Rolv T. Lie

Long-Term Medical and Social Consequences of Preterm Birth

BACKGROUND Advances in perinatal care have increased the number of premature babies who survive. There are concerns, however, about the ability of these children to cope with the demands of adulthood. METHODS We linked compulsory national registries in Norway to identify children of different gestational-age categories who were born between 1967 and 1983 and to follow them through 2003 in order to document medical disabilities and outcomes reflecting social performance. RESULTS The study included 903,402 infants who were born alive and without congenital anomalies (1822 born at 23 to 27 weeks of gestation, 2805 at 28 to 30 weeks, 7424 at 31 to 33 weeks, 32,945 at 34 to 36 weeks, and 858,406 at 37 weeks or later). The proportions of infants who survived and were followed to adult life were 17.8%, 57.3%, 85.7%, 94.6%, and 96.5%, respectively. Among the survivors, the prevalence of having cerebral palsy was 0.1% for those born at term versus 9.1% for those born at 23 to 27 weeks of gestation (relative risk for birth at 23 to 27 weeks of gestation, 78.9; 95% confidence interval [CI], 56.5 to 110.0); the prevalence of having mental retardation, 0.4% versus 4.4% (relative risk, 10.3; 95% CI, 6.2 to 17.2); and the prevalence of receiving a disability pension, 1.7% versus 10.6% (relative risk, 7.5; 95% CI, 5.5 to 10.0). Among those who did not have medical disabilities, the gestational age at birth was associated with the education level attained, income, receipt of Social Security benefits, and the establishment of a family, but not with rates of unemployment or criminal activity. CONCLUSIONS In this cohort of people in Norway who were born between 1967 and 1983, the risks of medical and social disabilities in adulthood increased with decreasing gestational age at birth.

Fetal and maternal contributions to risk of pre-eclampsia: population based study

Abstract Objective: To use familial patterns of recurrence of pre-eclampsia to investigate whether paternal genes expressed in the fetus contribute to the mothers risk of pre-eclampsia and whether mothers susceptibility to pre-eclampsia is related to maternal inheritance by mitochondrial DNA. Design: Linked data on pregnancies of different women who had children with the same father, and subsequently linked data on pregnancies of half sisters who either had same mother and different fathers or had same father and different mothers. Setting: Population based data from the Medical Birth Registry of Norway covering all births since 1967 (about 1.7 million) and the Norwegian Central Population Register. Main outcome measures: Relative risk of pre-eclampsia after a previous pre-eclamptic pregnancy in the family. Relative risks approximated by odds ratios. Results: If a woman becomes pregnant by a man who has already fathered a pre-eclamptic pregnancy in a different woman her risk of developing pre-eclampsia is 1.8 (95% confidence interval 1.2 to 2.6). If the woman has a half sister who had pre-eclampsia and with whom she shares the same mother but different fathers the risk of pre-eclampsia is 1.6 (0.9 to2.6). If the two sisters have the same father but different mothers the risk is 1.8 (1.01 to 2.9). Conclusions: Both the mother and the fetus contribute to the risk of pre-eclampsia, the contribution of the fetus being affected by paternal genes. Mitochondrial genes, which are transmitted by mothers, do not seem to contribute to the risk. Key messages Paternal genes in the fetus may contribute substantially to a pregnant womans risk of pre-eclampsia The role of the fetus may be as important as that of the mother Purely maternal inheritance (specifically by mitochondrial DNA) is probably not involved in pre-eclampsia Search for specific genes that predispose for pre-eclampsia should include the fetus as well as the mother

Disruption of an AP-2α binding site in an IRF6 enhancer is associated with cleft lip

Previously we have shown that nonsyndromic cleft lip with or without cleft palate (NSCL/P) is strongly associated with SNPs in IRF6 (interferon regulatory factor 6). Here, we use multispecies sequence comparisons to identify a common SNP (rs642961, G>A) in a newly identified IRF6 enhancer. The A allele is significantly overtransmitted (P = 1 × 10−11) in families with NSCL/P, in particular those with cleft lip but not cleft palate. Further, there is a dosage effect of the A allele, with a relative risk for cleft lip of 1.68 for the AG genotype and 2.40 for the AA genotype. EMSA and ChIP assays demonstrate that the risk allele disrupts the binding site of transcription factor AP-2α and expression analysis in the mouse localizes the enhancer activity to craniofacial and limb structures. Our findings place IRF6 and AP-2α in the same developmental pathway and identify a high-frequency variant in a regulatory element contributing substantially to a common, complex disorder.

A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4

Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635–0.778, P = 1.44 × 10−11; and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292–1.587, P = 5.01 × 10−12) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes remained similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24, whereas Asian families showed stronger evidence for association with MAFB and ABCA4. Expression studies support a role for MAFB in palatal development.

Folic acid supplements and risk of facial clefts: national population based case-control study

Objective To explore the role of folic acid supplements, dietary folates, and multivitamins in the prevention of facial clefts. Design National population based case-control study. Setting Infants born 1996-2001 in Norway. Participants 377 infants with cleft lip with or without cleft palate; 196 infants with cleft palate alone; 763 controls. Main outcome measures Association of facial clefts with maternal intake of folic acid supplements, multivitamins, and folates in diet. Results Folic acid supplementation during early pregnancy (≥400 �g/day) was associated with a reduced risk of isolated cleft lip with or without cleft palate after adjustment for multivitamins, smoking, and other potential confounding factors (adjusted odds ratio 0.61, 95% confidence interval 0.39 to 0.96). Independent of supplements, diets rich in fruits, vegetables, and other high folate containing foods reduced the risk somewhat (adjusted odds ratio 0.75, 0.50 to 1.11). The lowest risk of cleft lip was among women with folate rich diets who also took folic acid supplements and multivitamins (0.36, 0.17 to 0.77). Folic acid provided no protection against cleft palate alone (1.07, 0.56 to 2.03). Conclusions Folic acid supplements during early pregnancy seem to reduce the risk of isolated cleft lip (with or without cleft palate) by about a third. Other vitamins and dietary factors may provide additional benefit.

Recurrence of pre-eclampsia across generations: exploring fetal and maternal genetic components in a population based cohort

Abstract Objectives To assess the impact on risk of pre-eclampsia of genes that work through the mother, and genes of paternal origin that work through the fetus. Design Population based cohort study. Setting Registry data from Norway. Participants Linked generational data from the medical birth registry of Norway (1967-2003): 438 597 mother-offspring units and 286 945 father-offspring units. Main outcome measures Pre-eclampsia in the second generation. Results The daughters of women who had pre-eclampsia during pregnancy had more than twice the risk of pre-eclampsia themselves (odds ratio 2.2, 95% confidence interval 2.0 to 2.4) compared with other women. Men born after a pregnancy complicated by pre-eclampsia had a moderately increased risk of fathering a pre-eclamptic pregnancy (1.5, 1.3 to 1.7). Sisters of affected men or women, who were themselves born after pregnancies not complicated by pre-eclampsia, also had an increased risk (2.0, 1.7 to 2.3). Women and men born after pre-eclamptic pregnancies were more likely to trigger severe pre-eclampsia in their own (or their partners) pregnancy (3.0, 2.4 to 3.7, for mothers and 1.9, 1.4 to 2.5, for fathers). Conclusions Maternal genes and fetal genes from either the mother or father may trigger pre-eclampsia. The maternal association is stronger than the fetal association. The familial association predicts more severe pre-eclampsia.

Effect of Reducing Indoor Air Pollution on Women's Respiratory Symptoms and Lung Function: The RESPIRE Randomized Trial, Guatemala

Exposure to household wood smoke from cooking is a risk factor for chronic obstructive lung disease among women in developing countries. The Randomized Exposure Study of Pollution Indoors and Respiratory Effects (RESPIRE) is a randomized intervention trial evaluating the respiratory health effects of reducing indoor air pollution from open cooking fires. A total of 504 rural Mayan women in highland Guatemala aged 15-50 years, all using traditional indoor open fires, were randomized to either receive a chimney woodstove (plancha) or continue using the open fire. Assessments of chronic respiratory symptoms and lung function and individual measurements of carbon monoxide exposure were performed at baseline and every 6 months up to 18 months. Use of a plancha significantly reduced carbon monoxide exposure by 61.6%. For all respiratory symptoms, reductions in risk were observed in the plancha group during follow-up; the reduction was statistically significant for wheeze (relative risk = 0.42, 95% confidence interval: 0.25, 0.70). The number of respiratory symptoms reported by the women at each follow-up point was also significantly reduced by the plancha (odds ratio = 0.7, 95% confidence interval: 0.50, 0.97). However, no significant effects on lung function were found after 12-18 months. Reducing indoor air pollution from household biomass burning may relieve symptoms consistent with chronic respiratory tract irritation.

Birth weight and childhood onset type 1 diabetes: population based cohort study

Abstract Objective: To assess the associations between birth weight or gestational age and risk of type 1 diabetes. Design: Population based cohort study by record linkage of the medical birth registry and the National Childhood Diabetes Registry. Setting: Two national registries in Norway. Participants: All live births in Norway between 1974 and 1998 (1 382 602 individuals) contributed a maximum of 15 years of observation, a total of 8 184 994 person years of observation in the period 1989 to 1998. 1824 children with type 1 diabetes were diagnosed between 1989 and 1998. Main outcome measures: Estimates of rate ratios with 95% confidence intervals for type 1 diabetes from Poisson regression analyses. Results: The incidence rate of type 1 diabetes increased almost linearly with birth weight. The rate ratio for children with birth weights 4500 g or more compared with those with birth weights less than 2000 g was 2.21 (95% confidence interval 1.24 to 3.94), test for trend P=0.0001. There was no significant association between gestational age and type 1 diabetes. The results persisted after adjustment for maternal diabetes and other potential confounders. Conclusion: There is a relatively weak but significant association between birth weight and increased risk of type 1 diabetes consistent over a wide range of birth weights. What is already known on this topic Results of case-control studies of birth weight and risk of type 1 diabetes have been inconsistent It is possible that a relatively weak association exists, and large studies are needed to find out if this is the case What this study adds This is the largest study of birth weight and type 1 diabetes published to date, and the first one to use a cohort design The incidence of type 1 diabetes increased almost linearly with increasing birth weight over a wide range of birth weights, independent of gestational age, maternal diabetes, and other potential confounders The trend was highly significant, but the increment in risk with increasing birth weight was still relatively low

Familial risk of oral clefts by morphological type and severity: population based cohort study of first degree relatives

Objective To estimate the relative risk of recurrence of oral cleft in first degree relatives in relation to cleft morphology. Design Population based cohort study. Setting Data from the medical birth registry of Norway linked with clinical data on virtually all cleft patients treated in Norway over a 35 year period. Participants 2.1 million children born in Norway between 1967 and 2001, 4138 of whom were treated for an oral cleft. Main outcome measure Relative risk of recurrence of isolated clefts from parent to child and between full siblings, for anatomic subgroups of clefts. Results Among first degree relatives, the relative risk of recurrence of cleft was 32 (95% confidence interval 24.6 to 40.3) for any cleft lip and 56 (37.2 to 84.8) for cleft palate only (P difference=0.02). The risk of clefts among children of affected mothers and affected fathers was similar. Risks of recurrence were also similar for parent-offspring and sibling-sibling pairs. The “crossover” risk between any cleft lip and cleft palate only was 3.0 (1.3 to 6.7). The severity of the primary case was unrelated to the risk of recurrence. Conclusions The stronger family recurrence of cleft palate only suggests a larger genetic component for cleft palate only than for any cleft lip. The weaker risk of crossover between the two types of cleft indicates relatively distinct causes. The similarity of mother-offspring, father-offspring, and sibling-sibling risks is consistent with genetic risk that works chiefly through fetal genes. Anatomical severity does not affect the recurrence risk in first degree relatives, which argues against a multifactorial threshold model of causation.

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