Variable DNA methylation in neonates mediates the association between prenatal smoking and birth weight

There is great interest in the role epigenetic variation induced by non-genetic exposures may play in the context of health and disease. In particular, DNA methylation has previously been shown to be highly dynamic during the earliest stages of development and is influenced by in utero exposures such as maternal smoking and medication. In this study we sought to identify the specific DNA methylation differences in blood associated with prenatal and birth factors, including birth weight, gestational age and maternal smoking. We quantified neonatal methylomic variation in 1263 infants using DNA isolated from a unique collection of archived blood spots taken shortly after birth (mean = 6.08 days; s.d. = 3.24 days). An epigenome-wide association study (EWAS) of gestational age and birth weight identified 4299 and 18 differentially methylated positions (DMPs) respectively, at an experiment-wide significance threshold of p < 1 × 10 −7 . Our EWAS of maternal smoking during pregnancy identified 110 DMPs in neonatal blood, replicating previously reported genomic loci, including AHRR . Finally, we tested the hypothesis that DNA methylation mediates the relationship between maternal smoking and lower birth weight, finding evidence that methylomic variation at three DMPs may link exposure to outcome. These findings complement an expanding literature on the epigenomic consequences of prenatal exposures and obstetric factors, confirming a link between the maternal environment and gene regulation in neonates. This article is part of the theme issue ‘Developing differences: early-life effects and evolutionary medicine’.

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Maternal education and offspring birth weight for gestational age: the mediating effect of smoking during pregnancy

European Journal of Public Health ◽

10.1093/eurpub/ckaa076 ◽

2020 ◽

Vol 30 (5) ◽

pp. 1001-1006 ◽

Cited By ~ 1

Author(s):

Aurélie Nakamura ◽

Laura Pryor ◽

Morgane Ballon ◽

Sandrine Lioret ◽

Barbara Heude ◽

...

Keyword(s):

Birth Weight ◽

Educational Attainment ◽

Gestational Age ◽

Tobacco Smoking ◽

Mediation Analysis ◽

Maternal Smoking ◽

Maternal Education ◽

Mediating Effect ◽

Smoking During Pregnancy ◽

Child Birth

Abstract Background Small for gestational age (SGA) birth weight, a risk factor for infant mortality and delayed child development, is associated with maternal educational attainment. Maternal tobacco smoking during pregnancy could contribute to this association. We aimed to quantify the contribution of maternal smoking during pregnancy to social inequalities in child birth weight for gestational age (GA). Methods Data come from the French nation-wide ELFE cohort study, which included 17 155 singletons. Birth weights for GA were calculated using z-scores. Associations between maternal educational attainment, tobacco smoking during pregnancy and child birth weight for GA were ascertained using mediation analysis. Mediation analyses were also stratified by maternal pre-pregnancy body mass index. Results Low maternal educational attainment was associated with an increased odd of tobacco smoking during pregnancy [adjusted OR (ORa) = 2.58 (95% CI 2.34–2.84)] as well as a decrease in child birth weight for GA [RRa = 0.94 (95% CI 0.91–0.98)]. Tobacco smoking during pregnancy was associated with a decrease in offspring birth weight for GA [RRa = 0.73 (95% CI 0.70–0.76)]. Mediation analysis suggests that 39% of the effect of low maternal educational attainment on offspring birth weight for GA was mediated by smoking during pregnancy. A more important direct effect of maternal educational attainment on child birth weight for GA was observed among underweight women [RRa = 0.82 (95% CI 0.72–0.93)]. Conclusions The relationship between maternal educational attainment and child birth weight for GA is strongly mediated by smoking during pregnancy. Reducing maternal smoking could lessen the occurrence of infant SGA and decrease socioeconomic inequalities in birth weight for GA.

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Prenatal smoking and childhood behavior problems: is the association mediated by birth weight?

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174416000039 ◽

2016 ◽

Vol 7 (3) ◽

pp. 273-281 ◽

Cited By ~ 3

Author(s):

S. E. Parker ◽

B. R. Collett ◽

M. L. Speltz ◽

M. M. Werler

Keyword(s):

Birth Weight ◽

Behavior Problems ◽

Child Behavior ◽

Maternal Smoking ◽

Behavioral Outcomes ◽

Attention Problems ◽

Prenatal Smoking ◽

Teacher Report ◽

Smoking During Pregnancy ◽

Maternal Smoking During Pregnancy

Maternal smoking during pregnancy is associated with both reduced birth weight and adverse neurobehavioral outcomes. The aim of this study was to investigate longitudinal associations between maternal smoking during pregnancy and childhood behavioral outcomes, and to determine the role of birth weight in mediating such associations. The study included 489 mother–child pairs. Prenatal exposures were assessed via maternal interviews conducted on average 1 year after delivery and child behavior assessments were completed at 5–12 years of age using the Child Behavior Checklist (CBCL) and Teacher Report Form (TRF). Maternal smoking during pregnancy was associated with externalizing and total behavior problems according to both mother and teacher report. Maternal smoking was also associated with the following percentage increases in scores: 41% (CBCL) and 44% (TRF) for aggressive behavior and 65% (CBCL) and 47% (TRF) for attention problems. Associations with behavior problems were attenuated or no longer observed for mothers that quit smoking in early pregnancy. The proportion of the total effect of maternal smoking on behavioral outcomes explained by differences in birth weight was small and ranged from 6.6% for externalizing behavior on the CBCL to 20.1% for rule-breaking behavior on the CBCL. Our results suggest that birth weight differences explain only a small proportion of the magnitude of association between maternal smoking during pregnancy and selected behavioral outcomes.

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Etiology of individual differences in birth weight of twins as a function of maternal smoking during pregnancy

Twin Research ◽

10.1375/twin.1.3.123 ◽

1998 ◽

Vol 1 (3) ◽

pp. 123-130 ◽

Cited By ~ 27

Author(s):

Caroline GM van Baal ◽

Dorret I Boomsma

Keyword(s):

Birth Weight ◽

Gestational Age ◽

Maternal Smoking ◽

Structural Equation ◽

Smoking During Pregnancy ◽

Intrauterine Growth ◽

Equation Modelling ◽

Maternal Smoking During Pregnancy ◽

Lower Variability ◽

Genetic And Environmental Factors

AbstractBirth weight is in large extent influenced by gestational age. In addition genetic and environmental factors determine intrauterine growth and birth weight. The contributions of these factors may be influenced by maternal smoking during pregnancy. We examined birth weight and maternal smoking in a sample of 2930 twin pairs from the Netherlands Twin Register using structural equation modelling. Gestational age accounted for 27–44% of the variance in birth weight. A lower variability of birth weight and a lower association of birth weight with gestational age was found in twins whose mothers smoked during pregnancy. The variance not associated with gestational age was independent of maternal smoking during pregnancy. A systematic smaller part of the variability in birth weight was associated with variability in gestational age in second born twins compared to first born twins. The heritability of interindividual differences in birth weight was modest (10% for twins with non-smoking mothers and 11% for twins with smoking mothers). Common environmental influences other than gestational age accounted for a slightly larger part of the variance not associated with gestational age (17–20%).

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DNA methylation links prenatal smoking exposure to later life health outcomes in offspring

10.1101/428896 ◽

2018 ◽

Author(s):

Petri Wiklund ◽

Ville Karhunen ◽

Rebecca C Richmond ◽

Alina Rodriguez ◽

Maneka De Silva ◽

...

Keyword(s):

Dna Methylation ◽

Health Outcomes ◽

Maternal Smoking ◽

Psychiatric Morbidity ◽

Later Life ◽

Prenatal Smoking ◽

Smoking During Pregnancy ◽

Mediation Analyses ◽

Increased Risk ◽

Prenatal Maternal Smoking

AbstractMaternal smoking during pregnancy is associated with adverse offspring health outcomes across their life course. We hypothesize that DNA methylation is a potential mediator of this relationship. To test this, we examined the association of prenatal maternal smoking with DNA methylation in 2,821 individuals (age 16 to 48 years) from five prospective birth cohort studies and perform Mendelian randomization and mediation analyses to assess, whether methylation markers have causal effects on disease outcomes in the offspring. We identify 69 differentially methylated CpGs in 36 genomic regions (P < 1×10−7), and show that DNA methylation may represent a biological mechanism through which maternal smoking is associated with increased risk of psychiatric morbidity in the exposed offspring.

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Maternal Smoking and Socio-Demographic Characteristics in Correlation with Low Birth Weight: A Turin (Piedmont) Study

Slovenian Journal of Public Health ◽

10.2478/sjph-2014-0022 ◽

2014 ◽

Vol 53 (3) ◽

pp. 221-225

Author(s):

Alice Mannocci ◽

Claudia Vaschetto ◽

Leda Semyonov ◽

Giuseppina Poppa ◽

Azzurra Massimi ◽

...

Keyword(s):

Logistic Regression ◽

Birth Weight ◽

Low Birth Weight ◽

Gestational Age ◽

Maternal Smoking ◽

Goodness Of Fit ◽

Univariate Analysis ◽

Demographic Characteristics ◽

Smoking During Pregnancy ◽

Increased Risk

Abstract Introduction. 15 to 25% of women smoke during pregnancy. Scientific evidence suggests that exposure to smoking causes decreased birth weight. The aim of this study was to assess the correlation between smoking during pregnancy, maternal sociodemographic characteristics, and low birth weight. Methods. Data were derived from 1572 questionnaires administered to each woman that gave birth at the Gynecology Teaching Hospital “S. Anna” in Turin (Italy) during the period from 2008 to 2010. Multiple logistic analysis was used to evaluate the association between socio-demographic characteristics and birth weight; the stepwise approach with a “backward elimination” procedure was followed, and the goodness of fit of the model was estimated using the Hosmer-Lemeshow test. Results. The univariate analysis revealed that smoking cigarettes (17%), having a lower educational level (13%), and female sex of the infant (13%) seem to be risk factors, as they increase the risk of having a low birth weight child. Logistic regression analysis showed that gestational age and maternal smoking are the statistically associated variables. Conclusions. The results confirmed that birth weight increases proportionally with the length of the gestational age and that maternal smoking and the child’s sex (female) increase the risk of having a lower birth weight. Logistic regression demonstrated that the association between maternal smoking and low birth weight shows an increased risk for the whole population (OR=2.85), for male (OR=3.45) and for female newborns (OR=2.44)

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Trends and Variations in Smoking During Pregnancy and Low Birth Weight: Evidence From the Birth Certificate, 1990–2000

PEDIATRICS ◽

10.1542/peds.111.s1.1176 ◽

2003 ◽

Vol 111 (Supplement_1) ◽

pp. 1176-1180 ◽

Cited By ~ 6

Author(s):

Stephanie J. Ventura ◽

Brady E. Hamilton ◽

T. J. Mathews ◽

Anjani Chandra

Keyword(s):

Birth Weight ◽

Low Birth Weight ◽

Maternal Smoking ◽

Birth Certificate ◽

Birth Certificates ◽

Prenatal Smoking ◽

Smoking During Pregnancy ◽

Populations At Risk ◽

The Impact ◽

Hispanic White

Objective. This study compares patterns of tobacco use during pregnancy over time and across population subgroups and examines the impact of maternal smoking on the incidence of low birth weight (LBW). The study also evaluates the use of birth certificates to monitor prenatal smoking. Methods. The birth certificates of all states (except California) and the District of Columbia for 2000 provided to Centers for Disease Control and Prevention’s National Center for Health Statistics were analyzed. Trends in maternal smoking were examined with data from birth certificates and other relevant sources. Results. Smoking during pregnancy was reported for 12.2% of women who gave birth in 2000, down 37% from 1989 (19.5%), when this information was first collected on birth certificates. Throughout the 1990s, prenatal smoking rates were highest for older teenagers and women in their early 20s. Among population subgroups, the highest rates were reported for non-Hispanic white women who attended but did not complete high school. The incidence of LBW among singleton infants who were born to smokers was double that for nonsmokers. This relationship was observed in all age groups, for births to Hispanic and non-Hispanic white and black women, and within educational attainment subgroups. Even light smoking (<5 cigarettes daily) was associated with elevated rates of LBW. Conclusion. Although prenatal smoking may be underreported on the birth certificate, the trends and variations in smoking based on birth certificate data have been confirmed with data from other sources. Birth certificate data can be useful in monitoring prenatal smoking patterns. Changes in the birth certificate questions that are to be implemented beginning in 2003 will help to clarify the levels and changes in smoking behavior during pregnancy so that smoking cessation programs can be more effectively designed to meet the needs of the populations at risk.

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Mediation by Placental DNA Methylation of the Association of Prenatal Maternal Smoking and Birth Weight

American Journal of Epidemiology ◽

10.1093/aje/kwz184 ◽

2019 ◽

Vol 188 (11) ◽

pp. 1878-1886 ◽

Cited By ~ 11

Author(s):

Andres Cardenas ◽

Sharon M Lutz ◽

Todd M Everson ◽

Patrice Perron ◽

Luigi Bouchard ◽

...

Keyword(s):

Dna Methylation ◽

Birth Weight ◽

Maternal Smoking ◽

Cell Types ◽

Prenatal Smoking ◽

Association Analyses ◽

Lower Birth Weight ◽

Cpg Sites ◽

Prenatal Maternal Smoking ◽

Infant Birth

Abstract Prenatal maternal smoking is a risk factor for lower birth weight. We performed epigenome-wide association analyses of placental DNA methylation (DNAm) at 720,077 cytosine-phosphate-guanine (CpG) sites and prenatal maternal smoking among 441 mother-infant pairs (2010–2014) and evaluated whether DNAm mediates the association between smoking and birth weight using mediation analysis. Mean birth weight was 3,443 (standard deviation, 423) g, and 38 mothers (8.6%) reported smoking at a mean of 9.4 weeks of gestation. Prenatal maternal smoking was associated with a 175-g lower birth weight (95% confidence interval (CI): −305.5, −44.8) and with differential DNAm of 71 CpGs in placenta, robust to latent-factor adjustment reflecting cell types (Bonferroni-adjusted P < 6.94 × 10−8). Of the 71 CpG sites, 7 mediated the association between prenatal smoking and birth weight (on MDS2, PBX1, CYP1A2, VPRBP, WBP1L, CD28, and CDK6 genes), and prenatal smoking × DNAm interactions on birth weight were observed for 5 CpG sites. The strongest mediator, cg22638236, was annotated to the PBX1 gene body involved in skeletal patterning and programming, with a mediated effect of 301-g lower birth weight (95% CI: −543, −86) among smokers but no mediated effect for nonsmokers (β = −38 g; 95% CI: −88, 9). Prenatal maternal smoking might interact with placental DNAm at specific loci, mediating the association with lower infant birth weight.

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Effects of Chorionicity and Zygosity on Triplet Birth Weight

Twin Research and Human Genetics ◽

10.1375/twin.15.2.149 ◽

2012 ◽

Vol 15 (2) ◽

pp. 149-157 ◽

Cited By ~ 4

Author(s):

Diane J. Lamb ◽

Jacqueline M. Vink ◽

Christel M. Middeldorp ◽

Catharina E.M. van Beijsterveldt ◽

Monique C. Haak ◽

...

Keyword(s):

Regression Analysis ◽

Birth Weight ◽

Low Birth Weight ◽

The Netherlands ◽

Gestational Age ◽

Maternal Smoking ◽

Extremely Low Birth Weight ◽

Smoking During Pregnancy ◽

Individual Level ◽

Maternal Smoking During Pregnancy

Birth weight in triplets is, on average, lower than in singletons and twins, and more children are classified as having very low or extremely low birth weight. Still, there is limited research on factors that affect triplet birth weight, and samples under study are often small. Chorionicity and zygosity influence triplet birth weight, but it is unknown whether the effect of zygosity can be entirely ascribed to the effect of chorionicity or whether zygosity has an additional effect on triplet birth weight. This question was investigated in 346 triplets (from 116 trios) registered with the Netherlands Twin Register for whom data on chorionicity were available. ‘Triplet’ refers to one child and the set of three triplets is referred to as ‘trio’. Trios and triplets were classified based on zygosity and chorionicity. With regression analysis, the effects of zygosity and chorionicity on triplet birth weight were examined, while controlling for gestational age, sex, and maternal smoking during pregnancy. In addition, within the dizygotic trios a within-family comparison was made between the birth weight of the triplets that were part of a monozygotic pair (with some pairs sharing a chorion), and the birth weight of the dizygotic triplet. Based on the classification on individual level, monozygotic, monochorionic triplets had a lower mean birth weight than dizygotic, dichorionic triplets. Most remarkably, in dizygotic trios, monozygotic pairs only had a lower mean birth weight than their dizygotic sibling triplet when the pair shared a chorion. We conclude that having shared a chorion, rather than being monozygotic, increases the risk of a low birth weight.

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