Is pre-eclampsia more than one disease?

OBJECTIVES: The clinical characteristics of pre-eclampsia (gestational hypertension and proteinuria) may represent separate pathogenetic conditions. Pre-eclampsia accompanied by restricted fetal growth may originate from abnormal implantation, and appropriate or high birthweights may indicate a mixture of conditions, ranging from mild pre-eclampsia with modest placental involvement to hypertensive conditions without placental disease. DESIGN: Prospective, observational study. SETTING: General population. POPULATION: We used data from the Medical Birth Registry of Norway, a population-based registry that has recorded births since 1967. For this study, we used information on length of gestation and presence of pre-eclampsia among 1,679,205 singletons born between 1967 and 1998. Pre-eclampsia was diagnosed in 44,220 (2.6%) pregnancies. METHODS: We studied the risk of pre-eclampsia in relation to standardised measures (z scores) of birthweight, adjusted for length of gestation, and stratified by term and preterm delivery. We also explored whether gestational diabetes was more prevalent in conjunction with preterm than term pre-eclampsia. MAIN OUTCOME MEASURES: Pre-eclampsia diagnosed at term or preterm. RESULTS: For pre-eclampsia diagnosed around term, there was a U-shaped association with birthweight. Compared with appropriate birthweights for gestation, the risk of term pre-eclampsia was more than fourfold higher (relative risk [RR] 4.5, 95% confidence interval [CI], 4.3 to 4.7) if the baby's birthweight was lower than two standard deviations under the mean. For birthweights three standard deviations or higher than the mean, pre-eclampsia was more than twice as likely (RR 2.6, 95% CI 2.2-2.9). In contrast, the risk of preterm pre-eclampsia displayed an L-shaped association with birthweight. Low birthweight (less than -2 standard deviations) was associated with greatly increased risk (RR 9.9, 95% CI 9.1-10.9), but for high birthweights (>or=3 standard deviations), there was no association with the risk of preterm pre-eclampsia (RR 1.2, 95% CI 0.7-2.1). The prevalence of gestational diabetes was three times (prevalence ratio 3.3, 95% CI 2.6-3.6) higher in preterm than term pre-eclampsia. CONCLUSION: Whereas pre-eclampsia with preterm delivery associated with low birthweight may be caused by underlying placental abnormality, pre-eclampsia delivered at term may represent a mixture of conditions, ranging from mild pre-eclampsia with moderate placental affection to hypertensive conditions in pregnancy without placental dysfunction.     

Birthweight and perinatal mortality: paradoxes,social class,and sibling dependencies

BACKGROUND: Birthweight distributions among second-born infants depend on the birthweights of older siblings, with implications for weight-specific perinatal mortality. We wanted to study whether these relations were explained by socioeconomic levels, and to study time trends in a situation with decreasing perinatal mortality rates. METHODS: Births in the Norwegian Medical Birth Registry from 1967 to 1998 were linked to their mothers through their national identification numbers. The study population was 546 688 mothers with at least two singletons weighing >/==" BORDER="0">500 g at birth. Weight-specific perinatal mortality for second-born siblings in families with first-born siblings in either the highest or the lowest birthweight quartile was analysed. Maternal education and cohabitation status were used as measures of socioeconomic level. RESULTS: For all 500-g categories below 3500 g, mortality rates were significantly higher among second-born infants with an older sibling in the highest rather than the lowest weight quartile. This pattern was the same across three educational levels. The exclusion of preterm births did not change the effect pattern. A comparison of perinatal mortality among second siblings in terms of relative birthweight (z-scores) showed a reversal of the relative risks, although these were only significantly different from unity for the smallest infants. Conclusion The crossover in weight-specific perinatal mortality for second siblings by weight of first sibling is largely independent of socioeconomic level, and is not weakened by the decreasing perinatal mortality rates in the population over time. Family data should be taken into consideration when evaluating the risk of adverse pregnancy outcome relating to weight.     

Variants of developmental genes (TGFA,TGFB3, and MSX1) and their associations with orofacial clefts: a case-parent triad analysis

We selected 262 case-parent triads from a population-based study of orofacial clefts in Norway, and examined variants of developmental genes TGFA, TGFB3, and MSX1 in the etiology of orofacial clefts. One hundred seventy-four triads of cleft lip cases (CL+/-P) and 88 triads of cleft palate only cases (CPO) were analyzed. There was little evidence for an association of any of these genes with CL+/-P. The strongest association was a 1.7-fold risk with two copies of the TGFB3-CA variant (95% CI=0.9-3.0). Among CPO cases, there was a 3-fold risk with two copies of the TGFA TaqI A2 allele, and no increase with one copy. Assuming this to be a recessive effect, we estimated a 3.2-fold risk among babies homozygous for the variant (95% CI=1.1-9.2). Furthermore, there was strong evidence of gene-gene interaction. While there was only a weak association of the MSX1-CA variant with CPO, the risk was 9.7-fold (95% CI=2.9-32) among children homozygous for both the MSX1-CA A4 allele and the TGFA A2 allele. No association of CPO with the TGFA variant was seen among the other MSX1-CA genotypes. In conclusion, no strong associations were found between CL+/-P and variants at these three genes. There was a possible recessive effect of the TGFA TaqI variant on the risk of CPO, with a 3-fold risk among children homozygous for the variant. The effect of this TGFA genotype was even stronger among children homozygous for the MSX1-CA A4 allele, raising the possibility of interaction between these two genes.     

Cancer risk in children with birth defects and in their families: a population based cohort study of 5.2 million children from Norway and Sweden

BACKGROUND: Cancer and birth defects may share factors that influence risk. A malformation may involve physiologic changes or changes in lifestyle that might affect cancer risks. METHODS: In Norway and Sweden, the population-based medical birth and cancer registries were linked to identify subsequent cancer occurrence in children with birth defects and among their parents and siblings. Altogether, 5.2 million children and their families were included. The standardized incidence ratio (SIR) served as a measure of relative risk. RESULTS: There was an increased overall cancer risk in individuals with birth defects in the two countries [SIR, 1.7; 95% confidence interval (95% CI), 1.6-1.9], and the increased risk remained into early adulthood. Individuals with malformations in the nervous system were at increased risk of developing cancer in the brain/nervous system (Norway: SIR, 58; 95% CI, 41-80; Sweden: SIR, 8.3; 95% CI, 4.0-15), individuals with Down syndrome were at an increased risk of leukemia (Norway: SIR, 36; 95% CI, 26-48; Sweden: SIR, 36; 95% CI, 28-46), and there was an increased overall cancer risk for individuals with multiple birth defects (Norway: SIR, 5.5; 95% CI, 3.3-8.7; Sweden: SIR, 3.6; 95% CI, 2.2-5.4). There was no increased overall cancer risk among mothers (SIR, 1.0; 95% CI, 1.0-1.0), fathers (SIR, 1.0; 95% CI, 0.9-1.0), and siblings (SIR, 1.0; 95% CI, 0.9-1.1) of children with birth defects. CONCLUSIONS: We observed an increased overall cancer risk in individuals with birth defects. The highest risks were seen for individuals with malformations in the nervous system, Down syndrome, and multiple defects. No increased overall cancer risk was seen among their parents or siblings.     

Breast feeding and the sudden infant death syndrome in Scandinavia, 1992-95

Aims: To assess the effects of breast feeding habits on sudden infant death syndrome (SIDS). Methods: The analyses are based on data from the Nordic Epidemiological SIDS Study, a case–control study in which parents of SIDS victims in the Scandinavian countries between 1 September 1992 and 31 August 1995 were invited to participate, each with parents of four matched controls. The odds ratios presented were computed by conditional logistic regression analysis. Results: After adjustment for smoking during pregnancy, paternal employment, sleeping position, and age of the infant, the adjusted odds ratio (95% CI) was 5.1 (2.3 to 11.2) if the infant was exclusively breast fed for less than four weeks, 3.7 (1.6 to 8.4) for 4–7 weeks, 1.6 (0.7 to 3.6) for 8–11 weeks, and 2.8 (1.2 to 6.8) for 12–15 weeks, with exclusive breast feeding over 16 weeks as the reference. Mixed feeding in the first week post partum did not increase the risk. Conclusions: The study is supportive of a weak relation between breast feeding and SIDS reduction.     

Premorbid body weight and its relations to primary tumour diameter in breast cancer patients; its dependence on estrogen and progesteron receptor status

Hormonal mechanisms have been offered as an explanation for the higher frequency of large tumours, lymph node metastases and poorer prognosis in obese breast cancer patients than in lean ones. If hormonal mechanisms are important for these relations, they should probably act more strongly in patients with hormonal receptor positive tumours than in those with negative ones. We have examined if the relations between premorbid body weight or Quetelet's index (weight/height²) and tumour diameter are modified by estrogen receptor alpha (ER) and progesteron receptor (PgR) status. The analyses were based on 1,241 women with unilateral disease treated with modified radical mastectomy living in the geografic area of Haukeland Hospital. Their body weight and height have been measured as a mean 12.5years before presentation of the disease. Body weight and Quetelet's index have been adjusted for age. The relations were studied using linear regression analyses adjusting the effect of body weight with height and mean nuclear area of the tumour cells and adjusting the effect of Quetelet's index for mean nuclear area. The main findings showed that patients with high body weight or Quetelet's index presented more often with PgR positive tumours than lean ones. Quetelet's index was also positively related to ER. These relations were present in patients older than 50 years of age (older). Patients with large tumours (>2.0cm) had significantly higher body weight and Quetelet's index than those with small ones. These differences were significantly present in older patients and in patients with PgR negative and ER negative – PgR negative tumours. Linear regression analyses confirmed that tumour diameter increases with body weight and Quetelet's index. These relations were present in both lymph node groups and in older patients. Stratification according to hormonal receptor status showed these relations to be significant in patients with ER negative, with PgR negative and those with ER negative – PgR negative tumours only. Taking age and hormonal receptor status into consideration simultaneously, both body weight and Quetelet's index were significantly related to tumour diameter in older patients with hormone receptor negative tumours. In conclusion body size was positively related to hormone receptor status and to diameter of the primary tumour. The relation to tumour diameter was present in older patients with hormone receptor negative tumours. Although hormonal mechanisms able to act on the tumour can not be excluded, mechanisms acting independent of hormonal receptors must be considered. Different mechanisms related to body fat cytokines are discussed.     

Sudden infant death syndrome and post perinatal mortality in Norwegian birth cohorts 1967-1980

The well established effects of maternal age and birth order in sudden infant death syndrome (SIDS) formed the basis for a comparison with other categories of post perinatal death in an attempt to shed some light on the etiologic roles played by ante and postnatal factors. A total of 826,162 children, born 1967 through 1980 and recorded at the Medical Birth Registry of Norway was at risk to die during the post perinatal period (ages 7 through 364 days). Out of the 3,582 infants who died, 1,062 were considered SIDS. Strong effects of maternal age (negative) and birth order (positive) were found in the SIDS group, but not to the same extent in the non-SIDS group or the group of congenital malformations. Likewise, the excess risk in children of unmarried mothers was higher in the SIDS group. The suggested effects of postnatal factors in the causation of SIDS may seem promising from a preventive point of view. The strength of the effects of maternal age and birth order necessitate adjustment for these variables in future epidemiological studies of SIDS.     

Abdominal aortic aneurysms--a study of factors influencing postoperative mortality. Norwegian Aortic Aneurysm Trial

Factors which influenced outcome after surgery have been studied in 444 patients with abdominal aortic aneurysm included in a Norwegian multicentre study. Two-hundred and seventy-nine patients were treated electively, 51 had impending rupture and 114 had a ruptured aneurysm. In the elective group age, a large aneurysm, impaired renal function, the presence of angina pectoris and intraoperative blood loss of more than 4 units were found to significantly increase hospital mortality. In the impending rupture group excess blood loss during the operation had a negative influence on hospital death but the limited number of patients in this group restricts the value of analysis. A low systolic blood pressure and an older patient were the only 2 risk factors which had a detrimental effect on postoperative survival in the ruptured group. The formulation of a risk index for these patients was not possible although Odds ratios for the individual factors found to be of importance may give some risk estimates.