUSION: In this large animal model, a 10 mg/kg bolus administration of Sandimmun 5 min before reperfusion did not reduce the infarct size.

Sevoflurane improves myocardial ischaemic tolerance in a closed-chest porcine model.

AIMS: Volatile anaesthetics prevent experimental myocardial ischaemia-reperfusion injury (I/R) in several species, but this finding is partially inconsistent with clinical evidence. Some experimental models may not accurately represent the complex signal transduction pathways triggered by volatile anaesthetics. We therefore investigated sevoflurane I/R prevention in vivo in a porcine model with greater likeness to human physiology than models previously used and compared it with neutral anaesthetic. METHODS AND RESULTS: Myocardial infarct size [IS/AAR] was compared in three groups of pigs (N=35) randomised to Control anaesthesia (pentobarbital infusion, n=12), sevoflurane inhalation alone (end-tidal concentration 3.2%) (Sevo, n=9), or both Combined (n=14), throughout ischaemia and reperfusion. Anterior/septal myocardial infarcts resulted from distal LAD coronary artery occlusion by balloon catheter for 45 min followed by 120 min of reperfusion. [IS/AAR] was measured in tetrazolium-stained heart slices after standardised image processing with computer-assisted planimetry. Measurements included full invasive monitoring. Control animals developed infarction in 55.0 +/- 3.9% (SEM) of the area at risk, Sevo in 17.5 +/- 4.4% (P=0.0002), and Combined with pentobarbital in 24.3 +/- 3.8% (P=0.0001) of the AAR, sevoflurane reducing infarct size significantly (68% and 60%, respectively). CONCLUSIONS: Sevoflurane markedly decreased myocardial infarct size after prolonged coronary occlusion in a porcine model. In addition to novel sevoflurane cardioprotection in the closed-chest model, which is more comparable to normal human hearts than models previously used, sevoflurane cardioprotection is substantiated in the juvenile intact organism. The perspectives underline recommending volatile anaesthetics in risk patients and in cardiac surgery.

Sociodemographic characteristics and perinatal mortality among singletons in North East Tanzania: a registry-based study.

OBJECTIVES: Sub-Saharan Africa has the highest known perinatal mortality rates in the World, but few studies have assessed the importance of parental sociodemographic characteristics on perinatal mortality in this region. The aim of this study was to estimate how sociodemographic patterns affect perinatal mortality in Northern Tanzania. DESIGN AND SETTINGS: A registry-based study using births from 1999 to 2006 at a hospital in North Eastern Tanzania. PARTICIPANTS AND METHODS: 14 394 singleton births with birthweight 500 g or higher and a known perinatal survival status. Births of women with residence outside the local district who were referred to the hospital for delivery for medical reasons were excluded. RESULTS: Perinatal mortality was 41.1 per 1000 births. Factors independently associated with higher perinatal mortality were: higher paternal age (> 45) compared to age 26-35 (adjusted relative risk (ARR) 2.0; 95% CI 1.4 to 2.8), low paternal education (only primary) compared to secondary or higher (ARR 1.3; 95% CI 1.1 to 1.7), paternal ethnicity other than Chagga or Pare (ARR 1.4; 95% CI 1.1 to 1.7), paternal farming occupation (ARR 1.5; 95% CI 1.1 to 2.2), maternal service occupation (ARR 1.7; 95% CI 1.2 to 2.6), maternal height 150 cm or lower (ARR 1.4; 95% CI 1.0 to 1.8) and residence in the rural or semi-urban area (ARR 1.4; 95% CI 1.1 to 1.7). CONCLUSIONS: There are strong sociodemographic gradients in perinatal mortality in Africa. Paternal social characteristics appear to have stronger influence on perinatal mortality than maternal characteristics. This may reflect social and cultural conditions that need to be considered by policymakers in developing countries.

Post-conditioning reduces infarct size in an open-chest porcine acute ischemia-reperfusion model.

BACKGROUND: Timely reperfusion is a prerequisite for myocardial salvage; however, re-oxygenation of the ischemic myocardium initiates reperfusion injury. Post-conditioning diminishes the detrimental aftermath of an acute myocardial infarction through alleviation of reperfusion injury. Ischemic post-conditioning consists of a series of brief interruptions in the coronary blood supply that has to be applied within the first minutes after re-establishing the coronary flow. METHODS: Sixteen female mixed Danish Landrace and Yorkshire pigs weighing 20 kg were included. The heart was exposed through a midline sternotomy. A snare was positioned around the left anterior descending coronary artery downstream of the second diagonal branch. After randomization to either no treatment (control group) or treatment by ischemic post-conditioning (post-conditioning group), the pigs underwent 45 min of ischemia and 180 min of reperfusion. The post-conditioning group had a post-conditioning algorithm applied consisting of 15 s of reperfusion alternating with 15 s of re-occlusion repeated 10 times. RESULTS: The groups were comparable with regard to body weight, hemodynamics and the size of the area at risk. The post-conditioning group had an absolute reduction in infarct size of 18.1% [confidence interval (CI): 6.2: 30.0%] compared with the control group (P=0.0056). In the post-conditioning group, infarction developed in 39.6+/-12.0% (1 SD) of the area at risk compared with 57.8+/-10.2% (1 SD) in the control group. CONCLUSION: When ischemic post-conditioning was applied at reperfusion, we found an absolute reduction in infarct size of 18.1% presumably attributable to a diminished reperfusion injury. The model we have developed is suitable for further studies of this promising intervention.

Maternal HIV status and pregnancy outcomes in northeastern Tanzania: a registry-based study.

OBJECTIVES: The proportion of women delivering with known HIV status in sub-Saharan Africa is not well described. Risk of HIV transmission to newborns is a major concern, but there may also be increased risks for other adverse pregnancy outcomes. DESIGN: Hospital registry. SETTING: North East Tanzania (1999-2006). POPULATION: Singletons (n = 14,444). METHODS: Births were grouped by maternal HIV status and socio-demographic factors predicting HIV status, and associations between status and pregnancy outcomes were studied. MAIN OUTCOME MEASURES: Maternal HIV status, perinatal mortality, prematurity, small for gestational age (SGA), birthweight and low Apgar score. RESULTS: The proportion of mothers with known HIV status increased from 7% before 2001 to 78% after 2004. Single motherhood, rural residence, low maternal education, maternal and paternal farming and higher paternal age were associated with unknown HIV status. About 7.4% (95% CI 6.7-8.1%) of women were HIV infected, with increased likelihood of infection with higher gravidity, single motherhood, rural residence, maternal business or farming occupations and paternal tribe. Compared with HIV-uninfected women, the untreated HIV-infected women had a higher risk of SGA births (adjusted risk ratio [ARR] 1.6; 95% CI 1.1-2.4), preterm birth (ARR 1.8; 95% CI 1.1-2.7) and perinatal death (ARR 1.9; 95% CI 0.95-3.8). Women with unknown HIV status had moderately increased risks. Treated HIV-infected women had a risk similar to that of the HIV-uninfected women for all outcomes, except for low Apgar score. CONCLUSION: HIV testing and infection were associated with socio-demographic factors. Untreated HIV-infected women had higher risks of adverse pregnancy outcomes, and risks were also increased for women with unknown HIV status. There is still a need to increase availability of HIV testing, education and adequate therapy for pregnant women.

Lung function and symptoms among indigenous Mayan women exposed to high levels of indoor air pollution.

SETTING: Indoor air pollution from burning of biomass fuel in open fires is a known risk factor for chronic obstructive pulmonary disease (COPD) in developing countries. OBJECTIVE: To estimate the prevalence of respiratory symptoms and lung function among women in rural Guatemala and to describe the methods and practical issues associated with the assessment of respiratory health. DESIGN: Information about respiratory symptoms, lung function and individual measurement of exposure was collected cross-sectionally among 350 Mayan-Indian women aged 15-50 years who used traditional open fires. RESULTS: These women, exposed to indoor air pollution since birth, had a relatively high prevalence of cough (22.6%), phlegm (15.1%), wheeze (25.1%) and tightness in the chest (31.4%). Respiratory symptoms were positively associated with exposure levels. Lung function was higher than the most feasible reference population (average above predicted forced expiratory volume in 1 s [FEV(1)] +4.5% and forced vital capacity [FVC] +4.2%). Only one woman had a FEV(1)/FVC ratio lower than 70%. CONCLUSIONS: According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, almost one third of these young non-smoking women were at risk (stage 0) of developing COPD. The methodological issues encountered during the study highlight the importance of standardising approaches to local adaptation of established questionnaires to study respiratory health in rural areas of developing countries.

Case-parent triads: estimating single- and double-dose effects of fetal and maternal disease gene haplotypes.

Case-parent triad data are considered a robust basis for studying association between variants of a gene and a disease. Methods evaluating statistical significance of association, like the TDT-test and its extensions, are frequently used. When there are prior hypotheses of a causal effect of the gene under study, however, methods measuring penetrance of alleles or haplotypes as relative risks will be more informative. Log-linear models have been proposed as a flexible tool for such relative risk estimation. We demonstrate an extension of the log-linear model to a natural framework for also estimating effects of multiple alleles or haplotypes, incorporating both single- and double-dose effects. The model also incorporates effects of single- and double-dose maternal haplotypes on a fetus during pregnancy. Unknown phase of haplotypes as well as missing parents are accounted for by the EM algorithm. A number of numerical improvements to maximum likelihood estimation are also implemented to facilitate a larger number of haplotypes. Software for these analyses, HAPLIN, is publicly available through our web site. As an illustration we have re-analyzed data on the MSX1 homeobox-gene on chromosome 4 to show how haplotypes may influence the risk of oral clefts.

Research ethics and evidence based medicine.

In this paper, the author argues that the requirement to conduct randomised clinical trials to inform policy in cases where one wants to identify a cheaper alternative to known effective but expensive interventions raises an important ethical issue. This situation will eventually arise whenever there are resource constraints, and a policy decision has been made not to fund an intervention on cost effectiveness grounds. It has been thought that this is an issue only in extremely resource poor settings. This paper gives an example from the United Kingdom illustrating that this is also a problem faced by richer countries.

The standard of care debate: the Declaration of Helsinki versus the international consensus opinion.

The World Medical Association's revised Declaration of Helsinki endorses the view that all trial participants in every country are entitled to the worldwide best standard of care. In this paper the authors show that this requirement has been rejected by every national and international committee that has examined this issue. They argue that the consensus view now holds that it is ethically permissible, in some circumstances, to provide research participants less than the worldwide best care. Finally, the authors show that there is also consensus regarding the broad conditions under which this is acceptable.

Risk of selected birth defects by maternal residence close to power lines during pregnancy.

AIMS: To evaluate selected birth outcomes from a published Norwegian cohort study in a nested case-control design with improved exposure data. METHODS: Two controls matched for sex, year of birth, and municipality were selected randomly for children with the following defects: central nervous system (CNS) defects, cardiac defects, respiratory system defects, oesophageal defects, and clubfoot. The distances between maternal addresses, during pregnancy, and power lines were obtained from maps mainly of scale 1:5000. The magnetic fields in the residences were estimated based on distance, current, voltage, and configuration. RESULTS: The highest increased risks were seen for hydrocephalus (OR 1.73, 95% CI 0.26 to 11.64) and for cardiac defects (OR 1.54, 95% CI 0.89 to 2.68). CONCLUSION: This study does not support the hypothesis that residential exposure to electromagnetic fields from power lines causes any of the investigated outcomes.

Examination of IMPA1 and IMPA2 genes in manic-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder.

Manic-depressive (bipolar) illness is a serious psychiatric disorder with a strong genetic predisposition. The disorder is likely to be multifactorial and etiologically complex, and the causes of genetic susceptibility have been difficult to unveil. Lithium therapy is a widely used pharmacological treatment of manic-depressive illness, which both stabilizes the ongoing episodes and prevents relapses. A putative target of lithium treatment has been the inhibition of the myo-inositol monophosphatase (IMPase) enzyme, which dephosphorylates myo-inositol monophosphate in the phosphatidylinositol signaling system. Two genes encoding human IMPases have so far been isolated, namely myo-inositol monophosphatase 1 (IMPA1) on chromosome 8q21.13-21.3 and myo-inositol monophosphatase 2 (IMPA2) on chromosome 18p11.2. In the present study, we have scanned for DNA variants in the human IMPA1 and IMPA2 genes in a pilot sample of Norwegian manic-depressive patients, followed by examination of selected polymorphisms and haplotypes in a family-based bipolar sample of Palestinian Arab proband-parent trios. Intriguingly, two frequent single-nucleotide polymorphisms (-461C>T and -207T>C) in the IMPA2 promoter sequence and their corresponding haplotypes showed transmission disequilibrium in the Palestinian Arab trios. No association was found between the IMPA1 polymorphisms and bipolar disorder, neither with respect to disease susceptibility nor with variation in lithium treatment response. The association between manic-depressive illness and IMPA2 variants supports several reports on the linkage of bipolar disorder to chromosome 18p11.2, and sustains the possible role of IMPA2 as a susceptibility gene in bipolar disorder.

Anemia in pregnancy in rural Tanzania: associations with micronutrients status and infections.

OBJECTIVE: We studied the association between anemia in pregnancy and characteristics related to nutrition and infections. DESIGN: Cross-sectional study. SETTING: Four antenatal clinics in rural northern Tanzania. SUBJECTS/METHODS: A total of 2547 women were screened for hemoglobin (Hb) and malaria plasmodia in capillary blood and for infections in urine. According to their Hb, they were assigned to one of five groups and selected accordingly, Hb<70 g/l (n=10), Hb=70-89 g/l (n=61), Hb=90-109 g/l (n=86), Hb=110-149 g/l (n=105) and Hb> or =150 g/l (n=50). The 312 selected subjects had venous blood drawn, were interviewed, and their arm circumference was measured. The sera were analyzed for ferritin, iron, total iron binding capacity (TIBC), cobalamin, folate, vitamin A, C-reactive protein (CRP), and lactate dehydrogenase (LD). Transferrin saturation (TFsat) was calculated. Urine was examined by dipsticks for nitrite. MAIN OUTCOME MEASURES: Unadjusted and adjusted odds ratio (OR and AOR) of anemia with Hb<90 g/l. RESULTS: Anemia (Hb<90 g/l) was associated with iron deficiency (low s-ferritin; AOR 3.4). The association with vitamin deficiencies were significant in unadjusted analysis (low s-folate; OR 3.1, low s-vitamin A; OR 2.6). Anemia was also associated with markers of infections (elevated s-CRP; AOR 3.5, urine nitrite positive; AOR 2.4) and hemolysis (elevated s-LD; AOR 10.1). A malaria positive blood slide was associated with anemia in unadjusted analysis (OR 2.7). An arm circumference less than 25 cm was associated with anemia (AOR 4.0). The associations with less severe anemia (Hb 90-109 g/l) were similar, but weaker. CONCLUSIONS: Anemia in pregnancy was associated with markers of infections and nutritional deficiencies. This should be taken into account in the management of anemia at antenatal clinics. SPONSORSHIP: The study was supported by the Norwegian Research Council (NFR) and the Centre for International Health, University of Bergen.

Risk of birth defects by parental occupational exposure to 50 Hz electromagnetic fields: a population based study.

OBJECTIVES: To study the risk of birth defects by parental occupational exposure to 50 Hz electromagnetic fields. METHODS: The Medical Birth Registry of Norway was linked with census data on parental occupation. An expert panel constructed a job exposure matrix of parental occupational exposure to 50 Hz magnetic fields. Exposure to magnetic fields was estimated by combining branch and occupation into one of three exposure levels: <4 hours, 4-24 hours, and >24 hours/week above approximately 0.1 mu T. Risks of 24 categories of birth defects were compared across exposure levels. Out of all 1.6 million births in Norway in the period 1967-95, 836,475 and 1,290,298 births had information on maternal and paternal exposure, respectively. Analyses were based on tests for trend and were adjusted for parents' educational level, place of birth, maternal age, and year of birth. RESULTS: The total risk of birth defects was not associated with parental exposure. Maternal exposure was associated with increased risks of spina bifida (p=0.04) and clubfoot (p=0.04). A negative association was found for isolated cleft palate (p=0.01). Paternal exposure was associated with increased risks of anencephaly (p=0.01) and a category of "other defects" (p=0.02). CONCLUSION: The present study gives an indication of an association between selected disorders of the central nervous system and parental exposure to 50 Hz magnetic fields. Given the crude exposure assessment, lack of comparable studies, and the high number of outcomes considered, the results should be interpreted with caution.

Joint association of Apgar scores and early neonatal symptoms with minor disabilities at school age.

OBJECTIVE: To examine whether the combination of a low five minute Apgar score and symptoms of neonatal encephalopathy is associated with minor impairments at school age. DESIGN: Population based cohort study. SETTING: Norway. PARTICIPANTS: All 727 children of the cohort were born between 1983 and 1987, had normal birth weights, no congenital malformations, and no major neurological abnormalities. The cohort comprised three groups with five minute Apgar scores of 0-3, 4-6, and 7-10, and were followed from birth to 8-13 years of age by combining data from The Medical Birth Registry, questionnaires, hospital discharge summaries, and the National Insurance Scheme. MAIN OUTCOME MEASURE: Neurodevelopmental impairments such as learning, behavioural, and minor motor difficulties. RESULTS: Children with a five minute Apgar score of 3 or less and signs consistent with neonatal encephalopathy had a significantly increased risk of developing minor motor impairments (odds ratio (OR) 12.8, 95% confidence interval (CI) 2.6 to 63.2), epilepsy (OR 7.0, 95% CI 1.3 to 39.2), need of extra resources in kindergarten (OR 7.0, 95% CI 1.3 to 39.2) or at school (OR 3.4, 95% CI 1.8 to 6.3), and had reduced performance in reading (OR 4.6, 95% CI 2.3 to 9.5) and mathematics (OR 3.3, 95% CI 1.5 to 7.3), compared with children with normal Apgar scores and no neonatal symptoms. They also more often had problems related to tractability, aggressivity, passivity, anxiety, academic performance, and fine motor development. CONCLUSION: Children with low Apgar scores and subsequent signs of cerebral depression who do not develop cerebral palsy may still have an increased risk of developing a variety of neurodevelopmental impairments and learning difficulties.

Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study.

OBJECTIVE: To assess whether mothers and fathers have a higher long term risk of death, particularly from cardiovascular disease and cancer, after the mother has had pre-eclampsia. DESIGN: Population based cohort study of registry data. SUBJECTS: Mothers and fathers of all 626 272 births that were the mothers' first deliveries, recorded in the Norwegian medical birth registry from 1967 to 1992. Parents were divided into two cohorts based on whether the mother had pre-eclampsia during the pregnancy. Subjects were also stratified by whether the birth was term or preterm, given that pre-eclampsia might be more severe in preterm pregnancies. MAIN OUTCOME MEASURES: Total mortality and mortality from cardiovascular causes, cancer, and stroke from 1967 to 1992, from data from the Norwegian registry of causes of death. RESULTS: Women who had pre-eclampsia had a 1.2-fold higher long term risk of death (95% confidence interval 1.02 to 1.37) than women who did not have pre-eclampsia. The risk in women with pre-eclampsia and a preterm delivery was 2.71-fold higher (1.99 to 3.68) than in women who did not have pre-eclampsia and whose pregnancies went to term. In particular, the risk of death from cardiovascular causes among women with pre-eclampsia and a preterm delivery was 8.12-fold higher (4.31 to 15.33). However, these women had a 0.36-fold (not significant) decreased risk of cancer. The long term risk of death was no higher among the fathers of the pre-eclamptic pregnancies than the fathers of pregnancies in which pre-eclampsia did not occur. CONCLUSIONS: Genetic factors that increase the risk of cardiovascular disease may also be linked to pre-eclampsia. A possible genetic contribution from fathers to the risk of pre-eclampsia was not reflected in increased risks of death from cardiovascular causes or cancer among fathers.