y y y Nutritional Intervention Preconception and ption l l l - - PowerPoint PPT Presentation

Nutritional Intervention Preconception and During Pregnancy to Maintain Healthy Glucose Metabolism & OffspRing Health

Keith Godfrey, with Chan Shiao-Yng, Wayne Cutfield, Chong Yap Seng Director, NIHR Southampton Biomedical Research Centre in Nutrition Professor of Epidemiology & Human Development, MRC Lifecourse Epidemiology Unit & University of Southampton Visiting Professor, National University of Singapore Honorary Consultant, University Hospital Southampton NHS Foundation Trust Twitter @KeithMGodfrey

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• Fat, muscle & bone
• Heart, lungs & kidneys
• Metabolic & stress responses
• Mood & behaviour
• Ability to learn & cognitive function
• Timing of puberty, reproductive function
• Immune responses

The effects can be subtle, but they have lifelong consequences, altering how a person responds to their later environment & lifestyle

A healthy start to life has lasting benefits for multiple organs & control systems in the offspring

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Men ( ) & women ( ) born after a famine period ( ) contribute an excess of diabetic patients - total population of Austria

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Developmental influences

Genotype Uterine environment e.g. gestational diabetes, mother’s diet, mother’s stress Postnatal environment e.g. mode of delivery early nutrition Phenotype e.g. Birth weight Gestational age Body composition Phenotype e.g. Adiposity Growth Neurodevelopment Phenotype e.g. Health Disease

Epigenetic Modification

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“When scientists opened up the human genome, they expected to find the genetic components of common traits and diseases. But they were nowhere to be seen. Brendan Maher shines a light on six places where the missing loot could be stashed away.”

Nature, 6th November 2008

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Epigenetic processes

(DNA methylation, HDACi, miRNA)

Feeding bee larvae royal jelly for 6 days (vs the usual 3 days) alters growth & development

How is the “memory” of early life experience held - epigenetics

The development & maintenance of plants & animals is orchestrated by reactions that switch parts of their DNA on & off at strategic times & locations. Epigenetics is the study of these reactions & the factors that influence them.* Plants & animals use epigenetic processes to adapt their development to the environment experienced in early life

*Adapted from http://learn.genetics.utah.edu/content/epigenetics/

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Epigenetics & the human genome

Human genome: 3.2 billion CGAT bases, 200 GB data, 30 million CpG sites 3% protein coding (23,000 genes, ~half expressed in each cell) 77% proposed to have functional elements (ENCODE) Epigenetics underlies differences between cells Changes in gene function that do not depend on DNA sequence Gene expression changed: methylation of CpG sites & chemical changes in the histone proteins alter “packaging” of DNA; non-coding RNAs have a variety of roles that alter gene transcription Human body - 50 trillion cells: different but same DNA (2 metres /cell)

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>80% 10.0 15.0 20.0 25.0

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Princess Anne Hospital study children aged 9 years Southampton Women’s Survey children aged 6 years

Umbilical cord RXRA SH amp1 CpG13 methylation Umbilical cord RXRA SH amp1 CpG13 methylation

Epigenetic “marks” in perinatal tissue: strong associations with childhood fat mass & % fat in 2 independent cohorts

Values are means + SEM Godfrey, et al. Diabetes 2011

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Changing the mother or father’s nutrition before/during pregnancy can result in fat & lazy “couch potato” offspring …

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Doyle, Heckman, et al. Economics & Human Biology 2009

Investment in human capital antenatally & preschool results in increased rates of return

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Maternal supplementation with 1000 IU Vitamin D: MAVIDOS multicentre RCT in 965 pregnancies

36.9 83.3 Placebo 1000 IU/ day

34 k

Percent women 25(OH)D> 50nmol/ l

100 60 40 20 80

34 weeks gestation

Reduces maternal vitamin D insufficiency

Cooper et al. The Lancet Diabetes & Endocrinology 2016

…. and increases offspring bone mass in winter births

36.9 83.3 Placebo 1000 IU/ day

34 k

50 60 70 placebo 1000 iu/d

Winter

50 60 70

Mean (95% CI) p= 0.003

Percent women 25(OH)D> 50nmol/ l

100 60 40 20 80 70 60 50

Winter births (Dec to Feb)

Neonatal bone mineral content (g)

34 weeks gestation p= 0.003 p interaction treatment group x season = 0.03

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Pregnancy low glycemic index diet reduced infant fatness age 6 months

Reduction seen when 3 or more months exclusive breastfeeding No reduction from prenatal intervention if less than 3 months exclusive breastfeeding

Patel, Godfrey, Poston, et al, Int J Obesity 2017

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Triceps Skinfold Thickness (mm)

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UPBEAT UPBEAT

UPBEAT: UK Better Eating and Activity Trial

Beneficial effect of prenatal intervention dependent on prolonged breastfeeding:

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Public Health Canada – Preconception Health Recommendations

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Iodine status of 30 countries in the EUthyroid project

Background colour refers to the iodine status in the general population; line colour represents the iodine status of pregnant women. Countries with solid colours have the same iodine status in both the general population and in pregnant women.

TLDE 2016

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Child’s WASI full IQ age 7 years (z-score) Mother’s preconception urinary iodine:creatinine ratio μg/g

≥50 to <100 ≥100 to <150 ≥150 <50

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0.49 SD lower IQ age 7 years* in children whose mothers had preconception iodine deficiency (9% of 654 Southampton mothers)

*Adjusted for maternal IQ, maternal education and maternal pre-pregnancy BMI, breastfeeding duration, smoking in pregnancy (yes/no), sex, age & maternal iodine intakes in pregnancy Robinson, Godfrey, et al. J Nutrition 2018

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Singapore: ideal for studying ethnic differences

• Total Population

– 5 million (3.8 million citizens & permanent residents)

• Land Area

– 712 sq km

• Literacy Rate

– 95.9%

• Resident population living in

government-subsidized housing

– 82%

• Home Ownership Rate

– 87.2%

• Genetic

– 3 distinct ethnic groups – Intermarriage rate of about 18%

• Nutritional

– Distinct ethnic cuisines – Shared by all ethnic groups

• Cultural

– Distinct cultural practices – Increasingly globalized

• Environmental

– Very similar – >80% stay in similar government-subsidized housing

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Rank Country / Territory Population % of World population World 6.96 billion 100% 1 China 1.34 billion 19.24% 2 India 1.21 billion 17.38% 3 United States 0.31 billion 4.48% 4 Indonesia 0.24 billion 3.41% 5 Brazil 0.19 billion 2.74%

36.6%

Chinese, 74.1 Malay, 13.4 Indian, 9.2 Others, 3.3

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Singapore’s socioeconomic & nutritional transition: a model of precipitous prosperity

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Prevalence of type 2 diabetes in Singapore has risen from 1.9% in 1975 to 11.3% in 2010

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Prevalence of type 2 diabetes & obesity among ethnic groups

National Health Survey 2004, MOH

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• 1. Excessive (& inadequate) pregnancy weight gain, maternal
• verweight/obesity, high dietary glycemic load & gestational diabetes are

extremely common, with lasting effects on offspring adiposity 2. Low quality diets are extremely common among the population, & relate to how the baby grows in the womb & to growth & body fatness in childhood 3. Maternal vitamin insufficiencies/poor status (notably of particular B-group vitamins & vitamin D) are highly prevalent & are associated with postnatal gain in fatness +/- impaired bone development

Developmental influences on childhood growth

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Not just gestational diabetes, but normal higher fasting glucose levels lead to increased birthweight & adiposity

0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0% 35.0% 40.0% 1 2 3 4 5 6 Frequency (%) > 90th percentile Glucose category

Fasting plasma glucose

0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0% 35.0% 40.0% 1 2 3 4 5 6 Glucose category

2-hour plasma glucose (OGTT 2-hr)

Birthweight % body fat sum of skinfolds (<4.2) (≥5.3 mmol/L) (<5.1) (≥8.8mmol/L)

GUSTO cohort - significant linear trend for fasting glucose for all 3 adiposity

• utcomes (p<0.0005) but not for 2h glucose

Aris et al, JCEM 2014

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Recruitment completed 1731 women age 18-38 y UK (CI Godfrey), NZ, SG

n=~865 n=~550 (up to 12 months)

PRECONCEPTION PREGNANCY

D E L I V E R Y

n=~865 n=~300 n=~300

BABY FOLLOW-UP

Primary objective:

Randomised to determine the effect of a myo-inositol, probiotic & micronutrient nutritional drink preconception & during pregnancy on the maintenance of healthy glucose metabolism, with the goal of promoting maternal & offspring wellbeing, with particular focus on offspring body composition & adiposity.

Outcomes:

Primary outcome is maintenance of healthy glucose tolerance during pregnancy (28 wk oral glucose tolerance test), with secondary outcomes including infant adiposity, epigenetics & microbiome development.

Randomisation

First trial of its type, plus major discovery platform (deep phenotyping

• f mother, father & offspring, >800,000 biosamples)

NiPPeR: Nutritional Intervention Preconception & During Pregnancy to Maintain Healthy Glucose Metabolism & OffspRing Health

Godfrey, et al, Trials 2017;18:131

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The nutritional drink

Ingredient Daily dose (2 servings) Vitamin D (ug) 10 Vitamin B2 (mg) 1.8 Vitamin B6 (mg) 2.6 Vitamin B12 (ug) 5.2 Zinc (mg) 10 Myo-inositol (g) 4 Probiotic blend 109 cfu each Folic Acid (ug) 400 Iron (mg) 12 Calcium (mg) 150 Iodine (ug) 150 Beta-carotene (RE) 120 (720ug)

ACTIVE CONTROL

• Taken twice a day during pre-conception and pregnancy
• Time period of consumption:

– Min : 4 weeks (+/- protocol window) + pregnancy – Max: 12 months + pregnancy

• Standard dietary advice

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Review of 12 clinical trials treating - mild GI side effects reported only with doses of ≥12 g/day Previous trials: myo-inositol may enhance fertility if taken before conception, and may reduce the chance of gestational diabetes

myo-inositol

myo-inositol may increase insulin sensitivity by making more phosphatidylinositol available Naturally produced in the body in the kidney & by the action of gut bacteria on dietary fibres

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Probiotics

Two “friendly” bacteria associated with improved glucose metabolism:

• Lactobacillus rhamnosus
• Bifidobacterium animalis sp. lactis

Study: Pregnant women treated from first trimester

Laitinen et.al. Br J Nut 2009; Luoto et.al. Br J Nut 2010

Control n=85 Diet/Placebo n= 86 Diet/Probiotics n=85 P value

GDM at 26w Odds of GDM (95% CI) 25/73 (34%) 1.0 27/76 (36%) 1.08 (0.55, 2.12) 10/76 (13%) 0.27 (0.11, 0.62) 0.003 12 months post-delivery blood glucose in mother

(base-adjusted means; mmol/L)

5.02 5.01 4.87 0.025

Proposed mechanism of anti-diabetic effect: microbial-derived products (e.g. fatty acids) exert immunomodulatory effects, reduce oxidative stress, modify nutrient absorption and gut microbiota (Tilg & Moschen. Gut 2014)

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Vitamin D

• Insufficiency common in developed & developing communities
• Systematic review indicates a significant inverse relation of serum

25OHD & the incidence of gestational diabetes

Eur J Intern Med. 2012;23:465-9

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Studying the biosamples

Blood chemistry Including micronutrients Genotyping 1,000,000 genetic variants - Omniexpress+ arrays Epigenetic assessment 450,000 CpGs - Infinium 450K arrays 6 million CpGs – Reduced representation bisulfite sequencing (RRBS) Whole genome - 80 million reads - MeDIP-seq Transcriptome assessment 45,000 transcripts – Infinium HT12 v4 arrays Whole transcriptome – 25 million reads – RNAseq Chromatin and histone assessment Whole genome – 80 million reads - DNAase protection Whole genome – 25 million reads – ChIP-seq Microbiome assessment 16S RNA sequencing – 30K reads - 454 sequencing Metagenomics - 4.5 GB - shotgun sequencing

Umbilical cord and placenta Maternal and fetal blood Longitudinal buccal swabs Cord derived cells Longitudinal microbiota sampling

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Fleming, Godfrey, et al. Lancet 2018

Preconception maternal overnutrition & obesity, maternal undernutrition, related paternal factors, & assisted reproductive treatments all may change the phenotype & potential of gametes & early embryos, with enduring consequences. Our new data reveal that suboptimal maternal & paternal nutrition around conception have similar effects on offspring weight, but differing effects on offspring blood pressure.

The NiPPeR Study & Preconception Health

Evidence exists for developmental origins on later disease throughout pregnancy & beyond, but there is a growing consensus that a critical period is around conception. This emerging knowledge has significant societal & medical implications. In particular, it provides the basis for a new emphasis on preparation for pregnancy, before conception, to safeguard public health & as a means of disease prevention.

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The Lancet, 2018

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LifeLab Southampton - science & health literacy

Dedicated teaching programme at the heart of a major teaching hospital enables 4000 students per year to:

• Experience for themselves exciting

developments in science: focus on understanding how our early lives have effects on our later health

• Learn how they can improve their
• wn health & the health of their

future children under a framework of ‘Me, my health & my children’s health’

• Become enthusiastic about science

such that they consider further study & careers in scientific disciplines

LifeLab cluster randomised trial

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WHO 2106 Science & Evidence Working Group Chair Mark Hanson

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Hanson, Godfrey, Poston, Stephenson, Bustreo 2015

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Trial Management Group members

Professor Keith Godfrey University of Southampton, UK

most recently as Chief strategy, venture investment and most recently as

JProfessor Wayne

Cutfield University of Auckland, New Zealand

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Professor Chong Yap Seng Singapore Institute of Clinical Sciences & National University of Singapore Associate Professor Chang Shiao-yng National University of Singapore

• Heidi Nield

Clinical Trial Operations Director (CTOD) University of Southampton, UK

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