American Diabetes Awareness Month
The Effects of Preconception Supplementation on Glycemia and Preterm Birth
By: Alyson Schlieper, DO
Editor’s Note: November is American Diabetes Awareness Month and November 17th* marks World Prematurity Day – a day observed internationally to raise awareness of preterm babies and the concerns of their families. According to the World Health Organization, about 1 in 10 babies are born preterm each year and prematurity is increased in mothers with Type 2 diabetes. Alyson Schlieper, a former FACTS elective participant, summarized 2021 research published in Diabetes Care by researchers Godfrey et al. The researchers explored the role of supplements, including myo-inositol, on blood glucose levels and their impact on pregnancy outcomes and the potential to lower incidence of preterm birth.
*Join us this Thursday, November 17th at 8pm ET for our FACTS for the Future event. We will highlight our efforts to expand education in women’s health, so together we may impact even more lives!
Conception and pregnancy outcomes are affected by many factors, including the adverse effects of elevated maternal glucose levels and micronutrient insufficiencies. Godfrey et al explored the impact of supplementation during the preconception and prenatal periods on maternal blood sugar levels and overall maternal and fetal outcomes.  The study specifically investigated the effect of supplementation with myo-inositol, probiotics, and micronutrients often lacking in pregnant patients.
Researchers Godfrey et al recruited 1,729 women from Singapore, New Zealand, and the United Kingdom in a multicenter, double-blind randomized controlled trial. Eligibility criteria included women aged 18 to 38 planning to conceive within six months with access to future maternity care. Exclusion criteria included women already pregnant or lactating; women attempting to conceive via assisted reproductive technologies; women with known serious food allergies; women with preexisting type 1 or type 2 diabetes; women using oral, implanted, or intrauterine birth control; women using of metformin, systemic steroids, or anticonvulsants; and women who had undergone treatment for HIV or hepatitis B or C within the past six months.
Supplemental intervention and control formulations were packaged as a powder in sachets to be reconstituted in water and taken twice daily. Both the intervention and control formulas contained folic acid, iron, calcium, iodine, and beta-carotene. The intervention formula additionally included myo-inositol, vitamin D, riboflavin, vitamin B6, vitamin B12, zinc, and probiotics.
The primary outcome of the study was plasma glucose concentration, assessed via a fasting test and a 1- or 2-hour plasma glucose tolerance test at 28 weeks gestation. Secondary outcomes included gestational diabetes mellitus (GDM), large for gestational age babies, and preterm birth.
Of the 1,729 women recruited, there were 588 who had pregnancies that fulfilled the study criteria and reached 28 weeks gestation. Of these women, 296 were in the intervention group and 292 in the control: exactly 34% of each group met the criteria. Over 99% of these women underwent an oral glucose tolerance test and provided data on the primary outcome of glycemia at 28 weeks.
Unadjusted plasma glucose values between groups revealed no significant difference between the intervention group and the control group at any of the three time points: fasting, at 1 hour, and at 2 hours. Even after adjusting for site, ethnicity, and matched preconception glucose values, the plasma glucose values did not differ between groups at any of the time points. Incidence of gestational diabetes mellitus was also comparable between both groups.
Results were further examined in two special interest subgroups: women overweight or obese preconception and women with documented dysglycemia preconception. In women who were overweight or obese, the intervention did not change fasting or 1-hour glucose levels, although the 2-hour level was higher in the intervention group. In women with documented dysglycemia before conception, both glycemia at 28 weeks and incidence of GDM were similar between intervention and control groups.
The intervention group did demonstrate a lower incidence of preterm birth prior to 37 weeks gestation. Incidence of major postpartum hemorrhage was also lower in the intervention group, but there were no noted differences between groups for secondary outcomes of miscarriage, congenital anomalies, and intrauterine death.
“Women who received supplementation with myo-inositol, probiotics, and micronutrients did demonstrate a lower incidence of preterm birth prior to 37 weeks gestation.
Overall, participant adherence to supplementation routines, determined by sachet count, was good: over 80% reported an 80-100% adherence and just 3.4% reported a less than 60% adherence. Adherence rates were similar across intervention and control groups.
The global incidence of GDM is estimated at 14%. Although interventions commonly include lifestyle changes, oral hypoglycemic drugs, and insulin, none of these present strategies completely eliminate the risk of possible adverse maternal and fetal outcomes. Thus, it is hopeful that a preconception intervention could improve maternal glycemia without adverse pregnancy outcomes.
The study interventions failed to demonstrate any significant effects on maternal glycemia at 28 weeks gestation. Additionally, no change was observed in the incidence of gestational diabetes mellitus and large for gestational age infants. Subgroup analysis into overweight participants or participants with dysglycemia documented in the preconception period did not show any improvement on outcomes.
However, findings of reduced incidence of preterm birth are consistent with a meta-analysis of other myo–inositol studies and its impact on preterm birth.  Likewise, the reduction of preterm birth is also consistent with another meta-analysis of trials of multiple micronutrient supplements.  More specifically, myo-inositol supplementation showed a reduction in premature rupture of membranes (PPROM) and PPROM-associated preterm births, which likely contributed to the reduction in preterm births. Presently, researchers hypothesize that anti-inflammatory effects of myo-inositol and the synergistic role of micronutrient supplementation, vitamin D and zinc specifically, may reduce the likelihood of PPROM. 
“Myo-inositol supplementation showed a reduction in premature rupture of membranes (PPROM) and PPROM-associated preterm births, which likely contributed to the reduction in preterm births.”
The reduction of preterm birth rates in probiotic trials is a novel finding, as other recent studies have not demonstrated this association. Potentially confounding effects of myo-inositol and micronutrient supplementation must also be considered and the effects of probiotic supplementation explored further.
Although not specifically studied as a secondary outcome, the study found a reduction in major postpartum hemorrhage not previously reported with supplementation of myo-inositol, probiotics, or micronutrients. Findings could be investigated further, as postpartum hemorrhage poses a significant threat to maternal health.
“The study found a reduction in major postpartum hemorrhage not previously reported with supplementation of myo-inositol, probiotics, or micronutrients.”
Godfrey et al provided valuable insight into the potential for supplementation with myo-inositol, probiotics, and multiple micronutrients preconception and during pregnancy to reduce preterm birth, despite a failure to lower gestational glycemia. However, several study limitations should be considered. While the study was double-blind over both preconception and pregnancy periods, it is limited in the generalizability. The study populations included low numbers of Latina, Native American Indian, Black, and Polynesian participants. In addition, less than half of the participants were classified as overweight or obese, making it less representative of typical U.S. and Western populations.
Further studies are needed to investigate these interventions in a more diverse, representative population. The initiation and duration of interventions should also be more tightly controlled given the varying effects of supplements across differing times to conception. Other future research could assess varying doses of the micronutrient supplements, in addition to baseline and post-intervention microbiome assessments.
 Godfrey KM, Barton SJ, El-Heis S, et al. Myo-Inositol, Probiotics, and Micronutrient Supplementation From Preconception for Glycemia in Pregnancy: NiPPeR International Multicenter Double-Blind Randomized Controlled Trial. Diabetes Care. 2021;44(5).
 Santamaria A, Alibrandi A, Di Benedetto A, et al. Clinical and metabolic outcomes in pregnant women at risk for gestational diabetes mellitus supplemented with myo-inositol: a secondary analysis from 3 RCTs. Am J Obstet Gynecol. 2018;219(3):300.e1-300.e6.
 Keats EC, Haider BA, Tam E, Bhutta ZA. Multiple-micronutrient supplementation for women during pregnancy. Cochrane Database Syst Rev. 2019;3(3):CD004905. Published 2019 Mar 14. doi:10.1002/14651858.CD004905.pub6
 Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75-84. doi:10.1016/S0140-6736(08)60074-4
ABOUT THE AUTHOR
Alyson Schlieper, DO
Alyson Schlieper, DO is a first-year obstetrics and gynecology resident in Akron, Ohio. She completed the FACTS elective in the fall of 2021 as a medical student at Edward Via College of Osteopathic Medicine in Virginia.