Diabetes Care Volume 44, May 2021 1091 Myo-Inositol, Probiotics, and Keith M. Godfrey,1,2 Sheila J. Barton,1 Sarah El-Heis,1 Timothy Kenealy,3 Micronutrient Supplementation Heidi Nield,1 Philip N. Baker,4 Yap Seng Chong,5,6 Wayne Cutfield,3,7 From Preconception for Glycemia Shiao-Yng Chan,5,6 and NiPPeR Study Group* in Pregnancy: NiPPeR International Multicenter Double-Blind Randomized Controlled Trial Diabetes Care 2021;44:1091–1099 | https://doi.org/10.2337/dc20-2515 OBJECTIVE Better preconception metabolic and nutritional health are hypothesized to pro- mote gestational normoglycemia and reduce preterm birth, but evidence sup- 1MRC Lifecourse Epidemiology Unit, University porting improved outcomes with nutritional supplementation starting of Southampton, Southampton, U.K. CLIN CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL preconception is limited. 2NIHR Southampton Biomedical Research Centre, University Hospital Southampton, NHS RESEARCH DESIGN AND METHODS Foundation Trust, Southampton, Southampton, U.K. This double-blind randomized controlled trial recruited from the community 3Liggins Institute, University of Auckland, 1,729 U.K., Singapore, and New Zealand women aged 18–38 years planning con- Auckland, New Zealand 4 ception. We investigated whether a nutritional formulation containing myo-inosi- College of Life Sciences, Biological Sciences and Psychology, University of Leicester, tol, probiotics, and multiple micronutrients (intervention), compared with a Leicester, U.K. standard micronutrient supplement (control), taken preconception and through- 5Department of Obstetrics and Gynaecology, out pregnancy could improve pregnancy outcomes. The primary outcome was Yong Loo Lin School of Medicine, National combined fasting, 1-h, and 2-h postload glycemia (28 weeks’ gestation oral glu- University of Singapore and National University Health System, Singapore cose tolerance test). 6Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, RESULTS Singapore Between 2015 and 2017, participants were randomized to control (n 5 859) or in- 7A Better Start, New Zealand National Science tervention (n 5 870); 585 conceived within 1 year and completed the primary Challenge, Auckland, New Zealand outcome (295 intervention, 290 control). In an intention-to-treat analysis adjust- Corresponding author: Keith M. Godfrey, kmg@ mrc.soton.ac.uk ing for site, ethnicity, and preconception glycemia with prespecified P < 0.017 for Received 11 October 2020 and accepted 10 multiplicity, there were no differences in gestational fasting, 1-h, and 2-h glyce- February 2021 β À mia between groups ( [95% CI] loge mmol/L intervention vs. control 0.004 Clinical trial reg. no. NCT02509988, [À0.018 to 0.011], 0.025 [À0.014 to 0.064], 0.040 [0.004–0.077], respectively). clinicaltrials.gov, and Universal Trial Number Between the intervention and control groups there were no significant differ- U1111-1171-8056 ences in gestational diabetes mellitus (24.8% vs. 22.6%, adjusted risk ratio [aRR] This article contains supplementary material online fi 1.22 [0.92–1.62]), birth weight (adjusted β 5 0.05 kg [À0.03 to 0.13]), or gesta- at https://doi.org/10.2337/ gshare.13874705. W.C. and S.-Y.C. contributed equally to this tional age at birth (mean 39.3 vs. 39.2 weeks, adjusted β 5 0.20 [À0.06 to 0.46]), article. – but there were fewer preterm births (5.8% vs. 9.2%, aRR 0.43 [0.22 0.82]), adjust- *Members of the NiPPeR Study Group are listed ing for prespecified covariates. in the supplementary material online. © 2021 by the American Diabetes Association. CONCLUSIONS Readers may use this article as long as the Supplementation with myo-inositol, probiotics, and micronutrients preconcep- work is properly cited, the use is educational fi tion and in pregnancy did not lower gestational glycemia but did reduce preterm and not for pro t, and the work is not altered. More information is available at https:// birth. www.diabetesjournals.org/content/license. 1092 NiPPeR Supplement: Preconception and Pregnancy Diabetes Care Volume 44, May 2021 Suboptimal metabolic and nutritional reduced GDM (14). Low intakes and in- Women were recruited in Singapore, health around conception and during sufficiencies of several micronutrients Auckland (New Zealand), and South- pregnancy have important implications (vitamin B6, vitamin B12, riboflavin, ampton (U.K.), primarily from the com- for pregnancy outcomes, fetal growth, zinc) are prevalent in pregnancy and munity (Fig. 1). Our trial was approved adiposity, and long-term offspring have been linked with glucose intoler- by the U.K., Singapore, and New Zea- health (1). Adverse effects of higher ma- ance and pregnancy outcomes (15–17), land research ethics services at each ternal glucose concentrations increase but there are few intervention studies site (Southampton: Health Research Au- across the continuum of maternal glyce- (18). Vitamin D deficiency has also been thority National Research Ethics Service mia (2,3), and micronutrient insufficien- linked with GDM and preterm birth Committee South Central Research cy is highly prevalent in women. (19), but a trial of vitamin D supplemen- Ethics Committee reference 15/SC/ Interventions that optimize glycemia tation starting in early pregnancy 0142; the National Healthcare Group and nutritional status are thought to im- showed no preventive effects on preg- Domain Specific Review Board Singa- prove pregnancy and offspring out- nancy complications (20). Another trial pore reference 2015/00205; and the comes, but supportive evidence from of a nutritional supplement (containing Health and Disability Ethics Committee interventionstudiesissparse. protein, polyunsaturated fatty acids, New Zealand reference 15/NTA/21), Pregnancy is a state of relative mater- and micronutrients without inositols or with confirmation from the relevant nal insulin resistance, promoting glucose probiotics) in low-resource settings regulatory authorities that the formula- transfer to the fetus (4). Physiological showed improved birth length but no tion was not an investigational medici- insulin resistance and impaired insulin difference in preterm birth compared nal product. Trial oversight and secretion can be accentuated by individ- with no supplementation, with no dif- monitoring were provided by an inde- ual genetic and environmental vulner- ference between the group starting sup- pendent data and safety monitoring abilities and lead to gestational diabetes plementation preconception and the committee. mellitus (GDM) (5). The global GDM in- group starting in early pregnancy; glyce- cidence is rising, estimated at 14% (6). mia outcomes were, however, not re- Participants Following GDM diagnosis, lifestyle ported (21). On the basis of our previous popula- changes, oral hypoglycemic drugs, and Dysglycemia and maternal micronu- tion-based Southampton Women’sSur- insulin can improve some short-term trient insufficiency preconception or in vey our initial target was 1,800 recruits obstetric outcomes (7) but cannot fully early pregnancy are common in the to have 600 established pregnancies to mitigate pregnancy and offspring adver- general population and thought to influ- study. Recruitment was stopped at sity (8). Risk reduction strategies have ence the risk of adverse pregnancy out- 1,729 women when it became clear thus shifted toward GDM prevention. comes (1,5,17,22). We hypothesized that the projected number of pregnan- However, population trials of dietary, that a myo-inositol, probiotic, and mi- cies would exceed our target (final con- physical activity, or combined lifestyle cronutrient nutritional supplement com- 5 measures, mostly beginning in the first ceptions n 725) (Fig. 1). mencing before pregnancy could half of gestation, have had limited im- Women were eligible for trial enroll- collectively lower maternal glycemia – pact on preventing GDM (9,10). This has ment if they were aged 18 38 years, and improve pregnancy outcomes led to postulations that preconception were planning to conceive within 6 across the general population. We interventions could be more effective months, and had future maternity care therefore undertook an international, and that alternative approaches are at the recruiting centers. In Singapore, multicenter, double-blind randomized required. women had to be of homogeneous or controlled trial (the Nutritional Interven- Small clinical trials have suggested mixed Chinese, Malay, or Indian ethnici- tion Preconception and During Pregnan- that supplementation with myo-inositol ty. A priori, women conceiving within 1 cy to Maintain Healthy Glucose or probiotics from early pregnancy may year were followed through pregnancy Metabolism and Offspring Health [NiP- be beneficial; myo-inositol is a naturally and beyond. Women were excluded if PeR] study [23]) to investigate whether occurring six-carbon polyol with insulin they were pregnant or lactating at re- intervention with a nutritional supple- sensitizing actions arising from functions cruitment; were undergoing assisted ment containing myo-inositol, probiot- relating to many second messenger sig- conception (apart from taking clomi- ics, and additional micronutrients naling pathways and endogenous insu- phene or letrozole alone); had known (vitamins D, B6, and B12; riboflavin; and lin-mimetic factors (11). Meta-analysis serious food allergy or preexisting type of women given myo-inositol supple- zinc), compared with a standard precon- 1 or type 2 diabetes; or were using oral, mentation from the end of the first tri- ception micronutrient