By Ahizechukwu C. Eke, MD, PhD, MPH
Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
SYNOPSIS: Probiotics and synbiotics have shown promise in reducing insulin resistance and enhancing glycemic control, blood lipid profiles, and inflammation among women with gestational diabetes mellitus (GDM). Although they hold potential as a treatment option for GDM, conclusive recommendations await larger, well-designed randomized controlled trials with extended follow-up periods.
SOURCE: Suastika AV, Widiana IGR, Fatmawati NND, et al. The role of probiotics and synbiotics on treatment of gestational diabetes: Systematic review and meta-analysis. AJOG Glob Rep 2023;4:100285.
The prevalence of gestational diabetes (GDM), a condition marked by impaired glucose tolerance during pregnancy caused by pancreatic beta cell dysfunction and insulin resistance, is on the rise in the United States.1,2 According to the Centers for Disease Control and Prevention (CDC), 2% to 10% of pregnant women in the United States are diagnosed with GDM.3
Managing GDM is crucial, since it can lead to immediate complications for the fetus, such as fetal macrosomia, polyhydramnios, and metabolic disorders. Moreover, it poses long-term risks for both mother and her offspring, including an increased likelihood of developing type 2 diabetes and its associated complications later in life.4 Hence, there is an urgent need to develop treatments that not only address GDM but also mitigate potential long-term complications.
Probiotics, which are dietary supplements containing live microorganisms intended to confer health benefits to individuals when ingested in optimal amounts, and synbiotics, defined as non-digestible fibers that nourish beneficial gut bacteria, have increasingly been used for the management of GDM.5-7 Evidence supporting probiotic supplementation during pregnancy is substantial; systematic reviews and meta-analyses revealed their ability to lower GDM risk by improving glucose metabolism and insulin sensitivity.6-8 Additionally, probiotics can alleviate gastrointestinal symptoms such as constipation, enhancing glucose absorption and distribution.8 The rationale for using probiotics and synbiotics in GDM lies in addressing dysbiosis — a gut imbalance favoring inflammation, increasing pregnancy risks. By modulating gut bacteria, these supplements restore balance, reduce inflammation, and support healthy metabolism, potentially improving pregnancy outcomes.5,9
However, conflicting findings exist, with some meta-analytic studies showing no benefits.7 Suastika et al conducted this systematic review and meta-analysis to assess the efficacy of probiotics and/or synbiotics in GDM treatment, focusing on insulin resistance, lipid metabolism, anti-inflammatory effects, and pregnancy outcomes.10
This study is a systematic review and meta-analysis of all clinical trials that reported the use of probiotics and/or synbiotics for the management of GDM. Studies met inclusion criteria if they reported diagnosis of GDM, were written in English, were published after 2013, and had a clinical trial design.10 Studies were excluded if they did not report on any maternal or fetal outcomes in women diagnosed with GDM taking probiotics/synbiotics and if the studies were viewpoints, letters, or reviews.
The outcome measures comprised three categories: blood glucose markers, encompassing fasting blood glucose (FBG) level, fasting serum insulin (FSI) level, and homeostasis model assessment insulin resistance (HOMA-IR); blood lipid profiles, including triglyceride (TG), low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol; and markers of inflammation, including nitric oxide (NO) and C-reactive protein (CRP).
To examine the effect of probiotics and synbiotics on the glycemic, inflammatory, and lipid concentrations of pregnant women with GDM, the study employed the mean difference (MD) in a random-effects model to demonstrate treatment effects, with the Mantel-Haenszel formula used for continuous variables. Dichotomous variables were expressed with 95% confidence intervals (CIs) for the MD, and two-tailed P-values were used, with statistical significance set at < 0.05.
Heterogeneity was assessed using the Q-statistic test, and the I2 test considered variations across studies because of clinical or methodological differences. Regression and sensitivity analyses were conducted to identify bias, with a leave-out analysis employed alongside sensitivity analysis, systematically removing one study at a time to observe its effect on the results.
From a comprehensive analysis of 13 randomized controlled trials involving 896 patients who met inclusion criteria, pregnant women diagnosed with GDM supplemented with probiotics and synbiotics exhibited significant improvements in several key markers of metabolic health compared to control groups.
Specifically, there was a statistically significant reduction in HOMA-IR, with an MD of -0.72 (95% CI, -1.07, -0.38; I2 = 96%; P < 0.001). Moreover, FBG levels decreased significantly, with an MD of -3.79 mg/dL (95% CI, -6.24, -1.34; I2 = 93%; P < 0.001). Fasting serum insulin levels showed a significant de-crease, with an MD of -2.43 mg/dL (95% CI, -3.37, -1.48; I2 = 54%; P < 0.001).
In terms of lipid profiles, individuals receiving probiotics experienced a significant reduction in triglyceride levels, with an MD of -17.73 mg/dL (95% CI, -29.55, -5.9; P = 0.003). Furthermore, there was a significant decrease in CRP levels, with an MD of -1.93 mg/dL (95% CI, -2.3, -1.56; P < 0.001).
COMMENTARY
This systematic review and meta-analysis involving 896 patients demonstrated compelling evidence that probiotic and synbiotic supplementation confers significant improvements in metabolic health parameters among pregnant women with GDM. Notably, pregnant women with GDM receiving pro-biotics and synbiotics experienced a notable reduction in HOMA-IR, indicating enhanced insulin sensitivity. Moreover, FBG and FSI levels exhibited significant decreases, indicating improved glycemic control and insulin regulation, respectively.
Additionally, probiotic and synbiotic supplementation was associated with significant reductions in triglyceride levels, suggesting improved lipid metabolism, and CRP levels, indicating reduced inflammation. These findings, similar to results from other systematic reviews and meta-analyses, underscore the potential of probiotics and synbiotics as a valuable adjunctive therapy for addressing metabolic disturbances and reducing the risk of complications associated with conditions such as GDM.5
Previous systematic reviews and meta-analyses of randomized trials have indicated that probiotic supplementation may lower the incidence of GDM by approximately one-third (relative risk, 0.67; 95% CI, 0.47-0.95).6,11 These beneficial effects were observed across all trimesters of gestation.
Interestingly, these meta-analyses did not show any significant differences regarding the effects of probiotics on the incidence of macrosomia, hypoglycemia, and neonatal intensive care admissions in probiotic vs. control (placebo) groups despite reduction in GDM incidence.6,11 Although standardized formulations and dosage recommendations for probiotics and/or synbiotics are lacking, studies have suggested that dosages of ≥ 109 colony-forming units (CFU) per day may be more effective in reducing glucose biomarkers.12
Probiotics (most commonly containing Lactobacillus and Bifidobacterium) and synbiotics have been increasingly used during pregnancy.13,14 Although studies have suggested that probiotics do not appear to pose any safety concerns to pregnant and lactating women, one theoretical concern revolves around the possibility of probiotics and synbiotics entering the systemic circulation, potentially leading to severe infections during pregnancy, particularly given the immunosuppressed state typical of pregnancy.13-15
Although cases of probiotic-related infections have been documented, they are infrequent.15 The low prevalence of probiotic-induced bacteremia and fungemia suggests that the risk of these substances reaching the fetal systemic circulation is minimal, thus reducing the likelihood of fetal injury.13 Although probiotics can influence both the innate and adaptive immune systems by modulating cytokine secretion and dendritic cell function, there have been concerns about potentially overstimulating the immune response in certain individuals, which could result in autoimmune reactions or inflammation.16 However, it is important to note that despite this theoretical concern, there have been no reports of such adverse effects in human subjects.
There remains a clear need for continued research on the efficacy and safety of probiotics and synbiotic use during pregnancy, since there is limited research on the safety of specific probiotic strains during pregnancy. Concerns also exist regarding probiotics’ potential to alter the maternal gut microbiota composition, which could have unforeseen consequences for maternal, fetal, neonatal, and infant well-being. Moreover, there is a lack of standardized guidelines for probiotic supplementation during pregnancy, leading to variability in product quality and dosages.
Although the American College of Obstetricians and Gynecologists recommends several nutritional supplements for pregnant women, probiotics and synbiotics are not among them.17 Therefore, caution is warranted when considering probiotic use during pregnancy. Pregnant and lactating women should consult with their obstetricians before initiating probiotic and/or synbiotic supplementation to weigh the potential benefits against the risks.
REFERENCES
- Nakshine VS, Jogdand SD. A comprehensive review of gestational diabetes mellitus: Impacts on maternal health, fetal development, childhood outcomes, and long-term treatment strategies. Cureus 2023;15:e47500.
- Alejandro EU, Mamerto TP, Chung G, et al. Gestational diabetes mellitus: A harbinger of the vicious cycle of diabetes. Int J Mol Sci 2020;21:5003.
- Centers for Disease Control and Prevention. Gestational diabetes. Last reviewed Dec. 30, 2022. https://www.cdc.gov/diabetes/basics/gestational.html
- Sweeting A, Wong J, Murphy HR, Ross GP. A clinical update on gestational diabetes mellitus. Endocr Rev 2022;43:763-793.
- Mu J, Guo X, Zhou Y, Cao G. The effects of probiotics/synbiotics on glucose and lipid metabolism in women with gestational diabetes mellitus: A meta-analysis of randomized controlled trials. Nutrients 2023;15:1375.
- Pakmehr A, Ejtahed HS, Shirzad N, et al. Preventive effect of probiotics supplementation on occurrence of gestational diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials. Front Med (Lausanne) 2022;9:1031915.
- Chatzakis C, Goulis DG, Mareti E, et al. Prevention of gestational diabetes mellitus in overweight or obese pregnant women: A network meta-analysis. Diabetes Res Clin Pract 2019;158:107924.
- Han MM, Sun JF, Su XH, et al. Probiotics improve glucose and lipid metabolism in pregnant women: A meta-analysis. Ann Transl Med 2019;7:99.
- Sadagopan A, Mahmoud A, Begg M, et al. Understanding the role of the gut microbiome in diabetes and therapeutics targeting leaky gut: A systematic review. Cureus 2023;15:e41559.
- Suastika AV, Widiana IGR, Fatmawati NND, et al. The role of probiotics and synbiotics on treatment of gestational diabetes: Systematic review and meta-analysis. AJOG Glob Rep 2024;4:100285.
- Łagowska K, Malinowska AM, Zawieja B, Zawieja E. Improvement of glucose metabolism in pregnant women through probiotic supplementation depends on gestational diabetes status: Meta-analysis. Sci Rep 2020;10:17796.
- Pan YQ, Zheng QX, Jiang XM, et al. Probiotic supplements improve blood glucose and insulin resistance/sensitivity among healthy and GDM pregnant women: A systematic review and meta-analysis of randomized controlled trials. Evid Based Complement Alternat Med 2021;2021:9830200.
- Elias J, Bozzo P, Einarson A. Are probiotics safe for use during pregnancy and lactation? Can Fam Physician 2011;57:299-301.
- Sheyholislami H, Connor KL. Are probiotics and prebiotics safe for use during pregnancy and lactation? A systematic review and meta-analysis. Nutrients 2021;13:2382.
- Doron S, Snydman DR. Risk and safety of probiotics. Clin Infect Dis 2015;60 Suppl 2(Suppl 2):S129-134.
- Mazziotta C, Tognon M, Martini F, et al. Probiotics mechanism of action on immune cells and beneficial effects on human health. Cells 2023;12:184.
- American College of Obstetricians and Gynecologists. Nutrition during pregnancy. https://www.acog.org/store/products/patient-education/pamphlets/pregnancy/nutrition-during-pregnancy
Probiotics and synbiotics have shown promise in reducing insulin resistance and enhancing glycemic control, blood lipid profiles, and inflammation among women with gestational diabetes mellitus (GDM). Although they hold potential as a treatment option for GDM, conclusive recommendations await larger, well-designed randomized controlled trials with extended follow-up periods.
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