The Developmental Origins of Health and Disease (DOHaD) suggest lifelong health implications of fetal and maternal growth trajectories. Low birthweight, premature birth, maternal underweight and/or malnutrition, and intrauterine growth retardation (IUGR) have been related to an increased risk of hypertension, cardiovascular disease, type 2 diabetes mellitus, obesity and neuropsychiatric disorders later in life 
. Conversely, high birthweight, maternal obesity, high weight gain during pregnancy, and gestational diabetes have been linked to future risk of cancer, obesity, and type 2 diabetes in the offspring 
. The mechanisms underlying these associations are poorly understood. Fetal “programming” may reset the growth hormone/insulin-like growth factor axis but longitudinal studies connecting early life hormonal parameters to adult disease outcomes are lacking. It has recently been suggested that epigenetic mechanisms may be important contributors to fetal programming 
DNA methylation is an important component of the cells machinery to regulate gene expression and occurs primarily on cytosine residues in CpG dinucleotides 
. About half of human genes contain CpG-rich regions termed CpG islands in their promoter regions. Most lone CpG dinucleotides are in the introns of repetitive elements 
. While most CpG islands are unmethylated, permitting transcription, the lone CpGs in the repetitive elements are mostly methylated.
About 50% of the human genome is composed of repetitive sequences such as LINE (Long Interspersed Nuclear Elements) and SINEs (Short Interspersed Nuclear Elements), including Alu 
. These largely non-coding regions have been highly conserved throughout evolution but have lost their ability to move or make copies of themselves. The retrotransposition process involves recombination and two DNA single-strand breaks in close proximity, increasing the risk for chromosomal breaks, translocations, recombinations, and deletions 
. The evolutionary younger subfamilies such as LINE-1 can still transcribe when activated. LINE-1 methylation decreases with age and hypomethylation of LINE-1 has been linked to various cancer types, possibly by contributing to chromosomal instability, and may be an early marker or a prognostic indicator of disease 
DNA methylation marks are established in utero
and the resulting methylation pattern is largely preserved through subsequent cell divisions through maintenance methylation 
. Initial epigenetic reprogramming occurs during gametogenesis, allowing primordial germ cells to differentiate into mature oocyte and sperm 
. After fertilization, male pronucleus and zygote undergo another round of demethylation which restores totipotency, followed by a genome-wide de novo
methylation which contributes to cell fate commitment of the first cell lineages in preimplantation development 
. These reprogramming sequences makes the intrauterine period a target for environmental and metabolic factors that may affect the establishment of cytosine methylation.
The epigenetic signatures of the cord blood and the placenta need to be interpreted in the context of their different embryonic origins. The placenta is composed of extraembryonic tissue and develops upon implantation of the blastocyst the maternal endometrium. The outer layer of the blastocyst becomes the trophoblast which forms the outer layer of the placenta. The inner blastomeres form the embryonic tissue. Disruption of the epigenetic profile in the gametes may affect inner and outer blastomeres to the same degree, and hence be reflected in both cord blood and placenta tissue. Disruption after fertilization may affect the outer blastomeres of the preimplantation embryo and be reflected only in the placental tissue. The placenta has metabolic and endocrine activity. It produces hormones which maintain the pregnancy, stimulate growth of the fetus, and increase transfer of these nutrients to the fetus. The perfusion of the intervillous spaces of the placenta with maternal blood allows the transfer of nutrients and oxygen from the mother to the fetus and the transfer of waste products and carbon dioxide back from the fetus to the mother. Altered regulation of these physiologic processes due to differences in gene expression may affect fetal growth.
Aberrant DNA methylation, including global hypomethylation of DNA from peripheral blood leukocytes, has been linked to various chronic diseases including cancer and cardiovascular disease 
. The distribution of global methylation and frequency of hypomethylation at birth has not been studied. Whether changes in DNA methylation occur prenatally and predispose to disease, hence provide a mechanistic explanation for the DOHaD observations remains to be determined. Since birthweight is the best studied perinatal non-genetic marker of adult disease susceptibility we explored the association between birthweight and its predictors such as maternal prepregnancy BMI and maternal weight gain during pregnancy and LINE-1 methylation. We used data and biospecimens from the Epigenetic Birth Cohort at Brigham and Women's Hospital, Harvard Medical School, in Boston to explore the association between trajectories of fetal and maternal weight and LINE-1 methylation in 319 mother-child dyads.