Growing Curve of Babies After Birth Gestational Diabetes

Abstruse

We evaluated the growth patterns of infants born large-for-gestational-age (LGA) from birth to age one year compared to those born appropriate-for-gestational-historic period (AGA). In add-on, we investigated possible epigenetic changes associated with beingness born LGA. Seventy-1 newborns were classified by nascence weight as AGA (10^th–90^th percentile; n = 42) or LGA (>90^th percentile; n = 29). Mail-natal follow-upwards until age 1 twelvemonth was performed with clinical assessments at iii, 6 and 12 months. Genome-wide Dna methylation was analysed on umbilical tissue in 19 AGA and 27 LGA infants. At birth, LGA infants had greater weight (p < 0.0001), length (p < 0.0001), ponderal alphabetize (p = 0.020), every bit well as greater head (p < 0.0001), chest (p = 0.044) and abdominal (p = 0.007) circumferences than AGA newborns. LGA infants were withal larger at the age of 3 months, but by age vi months in that location were no more differences betwixt groups, due to higher length and weight increments in AGA infants betwixt 0 and 6 months (p < 0.0001 and p = 0.002, respectively). Genome-wide analysis showed no epigenetic differences between LGA and AGA infants. Overall, LGA infants had slower growth in early infancy, being anthropometrically similar to AGA infants by vi months of age. In addition, differences betwixt AGA and LGA newborns were not associated with epigenetic changes.

Introduction

There is no universal definition of oversize at birth. Nonetheless, babies born large-for-gestational-age (LGA) are ordinarily defined by weight, determined as >ninety^th percentile at birth according to gestational age and sex, although the 95^th or 97^th percentile take also been used. A systematic review and meta-analysis showed that high birth weight is independently associated with increased overweight gamble in childhood and adulthood¹. In addition, epidemiological studies accept shown a strong clan between beingness born LGA and later adverse metabolic outcomes, including type 2 diabetes and other cardiovascular disorders^2,three,four. The underlying mechanisms and developmental pathways to later disorders are still unclear, but both intrauterine environmental factors⁵ and early postnatal events⁶ seem to be involved.

More than than three decades ago, Davies et al. reported rapid downwards shift in length increase during the get-go 3 months of life in LGA infants, as well equally a slower than average weight gain in the first 6 months⁷. More recently, Taal et al. confirmed a 'catch-downwards' growth in both weight and length in LGA infants, mainly occurring during the beginning 3 months of life, leading to a substantial realignment on all growth parameters compared to infants born appropriate-for-gestational-age (AGA)^viii. Thus, information technology has been speculated that, after escaping the strong maternal influence on intrauterine growth, LGA infants return to their genetically-adamant growth trajectory^vii. In contrast however, other studies showed that infants born LGA were 4.6 and 2.2 times more likely to be overweight at half-dozen and 12 months of age than AGA infants⁹. In addition, greater key adiposity has been found at age 12 months in those LGA infants born of mothers with gestational diabetes¹⁰. Therefore, based on the broad heterogeneity of the available evidence, it is difficult to reach firm conclusions on the postnatal growth trajectories in infants born LGA^7,8,nine,10.

Sustained changes in growth and metabolism post-obit an adverse fetal or early neonatal environment have been associated with mechanisms involving environmental regulation of gene expression^xi. Environmental factors can trigger long-lasting changes through these epigenetic processes, which regulate gene expression without affecting the genetic sequence^12,xiii,14, such as DNA methylation¹⁵. In that location is a large number of animal studies showing that manipulation of the early life environment is associated with the development of adverse cardio-metabolic outcomes later in life^16,17. The possible link between epigenetic regulation in fetal tissues and intrauterine growth restriction has also been investigated^xviii,xix. Notably, specific epigenetic changes have been linked to growth restriction, including alterations in genomic imprinting and DNA methylation²⁰. Yet, the potential association betwixt Dna methylation and high birth weight has not been adequately explored and only very recently a candidate cistron (FGFR2) has been identified²¹.

Thus, in the present study we aimed to evaluate the growth patterns of infants born LGA from nascency to age 1 yr in comparison to those born AGA. In add-on, we aimed to assess whether there were epigenetic changes at birth associated with existence born LGA.

Patients and Methods

Ethics approval

Ethics approval for this report was provided by the Northern Y Regional Ethics Committee (Ministry of Health, New Zealand). Written informed consent was obtained from parents or guardians. This report was performed in accordance with all appropriate institutional and international guidelines and regulations for medical research, in line with the principles of the Declaration of Helsinki.

Participants

This written report involved a prospective cohort of good for you infants recruited at birth from the Newborn Services, Auckland Metropolis Hospital (New Zealand), between March and September 2011. All infants were born at term (37–41 weeks of gestation) from singleton and uneventful pregnancies. Infants were excluded if conceived by in vitro fertilisation, or built-in to mothers with type 1 diabetes or gestational diabetes, preeclampsia, gestational or pre-existing hypertension, chronic illnesses, or following maternal employ of recreational drugs, tobacco, or alcohol during pregnancy. Other exclusion criteria were chromosomal or single gene defects, syndromal diagnosis, also as having a first-caste relative or grandparent with diabetes or the metabolic syndrome.

Neonatal clinical cess

All neonatal auxological measures were obtained by a single written report investigator within 48 h of birth. These included weight, crown-heel length, as well as head, chest and abdominal circumferences. Nativity weight was measured to the nearest 10 grand using electronic babe scales and birth weight data were transformed into standard deviations scores (SDS)²². Crown-heel length was measured using a neonatometer (Holtain Ltd., Crymych, U.G.) and circumferential measurements were obtained to the nearest millimetre. Body mass index (BMI) and ponderal alphabetize were calculated as markers of adiposity. The study population was divided into 2 groups according to nativity weight: infants born AGA (birth weight between the 10^thursday and 90^th percentiles) or LGA (birth weight greater than the 90^th percentile)²³.

Gestational age was determined by hierarchical integration of the following variables: date of terminal menstrual period, menstrual cycle length, ultrasound primarily at xvi–20 weeks and clinical assessment of gestational age at birth^24,25. BMI at birth was calculated every bit per standard formula (kg/kⁱⁱ), with SDS corrected for sex activity only²⁶. BMI SDS was derived according to British 1990 standards²⁷. Ponderal index was calculated as birth weight in grams (×100) divided past the cube of the crown-heel length in centimetres²⁸.

Maternal obstetric history was recorded to clarify age at time of commitment, mode of delivery (vaginal commitment or caesarean section), parity and the nascency order of each infant. Maternal and paternal weights and heights, maternal pre-pregnancy weight and BMI and weight and BMI at the end of pregnancy were obtained. Mean parental BMI was calculated as the average of maternal and paternal BMI. Mid-parental height SDS was calculated using standard formulae²⁹. Ethnicity was recorded by self-report using a prioritized arrangement, such that if multiple ethnicities were selected, the patient was assigned to a single category, following a hierarchical system of classification³⁰.

Umbilical string tissue was collected at nascency and frozen at −80 °C for later genome-broad DNA methylation analysis.

Longitudinal clinical assessment

All participants were re-evaluated by the same study investigator at 3, half-dozen and 12 months of age. Anthropometric measures, including weight, length, as well as head, breast and intestinal circumferences were measured.

Genome-wide methylation assay

Genomic DNA was isolated from umbilical tissue samples using the KingFisher Cell and Tissue DNA kit (Thermo Fisher Scientific, Vantaa, Finland) according to manufacturer's instructions. One μg of DNA was bisulfite treated using the EZ DNA Methylation™ Kit (Zymo Research, Orangish, CA, USA) and 500 ng of bisulfite-treated DNA was analysed using the Illumina Infinium 450 M methylation assortment platforms. To assess Dna methylation contour, we used the standard Illumina protocols. The bisulfide-converted samples were whole-genome amplified and the amplified products were fragmented by an endpoint enzymatic process. The fragmented Dna was purified and hybridized to the Infinium Human Methylation 450 Grand BeadChips (Illumina Inc., San Diego, CA, Us). During hybridization, the amplified and fragmented Deoxyribonucleic acid samples anneal to locus-specific Deoxyribonucleic acid oligomers residing on the bead chips. Single base extension reaction, washing and staining were carried out using a TECAN Te-Menses chamber. The stained arrays were assessed for fluorescence intensities at the methylated and unmethylated dewdrop sites using Illumina BeadArray Reader (Illumina Inc.). Quality control was performed using built-in controls. All samples passed quality command criteria (<5% of probes were invalid). Deoxyribonucleic acid methylation signals (β-values) from the scanned arrays were extracted using the methylation module of GenomeStudio® software version 2011.1 (Illumina Inc.). The β-value was used to gauge the methylation level of the CpG locus by calculating the ratio of intensities between methylated and unmethylated alleles (i > average β > 0 represents fully methylated to un-methylated alleles). R package Lumi³¹ and wateRmelon³² were used for sample quality filtering and cess, for all β-values pre-processing, correction and normalisation steps. Differential methylation analysis to determine an association between CpG methylation at each site as a function of the phenotype of interest (LGA versus AGA) was performed using the R parcel CpGassoc³³ and RnBeads³⁴.

Statistical analyses

Demographic characteristics betwixt groups were compared with one-way ANOVA and Fisher's exact tests. Anthropometric differences betwixt groups were analysed using full general linear regression models. Models deemed for important confounding factors (gestational age, sex, ethnicity). Models examining differences between LGA and AGA infants at 3, six and 12 months included age as a covariate. Binary logistic regressions were carried out to examine the factors affecting the likelihood of beingness born LGA or undergoing a caesarean department. Statistical analyses were carried out in SAS version nine.3 (SAS Institute Inc. Cary NC, Usa) and Minitab v.sixteen (Pennsylvania Land University, State College, PA, USA). All statistical tests were two-tailed and maintained at a 5% significance level. Demographic information are presented as means ± standard deviations. Upshot information are presented as model-adjusted means (estimated marginal means adjusted for the confounding factors in the models), with associated 95% confidence intervals.

For statistical analysis on differential methylation levels, probes with detection p-value > 0.05 were excluded. CpG sites with missing data for >10% of samples were also excluded from analysis. All CpGs residing on 10 and Y chromosomes were dropped from the assay to eliminate systematic sexual activity differences. Nosotros performed a multivariate linear mixed regression analysis that modelled the β-values equally the dependent variables, with the variable group (AGA or LGA) as the principal independent variable and including covariates for sex, birth weight and ethnicity to accommodate for potential effects of other covariate-dependent methylation. To assess significance while accounting for multiple testing, we used the Benjamini-Hochberg imitation discovery rate (FDR) procedure³⁵. Statistical significance of the differentially methylated CpGs was determined using the FDR with a cut-off of 0.05 to correct for multiple hypothesis testing. Running parallel to the CpGassoc method, a linear modelling using the limma³⁶ package in RnBeads was used for computing the CpGs site specific p-values, with a FDR cut-off of 0.05.

Results

Study cohort

Eligible meaning women in early labour were recruited from the Delivery Suite at Auckland City Hospital. We aimed to recruit at a ratio of approximately 2 controls for each LGA participant. Of 57 LGA and 108 AGA babies eligible at nascence, seventy-one infants (43%) attended all follow-up assessments (at 3, 6 and 12 months of age) and were included in this study: 42 built-in AGA (18 boys) and 29 built-in LGA (18 boys) (Supplementary Effigy one). The primary reasons for losing infants from the original accomplice to the longitudinal function of the study were living outside the Auckland region, being uncontactable and lack of parental interest in ongoing participation in the report. However, AGA participants were similar in all birth and parental characteristics to AGA infants excluded (data not shown). The aforementioned practical to LGA subjects, except that LGA participants had greater abdominal circumference than LGA infants excluded (p = 0.004).

The parents of LGA children were considerably fatter than the parents of AGA infants, with a 2.4 kg/thou² difference in hateful parental BMI (p = 0.004). Prior to pregnancy, LGA mothers had BMI that was 2.seven kg/yard² greater than mothers of the AGA group (p = 0.004). Not surprisingly, every ane kg/yard² increase in maternal pre-pregnancy BMI was associated with an 11% increase in the odds of a LGA babe being built-in (p = 0.014). In addition, increasing birth lodge was associated with an increased likelihood of LGA nascency (odds ratio 1.66; p = 0.034) (Table i). The rate of delivery past caesarian section was 21% amongst those born LGA in comparing to 10% for the AGA group (odds ratio 3.0; p = 0.036).

Tabular array 1 Demography of the study population and parental features.

Total size table

Auxology at nativity

At birth, LGA were larger than AGA infants based on all parameters assessed (Table ii). LGA infants were 800 g heavier (p < 0.0001), two.7 cm longer (p < 0.0001), with a ponderal index 0.xv g*100/cm^three greater (p = 0.020) than AGA infants. Farther, LGA infants had greater circumference of the caput (+i.9 cm; p < 0.0001), chest (+0.9 cm; p = 0.044) and belly (+1.5 cm; p = 0.007).

Table two Characteristics of the study population at nativity.

Full size tabular array

Longitudinal assessment over the first yr of life

By 3 months of historic period, at that place were persisting differences between LGA and AGA infants. LGA subjects were still 1.5 cm longer (p = 0.006), 713 1000 heavier (p < 0.0001) and of BMI 1 kg/m² greater (p = 0.030) and had greater head (+ane.1 cm; p = 0.004) and abdominal (+1.iv cm; p = 0.042) circumferences. However, there were no significant differences in ponderal index or chest circumference.

In the outset six months of life, LGA infants grew significantly slower than those born AGA: length increase 15.1 vs xviii.three cm, respectively (p < 0.0001) and weight increment 4.thirteen vs iv.87 kg, respectively (p = 0.002) (Fig. 1). These differences deemed for the fact that both groups were anthropometrically similar by 6 months of age. LGA and AGA infants were still similar at the ane-year follow-upward (Table 3), as length and weight increments were virtually identical in the two groups between 6 and 12 months of historic period (vii.seven cm and 2.1 kg for both groups).

Table iii Characteristics of the study population at the one-year follow-upward.

Full size tabular array

Genome-wide methylation analysis

The genome-wide methylation analysis was carried out on samples from 46 infants, including 19 AGA and 27 LGA infants. For this analysis, more than 485,000 DNA methylation sites covering 99% of human being NCBI Reference Sequence (RefSeq) genes were examined at nascency. 449,691 probes (92.6%) out of 485,577 passed the probe filtering criteria. The differential methylation analysis of CpGs sites showed no significant differences between LGA and AGA infants at birth (all p > 0.05) (Fig. 2 and Supplementary Figure 2).

Discussion

Our results indicate that, despite being born oversized, LGA infants displayed slower length and weight velocity, and so that by the age of six months LGA infants were anthropometrically like to AGA infants. This suggests that LGA infants experience a slowing in growth in early infancy. In addition, no epigenetic differences in genome-wide methylation were found in LGA infants at nascency.

Alterations in the intrauterine environment can induce fetal developmental adaptations that might have long-lasting detrimental effects on the offspring³⁷. Maternal factors exert a critical role in determining the overall health of newborns, with maternal obesity and gestational diabetes accounting for a marked increase in the number of LGA infants^5,38. Nonetheless, a considerable number of these infants are built-in to healthy and normoglycemic women³⁸ and in such cases the underlying mechanisms for oversize at nascence are yet to be identified.

Every bit mentioned previously, there is a paucity of information on growth outcomes of LGA infants. Our data corroborate previous studies showing that LGA newborns more often than not present greater adiposity besides being born oversized^39,40. We observed that LGA subjects had greater ponderal index and abdominal circumference than AGA infants at at birth and however greater abdominal circumference at 3 months of age. Although both are indirect measures of neonatal adiposity, they provide useful data on newborn torso fat mass⁴¹.

Nevertheless, nosotros observed a subsequent slower growth in LGA infants, culminating in similar anthropometry in LGA and AGA groups past 6 months of age, which remained so at 12 months. These findings are in line with previous data showing a slowdown in weight and length gain from birth to age half-dozen months in well-nigh LGA infants^7,eight. In order to explicate the reduced growth ex utero in those born LGA, a putative role has been attributed to maternal influences to account for their increased growth in utero. For instance, fetal overgrowth in oversized infants of non-diabetic mothers has been linked to an free energy-rich fetal environment associated with mild maternal hyperglycemia (below the cut-off levels for gestational diabetes), maternal obesity, or excessive gestational weight gain^42,43. Thus, it is speculated that later on nativity LGA infants are gratis from these intrauterine stimuli, leading to the natural expression of their genetic growth patterns.

However, the data on LGA infants are inconsistent and our results are in dissimilarity with some studies reporting greater central adiposity at historic period 12 months in those born LGA compared to AGA infants^nine,44. In particular, Vohr et al. reported a unique pattern of adiposity (based on a higher BMI, abdominal circumference and abdominal skinfold) at birth and still at age 12 months in LGA infants of diabetic mothers, in comparison to LGA of healthy mothers and AGA infants of diabetic mothers, supporting the additional detrimental effects of maternal diabetes on offspring growth^ten. As a result, nosotros excluded infants built-in to mothers with gestational diabetes or who had a first-caste relative or grandparent with diabetes, in order to minimize the potential furnishings of such confounders. This may explain the lack of observed differences between AGA and LGA from vi months of age in our written report.

There is a large body of evidence showing that changes in the early life environment are associated with increased cardio-metabolic risk later in life^{sixteen,17,45}. Epigenetics (a dynamic process that alters gene expression without changes in Dna sequence) has been linked to the regulation of fetal tissue growth and development^18,19 and epigenetic changes accept been associated with abnormal intrauterine growth^twenty,46. Genes such as IGF2 and H19 are known to affect the fetal development⁴⁷ and epigenetic modifications in their imprinting control regions can therefore bear on fetal growth. For case, hypomethylation has been associated with a repressed IGF2 expression responsible for pre- and mail service-natal growth restriction (roughly 30% of Silver Russell syndrome cases), while hypermethylation induces IGF2 overexpression leading to overgrowth (Beckwith-Wiedemann syndrome)⁴⁷. In that location is also increasing testify that a range of genes associated with an increased run a risk of obesity are susceptible to epigenetic changes⁴⁸.

Potential epigenetic changes in utero associated with the LGA phenotype, which could possibly lead to heavier nascence weight and altered body composition and metabolism, take merely recently been examined²¹. Methylation at three CpGs in the FGFR2 gene were identified as being associated with high nascency weight²¹. Withal, we observed no epigenetic alterations in genome-wide methylation analysis at birth in LGA infants. It has to exist best-selling that we undertook the Deoxyribonucleic acid methylation analysis in cord samples from a subgroup of AGA and LGA newborns and it is conceivable that there is differential Dna methylation in other tissues. Still, it is not feasible to sample Dna from multiple organs and tissues in newborn infants. In addition, string samples have been constitute to be advantageous as they provide a great amount of fetal mesenchymal cells and vascular tissue⁴⁹. Nonetheless, further studies are needed to appraise whether umbilical cord tissues tin indeed be used every bit reliable markers of Deoxyribonucleic acid methylation in other tissues.

In determination, our report showed that although LGA babies were larger and had greater adiposity at birth, a slowing in growth (length and weight) occurs in these infants in early infancy, leading to a like anthropometry to AGA infants by 6 months of age. Of note, the differences observed in early life between LGA and AGA infants were non associated with epigenetic changes. Farther enquiry is needed to clarify the growth design of those born LGA in early on infancy and childhood and to elucidate possible mechanisms associated with overgrowth in utero.

Additional Information

How to cite this article: Chiavaroli, V. et al. Infants built-in large-for-gestational-historic period display slower growth in early on infancy, but no epigenetic changes at birth. Sci. Rep. 5, 14540; doi: 10.1038/srep14540 (2015).

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Acknowledgements

We thank the Paykel Trust for long-term support of the Maurice & Agnes Paykel Clinical Inquiry Unit at the Liggins Plant, University of Auckland. We likewise thank all the participants and their families for their time and assistance with this written report. In add-on, we are grateful to the Gillberg Foundation, the Solstickan Foundation, the Swedish Medical Society, Her Royal Highness the Crown Princess Lovisas Club for child wellness care and the Swedish Club for Medical Research. This inquiry was supported by Gravida (National Eye for Growth and Evolution) and the Australasian Paediatric Endocrine Group (APEG). The authors accept no financial or nonfinancial conflict of interests to disclose that may be relevant to this work. The funders had no role in study blueprint, data collection and analysis, decision to publish or preparation of this manuscript.

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Fredrik Ahlsson

Present address: Department of Women's and Children'southward Health, Uppsala University, Uppsala, Sweden

Affiliations

Liggins Constitute, University of Auckland, Auckland, New Zealand

Valentina Chiavaroli, Wayne S. Cutfield, José 1000. B. Derraik, Zengxiang Pan, Sherry Ngo, Allan Sheppard, Susan Craigie & Fredrik Ahlsson
Department of Obstetrics and Gynaecology, Kinesthesia of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

Peter Rock
National Women's Wellness, Auckland District Health Board, Auckland, New Zealand

Lynn Sadler

Contributions

F.A. and W.South.C. conceptualized and designed the report; V.C. drafted the manuscript; J.G.B.D. carried out the statistical analyses (other than genetic) and drafted the manuscript; Z.P., S.N. and A.S. carried out the genetic analyses; F.A. and South.C. were responsible for recruitment and follow-upwardly assessments of participants; P.S. and L.S. assisted with experimental pattern and recruitment. All authors have contributed to discussion and critically reviewed the manuscript.

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The authors declare no competing financial interests.

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Chiavaroli, V., Cutfield, W., Derraik, J. et al. Infants born large-for-gestational-historic period display slower growth in early on infancy, simply no epigenetic changes at nativity. Sci Rep 5, 14540 (2015). https://doi.org/10.1038/srep14540

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Received: 16 March 2015
Accepted: 26 August 2015
Published: 30 September 2015
DOI : https://doi.org/ten.1038/srep14540

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Source: https://www.nature.com/articles/srep14540