Changes in frequency and indications for cesarean section in Norway 1967-1984

We have studied the cesarean section frequencies and changing spectrum of indications in Norway during six consecutive 3-year periods from 1967 to 1984. The data set consists of 1,046,162 births notified to the Medical birth registry of Norway, of which 52,426 were specified as cesarean sections, the frequency rising from 1.9% in 1967-69 to 9.7% in 1982-84. A check for completeness of cesarean section notification was made against the birth protocols of the largest obstetrical unit in Norway. The error rate was about 3%. Information on the indication for performing cesarean section was missing in 11.4% of the cases. We grouped thirty-one specified indications under seven headings. In 1967-69 the operation was most often performed for 'maternal' reasons, followed by 'mechanical', 'abnormalities of fetal presentation' and 'acute placental' conditions. Throughout the study period, 'mechanical' (which can also be labelled 'dystocia') accounted for about one third of the indications for cesarean section, while 'maternal' (including high maternal age and pre-eclampsia) and 'acute placental' (placenta praevia and placental abruption) decreased in relative importance. 'Fetal presentation' (including twins) doubled its relative share, while increasing from 2.4 per 1000 births in 1967-69 to 24.8 per 1000 births in 1982-84. A steep rise in the group 'fetal asphyxia' corresponded to the period when the mass of electronic monitoring devices was introduced, in the early 1970s. 'Fetal asphyxia' had a higher relative share of the indications among para 0 mothers than in the total birth population.     

Low birthweight and mortality: the tendency to repeat low birthweight and its association with early neonatal and infant morbidity and mortality

Previous studies have demonstrated the tendency to repeat gestational age and birthweight in successive pregnancies and that this tendency is associated with infant survival. Thus, newborn outcome and survival is less favourable if the gestational age and size departs from this maternal tendency. This paper aims to study diseases or conditions that might be associated with this effect. Data were provided through a linkage between three Danish health registries: the Danish Fertility Database, the National Hospital Registry, and the Registry for Preventive Medicine. Such linkage was possible due to the use of unique ID-person numbers. The study included all 8219 second-order low-birthweight (LBW) singleton Danish births, 1980-94, of whom 7811 were liveborn. It was also required that the mother's first delivery took place during that period. The analysis considered 7803 of these births; eight were excluded due to insufficient information. Of the second-order LBW children, 26% had an elder sibling who was also LBW. Early neonatal mortality of a 'non-repeat' LBW birth was 1.3 times higher than 'repeat' LBW births [53.8 vs. 41.2 per 1000; RR 1.31; 95% CI 1.03, 1.65], as was infant mortality [78.4 vs. 60.8 per 1000; RR 1.30; 95% CI 1.06, 1.56]. Also, proportionately more LBW repeat births had Apgar scores of >or=7 after 1 and 5 min. Overall, repeat second-order LBW babies weighed 68 g more than non-repeat LBW babies (P < 0.001). At term, the weight difference was 160 g higher among repeat LBW births (P < 0.001). The mean number of hospitalisations during the first year of life was lower among repeat than non-repeat LBW babies (2.30 vs. 2.46, P < 0.001), while the mean duration of stay was 23.71 vs. 23.97 days (P > 0.05). Newborn immaturity was the most common diagnosis for hospitalisation, and infections the second most common. There were no differences between repeat and non-repeat LBW births in the proportion with each diagnosis. Apart from the differences in birthweight, we were unable to explain the improved survival for repeat compared with non-repeat LBW babies. Except for differences in Apgar scores, we observed no differences in morbidity based on registered hospitalisations during infancy.     

Recurrence risk in hyperemesis gravidarum

OBJECTIVES: To compare the risk of hyperemesis gravidarum in second pregnancies in women with and without hyperemesis in their first pregnancy, and to determine if this risk changes with changes in paternity or with the interval between deliveries. DESIGN: Cohort study. SETTING: Data from the population-based Medical Birth Registry of Norway, 1967-1998. Sample All women in the registry with records of their first and second singleton delivery, a total of 547,238 women. METHODS: The relative risk of hyperemesis in the second delivery was estimated as odds ratios (ORs) in logistic regression models, controlling for potential confounding factors. MAIN OUTCOME MEASURES: The main outcome measure was the risk of hyperemesis in the second pregnancy according to hyperemesis in the first pregnancy, interval between deliveries and change in paternity. RESULTS: The risk of hyperemesis was 15.2% in the second pregnancy in women with and 0.7% in women without previous hyperemesis [OR=26.4, 95% confidence interval (CI) 24.2, 28.7]. The OR did not change after adjustment for maternal age, change in paternity, period of the first delivery and time interval between deliveries. After a change in paternity, the risk of recurrent hyperemesis was 10.9% compared with 16.0% in women without a change in paternity [adjusted OR (aOR)=0.60, 95% CI 0.39, 0.92]. The risk of hyperemesis in the second pregnancy increased with increasing time interval between deliveries, but only in women with no previous hyperemesis. CONCLUSIONS: The primary finding was the high risk of recurrence observed in women with hyperemesis in the first pregnancy. The risk was reduced by a change in paternity. For women with no previous hyperemesis, a long interval between births slightly increased the risk of hyperemesis in the second pregnancy. Further studies are needed to explore the relative impact of genetic and environmental factors and their possible interactions in hyperemesis gravidarum.     

Genome wide study of maternal and parent-of-origin effects on the etiology of orofacial clefts

We performed a genome wide association analysis of maternally-mediated genetic effects and parent-of-origin (POO) effects on risk of orofacial clefting (OC) using over 2,000 case-parent triads collected through an international cleft consortium. We used log-linear regression models to test individual SNPs. For SNPs with a P-value <10(-5) for maternal genotypic effects, we also applied a haplotype-based method, TRIMM, to extract potential information from clusters of correlated SNPs. None of the SNPs were significant at the genome wide level. Our results suggest neither maternal genome nor POO effects play major roles in the etiology of OC in our sample. This finding is consistent with previous genetic studies and recent population-based cohort studies in Norway and Denmark, which showed no apparent difference between mother-to-offspring and father-to-offspring recurrence of clefting. We, however, cannot completely rule out maternal genome or POO effects as risk factors because very small effects might not be detectable with our sample size, they may influence risk through interactions with environmental exposures or may act through a more complex network of interacting genes. Thus, the most promising SNPs identified by this study may still be worth further investigation.     

Application of a novel hybrid study design to explore gene-environment interactions in orofacial clefts

Orofacial clefts are common birth defects with strong evidence for both genetic and environmental causal factors. Candidate gene studies combined with exposures known to influence the outcome provide a highly targeted approach to detecting GxE interactions. We developed a new statistical approach that combines the case-control and offspring-parent triad designs into a "hybrid design" to search for GxE interactions among 334 autosomal cleft candidate genes and maternal first-trimester exposure to smoking, alcohol, coffee, folic acid supplements, dietary folate and vitamin A. The study population comprised 425 case-parent triads of isolated clefts and 562 control-parent triads derived from a nationwide study of orofacial clefts in Norway (1996-2001). A full maximum-likelihood model was used in combination with a Wald test statistic to screen for statistically significant GxE interaction between strata of exposed and unexposed mothers. In addition, we performed pathway-based analyses on 28 detoxification genes and 21 genes involved in folic acid metabolism. With the possible exception of the T-box 4 gene (TBX4) and dietary folate interaction in isolated CPO, there was little evidence overall of GxE interaction in our data. This study is the largest to date aimed at detecting interactions between orofacial clefts candidate genes and well-established risk exposures.     

Folate and one-carbon metabolism gene polymorphisms and their associations with oral facial clefts

Folate metabolism plays a critical role in embryonic development. Prenatal folate supplementation reduces the risk of neural tube defects and probably oral facial clefts. Previous studies of related metabolic genes have associated polymorphisms in cystathionine-beta-synthase (CBS) and 5,10-methylenetetrahydrofolate reductase (MTHFR) with cleft risk. We explored associations between genes related to one-carbon metabolism and clefts in a Norwegian population-based study that included 362 families with cleft lip with or without cleft palate (CL/P) and 191 families with cleft palate only (CPO). We previously showed a 39% reduction in risk of CL/P with folic acid supplementation in this population. In the present study we genotyped 12 polymorphisms in nine genes related to one-carbon metabolism and looked for associations of clefting risk with fetal polymorphisms, maternal polymorphisms, as well as parent-of-origin effects, using combined likelihood-ratio tests (LRT). We also stratified by maternal periconceptional intake of folic acid (>400 microg) to explore gene-exposure interactions. We found a reduced risk of CL/P with mothers who carried the CBS C699T variant (rs234706); relative risk was 0.94 with one copy of the T allele (95% CI 0.63-1.4) and 0.50 (95% CI 0.26-0.96) with two copies (P = 0.008). We found no evidence of interaction of this variant with folate status. We saw no evidence of risk from the MTHFR C677T variant (rs1801133) either overall or after stratifying by maternal folate intake. No associations were found between any of the polymorphisms and CPO. Genetic variations in the nine metabolic genes examined here do not confer a substantial degree of risk for clefts.     

Genes as instruments for studying risk behavior effects: an application to maternal smoking and orofacial clefts

This study uses instrumental variable (IV) models with genetic instruments to assess the effects of maternal smoking on the child's risk of orofacial clefts (OFC), a common birth defect. The study uses genotypic variants in neurotransmitter and detoxification genes relateded to smoking as instruments for cigarette smoking before and during pregnancy. Conditional maximum likelihood and two-stage IV probit models are used to estimate the IV model. The data are from a population-level sample of affected and unaffected children in Norway. The selected genetic instruments generally fit the IV assumptions but may be considered "weak" in predicting cigarette smoking. We find that smoking before and during pregnancy increases OFC risk substantially under the IV model (by about 4-5 times at the sample average smoking rate). This effect is greater than that found with classical analytic models. This may be because the usual models are not able to consider self-selection into smoking based on unobserved confounders, or it may to some degree reflect limitations of the instruments. Inference based on weak-instrument robust confidence bounds is consistent with standard inference. Genetic instruments may provide a valuable approach to estimate the "causal" effects of risk behaviors with genetic-predisposing factors (such as smoking) on health and socioeconomic outcomes.     

Design efficiency in genetic association studies

Selecting the best design for genetic association studies requires careful deliberation; different study designs can be used to scan for different genetic effects, and each design has its own set of strengths and limitations. A variety of family and unrelated control configurations are amenable to genetic association analyses, including the case-control design, case-parent triads, and case-parent triads in combination with unrelated controls or control-parent triads. Ultimately, the goal is to choose the design that achieves the highest statistical power using the lowest cost. For given parameter values and genotyped individuals, designs can be compared directly by computing the power. However, a more informative and general design comparison can be achieved by studying the relative efficiency, defined as the ratio of variances of two different parameter estimators, corresponding to two separate designs. Using log-linear modeling, we derive the relative efficiency from the asymptotic variance of the parameter estimators and relate it to the concept of Pitman efficiency. The relative efficiency takes into account the fact that different designs impose different costs relative to the number of genotyped individuals. We show that while optimal efficiency for analyses of regular autosomal effects is achieved using the standard case-control design, the case-parent triad design without unrelated controls is efficient when searching for parent-of-origin effects. Due to the potential loss of efficiency, maternal genes should generally not be adjusted for in an initial genome-wide association study scan of offspring genes but instead checked post hoc. The relative efficiency calculations are implemented in our R package Haplin.