Association of preterm birth with long-term survival, reproduction, and next-generation preterm birth

Context  Preterm birth is a major cause of infant morbidity and mortality. Less is known about long-term health among persons born preterm. Objective  To determine the long-term effects of preterm birth on survival, reproduction, and next-generation preterm birth. Design, Setting, and Participants  Population-based, observational, longitudinal study using registry data from 1 167 506 singleton births in the Medical Birth Registry of Norway in 1967-1988. The cohort was followed up through 2002 for survival. The cohort was truncated to births from 1967-1976 for assessment of educational achievement and reproductive outcomes through 2004. Main Outcome Measures  In relation to sex and gestational age at birth, absolute mortality, risk of fetal, infant, child, and adolescent mortality, and incidence and risk of reproduction and next-generation preterm birth. Singleton term (37-42 weeks) fetal deaths and live births, stratified by sex, served as the reference group for all analyses. Results  The percentage who were born preterm was higher among boys (5.6%) than among girls (4.7%). Preterm participants had an increased risk of mortality throughout childhood. For boys born at 22 to 27 weeks, mortality rates were 1.33% and 1.01% for early and late childhood death, with relative risks (RRs) of 5.3 (95% confidence interval [CI], 2.0-14.2) and 7.0 (95% CI, 2.3-22.0), respectively. The mortality rate for girls born at 22 to 27 weeks was 1.71% for early childhood death, with an RR of 9.7 (95% CI, 4.0-23.7); there were no late childhood deaths. For 28 to 32 weeks, the early and late childhood mortality rates among boys were 0.73% and 0.37%, with RRs of 2.5 (95% CI, 1.6-3.7) and 2.3 (95% CI, 1.3-4.1), respectively. Girls born at 28 to 32 weeks did not have a significantly increased risk of childhood mortality. Reproduction was diminished for index participants born preterm. For men and women born at 22 to 27 weeks, absolute reproduction was 13.9% and 25%, with RRs of 0.24 (95% CI, 0.17-0.32) and 0.33 (95% CI, 0.26-0.42), respectively. For 28 to 32 weeks, absolute reproduction was 38.6% and 59.2% for men and women, with RRs of 0.7 (95% CI, 0.66-0.74) and 0.81 (95% CI, 0.78-0.85), respectively. Preterm women but not men were at increased risk of having preterm offspring. Conclusion  In persons born in Norway in 1967-1988, preterm birth was associated with diminished long-term survival and reproduction.      

Genetic and environmental influences on birth weight, birth length, head circumference, and gestational age by use of population-based parent-offspring data

Familial correlations in birth weight and gestational age have been explained by fetal and maternal genetic factors, mainly in studies on offspring of twins. The aim of the present intergenerational study was to estimate and compare fetal and maternal genetic effects and shared sibling environmental effects on birth weight and gestational age and also on crown-heel length and head circumference. The authors used path analysis and maximum likelihood principles to estimate these effects and, at the same time, to adjust for covariates. Parent-offspring data were obtained from the Medical Birth Registry of Norway from 1967 to 2004. For the analysis of birth weight and crown-heel length, 101,748 families were included; for gestational age, 91,617 families; and for head circumference, 77,044 families. Assuming no cultural transmission and random mating, the authors found that fetal genetic factors explained 31% of the normal variation in birth weight and birth length, 27% of the variation in head circumference, and 11% of the variation in gestational age. Maternal genetic factors explained 22% of the variation in birth weight, 19% of the variation in birth length and head circumference, and 14% of the variation in gestational age. Relative to the proportion of explained variation, fetal genes were most important for birth length and head circumference.     

Identification of DNA Methylation Changes in Newborns Related to Maternal Smoking during Pregnancy

Background: Maternal smoking during pregnancy is associated with significant infant morbidity and mortality, and may influence later disease risk. One mechanism by which smoking (and other environmental factors) might have long-lasting effects is through epigenetic modifications such as DNA methylation.Objectives: We conducted an epigenome-wide association study (EWAS) investigating alterations in DNA methylation in infants exposed in utero to maternal tobacco smoke, using the Norway Facial Clefts Study.Methods: The Illumina HumanMethylation450 BeadChip was used to assess DNA methylation in whole blood from 889 infants shortly after delivery. Of 889 mothers, 287 reported smoking—twice as many smokers as in any previous EWAS of maternal smoking. CpG sites related to maternal smoking during the first trimester were identified using robust linear regression.Results: We identified 185 CpGs with altered methylation in infants of smokers at genome-wide significance (q-value < 0.05; mean Δβ = ± 2%). These correspond to 110 gene regions, of which 7 have been previously reported and 10 are newly confirmed using publicly available results. Among these 10, the most noteworthy are FRMD4A, ATP9A, GALNT2, and MEG3, implicated in processes related to nicotine dependence, smoking cessation, and placental and embryonic development.Conclusions: Our study identified 10 genes with newly established links to maternal smoking. Further, we note differences between smoking-related methylation changes in newborns and adults, suggesting possible distinct effects of direct versus indirect tobacco smoke exposure as well as potential differences due to age. Further work would be needed to determine whether these small changes in DNA methylation are biologically or clinically relevant. The methylation changes identified in newborns may mediate the association between in utero maternal smoking exposure and later health outcomes.Citation: Markunas CA, Xu Z, Harlid S, Wade PA, Lie RT, Taylor JA, Wilcox AJ. 2014. Identification of DNA methylation changes in newborns related to maternal smoking during pregnancy. Environ Health Perspect 122:1147–1153; http://dx.doi.org/10.1289/ehp.1307892     

Secular trends of sudden infant death syndrome in Norway 1967–1988: application of a method of case identification to Norwegian registry data

Summary. In Norway, towards the end of the 1980s, sudden infant death syndrome (SIDS) was the most frequent cause of infant death. Both SIDS and the total post-perinatal mortality rates had increased. This paper presents a procedure for identifying SIDS from death certificates. Supplemented with additional information, a database was established to evaluate secular trends of SIDS and for further analytical research. The Medical Birth Registry of Norway comprises 1.3 million births from 1967 to 1988. Of these, 5447 infants died in the post-perinatal period. The cause of death was reviewed by an expert panel and 1984 cases of SIDS were retrieved.
Low maternal age, higher birth order, male gender, and lower birthweight were confirmed as risk factors for SIDS. In 1988, the rate for SIDS and for total post-perinatal deaths reached 2.69 and 5.02 per 1000 infants at risk. The incidence of SIDS increased 2.2 times from the period 1967–1971 to the period 1987–1988. Adjusted for maternal age, birth order, and birthweight, the odds ratio was 3.1. The increase is due to factors not yet accounted for. Adjusted mortality rates for the other post-perinatal deaths were not different from the crude rates.     

Selective fertility and the distortion of perinatal mortality

Data from the Medical Birth Registry of Norway, covering more than one million births for the period 1967-1984, were used to study the magnitude and effects of selective fertility, which is the tendency for a woman to replace a perinatal loss. Variation in fertility after the first three births is studied, controlling for perinatal outcome of previous births, maternal age, and year of birth. Even after the first birth, fertility is higher after a perinatal loss. Selective fertility is more strongly present at each successive birth order, and at each birth order it is stronger among older women. As the average number of births per woman decreases, the force of selective fertility increases; that is, its importance has increased over time. Perinatal mortality at the third and fourth birth orders is particularly distorted by the mechanism of selective fertility in studies based on cross-sectional data. Mortality at second birth is exaggerated by 1%, at third birth by 8% to 20%, and at fourth birth by 18% to 27%, with the largest effects seen in the later periods. A major portion of the increase in perinatal mortality from the second to fourth birth seen in most studies based on cross-sectional data can be explained by the mechanism of selective fertility.