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

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1 Nutritional Intervention Preconception and During Pregnancy to Maintain Healthy Glucose Metabolism & OffspRing Health Timothy Kenealy Counties Manukau Research Week June 2016

2 Primary Objective To determine the effect of a nutritional drink preconception and during pregnancy on the maintenance of healthy glucose metabolism, with the goal of promoting maternal and offspring wellbeing, with particular focus on offspring body composition and adiposity. Standard RCT, plus major discovery platform, biobanking 20yrs, first of it s kind

3 Professor Keith Godfrey MRC Lifecourse Epidemiology Unit, Southampton Professor Phil Baker / Wayne Cutfield A/P Tim Kenealy Gravida, Liggins Institute, Auckland Professor Chong Yap Seng A/P Chan Shiao-Yng National University of Singapore Funding is primarily from governmental and other academic research funding awards to the MRC Lifecourse Epidemiology Unit the Singapore Institute for Clinical Sciences and Gravida: National Centre for Growth and Development, together with a research collaboration with Nestec Ltd, Switzerland.

4 OTHER INVESTIGATORS Dr Joanna Holbrook, Singapore Institute for Clinical Sciences; Dr Neerja Karnani, Singapore Institute for Clinical Sciences; Dr Anne Rifkin-Graboi, Singapore Institute for Clinical Sciences ; anne_rifkin@sics.a-star.edu.sg Professor Lee Yung Seng, Singapore Institute for Clinical Sciences (National University of Singapore); yung_seng_lee@nuhs.edu.sg Dr Marielle Fortier, KKH Hospital Singapore; Marielle.Fortier@kkh.com.sg Dr Silas Villas-Boas, University of Auckland; s.villas-boas@auckland.ac.nz Dr Brett Cowan, University of Auckland; b.cowan@auckland.ac.nz Professor David Cameron Smith, University of Auckland; d.cameron-smith@auckland.ac.nz Professor Lesley McCowan, University of Auckland; l.mccowan@auckland.ac.nz Dr Allan Sheppard, University of Auckland: a.sheppard@auckland.ac.nz Professor Cyrus Cooper, MRC Lifecourse Epidemiology Unit; cc@mrc.soton.ac.uk Dr Nick Harvey, MRC Lifecourse Epidemiology Unit; nch@mrc.soton.ac.uk Professor Christopher Byrne, University of Southampton; C.D.Byrne@soton.ac.uk Professor Philip Calder, University of Southampton; P.C.Calder@soton.ac.uk Professor Nick Macklon, University of Southampton; N.S.Macklon@soton.ac.uk Professor Richard Holt, University of Southampton; r.i.g.holt@soton.ac.uk Dr Charles Peebles, University Hospital Southampton NHS Foundation Trust; Charles.peebles@uhs.nhs.uk Prof Jeya Henry, Singapore Institute for Clinical Sciences ; jeya_henry@sics.a-star.edu.sg Professor Hazel Inskip, MRC Lifecourse Epidemiology Unit; hmi@mrc.soton.ac.uk Professor Michael Meaney, Singapore Institute for Clinical Sciences ; michael.meaney@mcgill.ca Professor Shek Pei-Chi Lynette, National University Hospital Singapore; lynette_shek@nuhs.edu.sg

5 Developmental influences on childhood body composition 1. Excessive (& inadequate) pregnancy weight gain, maternal overweight/obesity, high dietary glycemic load & gestational diabetes are common, with lasting effects on offspring adiposity 2. An imprudent dietary pattern is common and in pregnancy relates to fetal adaptations & childhood body composition 3. Maternal micronutrient insufficiencies are highly prevalent & are associated with postnatal gain in adiposity +/- impaired bone development 4. Large amount of work has already identified a range of biomarkers for altered adiposity with developing knowledge of their functional relevance

Control group Iron 12mg Folic acid 400mcg Calcium 150mg Iodine 150mg β-carotene 720mcg Intervention As for Control group, plus Myo-inisotol 4g Vit D 400IU Vit B6 2.6mg Vit B12 5.2mcg Riboflavin 1.

6 Control group Iron 12mg Folic acid 400mcg Calcium 150mg Iodine 150mg β-carotene 720mcg Intervention As for Control group, plus Myo-inisotol 4g Vit D 400IU Vit B6 2.6mg Vit B12 5.2mcg Riboflavin 1.8mg Zinc 10mg Probiotic Lactobacillus rhamnosus+ Bifidobacterium animalis sp. lactis Daily amounts Given in a drink taken twice a day Orange colour (β-carotene) Watery taste Not a commercial product

7 Primary outcome: glycaemic control at 28 wks gestation (FPG 0.1 mmol/l and 2 hr OGTT glucose 0.3 mmol/l lower) maternal impaired glucose tolerance may be on the causal pathway linking maternal micronutrient deficiency to offspring adiposity and future obesity risk.

8 Confidential Secondary objectives The contributions of: preconception, early & late pregnancy nutrition socioeconomic status, ethnicity, nutritional and lifestyle factors genomics, epigenomics, transcriptomics, metabolomics paternal genotype, nutritional and epigenetic influences To: maintenance of a healthy pregnancy adequate pregnancy weight gain maternal wellbeing/mood size & adiposity of baby at birth healthy growth, body composition, metabolism & wellbeing in infancy healthy growth and development to the age of 5 years, with specific focus on body composition, neuropsychological and allergic health Longterm reducing obesity and diabetes in the offspring

myo-inositol Naturally produced in the body by the action of gut bacteria on dietary fibres may increase insulin sensitivity by making more phosphatidylinositol available Review of 12 clinical trials

9 myo-inositol Naturally produced in the body by the action of gut bacteria on dietary fibres may increase insulin sensitivity by making more phosphatidylinositol available Review of 12 clinical trials treating PCOS, erectile dysfunction, depression, & psychiatric disorders - mild GI side effects reported only with doses of 12 g/day 3 RCTs in pregnancy: no increase in preterm birth with myo-inositol supplementation Maternally infused labelled myo-inositol in term normal pregnancies: <10% of fetal inositol was maternally derived

10 myo-inositol may prevent GDM in PCOS women PCOS pregnant women treated with myo-inositol 4 g/day (n=46) or metformin (n=37) Prevalence of GDM in the myo-inositol group was 17.4% versus 54% in the metformin group (GDM OR in metformin group 2.4 (95% CI ) Gynecological Endocrinology, 2012; 28:

11 myo-inositol may prevent GDM in women with family history of type 2 diabetes 2-year RCT, open-label, pregnant women with a parent with type 2 diabetes 2 g myo-inositol mg folic acid twice daily (n= 110) vs Placebo + 200mg folic acid twice daily (n= 110) GDM (IADPSG) 6% myo-inositol vs. 15.3% placebo (p 0.04) fetal macrosomia (OR 0.35); no change in gestational hypertension, preterm delivery, caesarean section, shoulder dystocia, neonatal hypoglycemia, neonatal distress respiratory syndrome Diabetes Care 2013;36:

12 Probiotic RCT first trimester of pregnancy (n=256) intensive dietary counselling & probiotics (same as Nipper) vs diet + placebo vs diet GDM: probiotic 13 % placebo 36% control 34 % P = Luoto et al. Br J Nutr. 2010;103:1792-9

13 Vitamin D Insufficiency common in developed & developing communities Strongly linked to gestational diabetes in several settings Systematic review indicates a significant inverse relation of serum 25-OH vit D & the incidence of GDM Eur J Intern Med. 2012;23:465-9

14 Confidential Maternal micronutrient deficiency/insufficiency highly prevalent in the Southampton & Singaporean populations Vitamin D insufficiency 1 : SWS 39%, GUSTO 47% Vitamin B6 deficiency 2 : SWS 70%, GUSTO 16% Vitamin B12 deficiency 3 (severe deficiency 4 ): SWS 65% (27%), GUSTO 62% Zinc deficiency 7 : SWS 40% Magnesium deficiency 8 : SWS 35% Few subjects folate 5 (SWS/GUSTO 1%), copper (0%) or iron 6 (SWS 4%, GUSTO 7%) 6 deficient Lower maternal status: associated with child adiposity & perinatal epigenetics Vitamin D insufficiency: infants thin at birth, caught up age 4 yrs, fatter age 6 yrs Riboflavin: lower status - greater adiposity age 6 yrs, lower intake lower CDKN2A methylation Vitamin B6 deficiency: greater adiposity ages 4 & 6 yrs, & CDKN2A/FEN1 methylation Vitamin B12 severe deficiency: greater adiposity age 4 & 6 yrs, & FEN1 methylation Folate status unrelated to perinatal methylation/later adiposity maternal n-6 PUFA related to offspring fat mass & n-3 PUFA to lean mass age 4 years Zinc deficiency : borderline significant associations with greater adiposity ages 4 & 6 years Late pregnancy serum: 1 25-OH vitamin D <50 nmol/l; 2 PLP <20 nmol/l; 3,4 B12 <200, <135.5 pg/ml; 5 folate <3 ng/ml; 6 ferritin SWS <15 ng/ml, GUSTO <30 nmol/l; 7 zinc <700 µg/l; 8 magnesium <18.25 mg/l

15 Confidential Pre-pregnancy 1,800 women RECRUITMENT - Women planning to conceive within 6 months. Randomisation to intervention or control group PHENOTYPING Anthropometry, Nutritional assessment (blood/urine), hair, Oral glucose tolerance test, EPDS/STAI mood/anxiety questionnaires, buccal smear (two clinical visits), MRI / DXA (Subset) Pregnancy 600 established pregnancies 5 clinic visits Abdominal ultrasound (at each of the 5 clinical visits), Anthropometry, Nutritional assessment (blood/urine), fasting glucose test, Oral glucose tolerance test, EPDS/STAI mood/anxiety questionnaires, buccal smear, physical activity; Paternal measures Post-pregnancy Mother & infant 550 infants MOTHER: Anthropometry, Nutritional assessment, Oral glucose tolerance test, buccal smear, blood sample EPDS/STAI mood/anxiety questionnaires INFANT: cord and cord blood samples, placental samples, neonatal & infant anthropometry, buccal smear, Peapod, MRI (subset); allergy & neurocognitive phenotyping.

16 Target 600 women NZ (600 Singapore, 600 UK) Power calculations based on 200 pregnant Started August 2015 Study Sites Mangere, Grafton CMDHB staff, Maternity services, Laboratory, DEXA, PeaPod >350 randomised, >70 pregnancies, 2 babies

Gestational diabetes mellitus in a multi-ethnic Asian cohort Turning Discovery into Healthier Communities. Gestational Diabetes Mellitus (GDM)

Gestational diabetes mellitus in a multi-ethnic Asian cohort Turning Discovery into Healthier Communities MARY CHONG Assistant Professor, Saw Swee Hock School of Public Health, NUS Principal Investigator,