Probiotic treatment for women with gestational diabetes to improve maternal and infant health and well-being

Karaponi Am Okesene-Gafa, Abigail E Moore, Vanessa Jordan, Lesley McCowan, Caroline A Crowther, Karaponi Am Okesene-Gafa, Abigail E Moore, Vanessa Jordan, Lesley McCowan, Caroline A Crowther

Abstract

Background: Gestational diabetes mellitus (GDM) is carbohydrate intolerance first recognised during pregnancy and associated with complications for mothers and babies. Probiotics are naturally occurring micro-organisms, which when ingested in adequate amounts, may confer health benefits. Evidence of the role of probiotics as treatment for GDM is limited.

Objectives: To evaluate the safety and effectiveness of probiotics in treating women with GDM on maternal and infant outcomes.

Search methods: We searched the Cochrane Pregnancy and Childbirth's Trials Register ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP) (24 July 2019), and reference lists of retrieved studies.

Selection criteria: Randomised controlled trials (RCTs) comparing the use of probiotics versus placebo/standard care for the treatment of GDM.

Data collection and analysis: Two review authors independently assessed study eligibility, extracted data, checked data accuracy, and assessed risk of bias of included trials. The certainty of evidence for selected maternal and infant/child outcomes was assessed using GRADE.

Main results: Nine RCTs (695 pregnant women with GDM) comparing probiotics versus placebo were identified. The overall risk of bias in the nine RCTs was low to unclear and the evidence was downgraded for imprecision due to the small numbers of women participating in the trials. The trials were carried out in hospitals and universities in Iran (seven trials), Thailand (one trial) and Ireland (one trial). All trials compared probiotics with placebo. Maternal outcomes We are uncertain if probiotics have any effect compared with placebo on hypertensive disorders of pregnancy, (risk ratio (RR) 1.50, 95% confidence interval (CI) 0.64 to 3.53; participants = 256; studies = 3; low-certainty evidence) and mode of birth as caesareans (average RR 0.64, 95% CI 0.30 to 1.35; participants = 267; studies = 3; low-certainty evidence) because the certainty of evidence is low and the 95% CIs span possible benefit and possible harm. No trials reported primary outcomes of: mode of birth as vaginal/assisted and subsequent development of type 2 diabetes. We are uncertain if probiotics have any effect compared with placebo on induction of labour (RR 1.33, 95% CI 0.74 to 2.37; participants = 127; studies = 1; very low-certainty evidence). For other secondary maternal outcomes, we are uncertain if there are differences between probiotics and placebo for: postpartum haemorrhage; weight gain during pregnancy intervention and total gestational weight gain; fasting plasma glucose and need for extra pharmacotherapy (insulin). Probiotics may be associated with a slight reduction in triglycerides and total cholesterol. In probiotics compared with placebo, there was evidence of reduction in markers for insulin resistance (HOMA-IR) and HOMA-B; and insulin secretion. There was also an increase in quantitative insulin sensitivity check index (QUICKI). Probiotics were associated with minor benefits in relevant bio-markers with evidence of a reduction in inflammatory markers high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), and marker of oxidative stress malondialdehyde; and an increase in antioxidant total glutathione, but we are uncertain if there is any difference in total antioxidant capacity. No trials reported secondary outcomes: perineal trauma, postnatal weight retention or return to pre-pregnancy weight and postnatal depression. Infant/child/adult outcomes We are uncertain if probiotics have any effect, compared with placebo, on the risk of large-for-gestational-age babies (RR 0.73, 95% CI 0.35 to 1.52; participants = 174; studies = 2; low-certainty evidence) or infant hypoglycaemia (RR 0.85, 95% CI 0.39 to 1.84; participants = 177; studies = 3; low-certainty evidence) because the certainty of evidence is low and the 95% CIs span possible benefit and possible harm. No trials reported primary outcomes of: perinatal (fetal/neonatal) mortality; or neurosensory disability. For other secondary outcomes, we are uncertain if there is any difference between probiotics and placebo in gestational age at birth, preterm birth, macrosomia, birthweight, head circumference, length, infant hypoglycaemia, and neonatal intensive care unit (NICU) admissions. There was evidence of a reduction in infant hyperbilirubinaemia with probiotics compared with placebo. No trials reported secondary outcomes: infant adiposity, and later childhood adiposity. There were no adverse events reported by any of the trials.

Authors' conclusions: Low-certainty evidence means we are not certain if there is any difference between probiotic and placebo groups in maternal hypertensive disorders of pregnancy, caesareans; and large-for-gestational-age babies. There were no adverse events reported by the trials. Due to the variability of probiotics used and small sample sizes of trials, evidence from this review has limited ability to inform practice. Well-designed adequately-powered trials are needed to identify whether probiotics may improve maternal blood glucose levels and/or infant/child/adult outcomes; and whether they can be used to treat GDM.

Trial registration: ClinicalTrials.gov NCT03864549.

Conflict of interest statement

Karaponi Okesene‐Gafa ‐ was recently involved with the Healthy Mums and Babies (HUMBA) randomised controlled demonstration trial, which has now been completed and published. The HUMBA RCT is not be eligible for inclusion in this review. In kind we have been provided with probiotics (Lactobacillus rhamnosus GG and Bifidobacterium lactis BB12) and placebo capsules free of charge from Christian Hansen Denmark (http://www.chr‐hansen.com/en) for our HUMBA trial (http://humba.ac.nz/). In this randomised controlled double‐blind trial, women were randomised to receive probiotics or placebo capsules with the main aim of reducing pregnancy weight gain and infant birthweight (ANZCTR registration number 12615000400561). In kind: Roche International‐ equipment and consumables for HBA1c for the HUMBA trial. National Heart Foundation assisted by letting us use some of their resources for the study and development of some of the content in the text messages as part of HUMBA trial. Public interest funding for the Healthy Mums and Babies (HUMBA) trial was received from Cure Kids, Counties Manukau Health, Mercia Barnes Trust Fund, University of Auckland Faculty Research Development Fund and Lottery Health Research Fund. Karaponi Okesene‐Gafa received funding from her organisation (Department of Obstetrics and Gynaecology, University of Auckland) for her PhD, with this review forming part of her thesis.

Abigail Moore is a medical student and declares no conflict of interest.

Vanessa Jordan is a Research Fellow in the University of Auckland and declares no conflict of interest.

Lesley McCowan ‐ was also involved with the Healthy Mums and Babies (HUMBA) randomised controlled demonstration trial. The HUMBA RCT is not be eligible for inclusion in this review. In kind we have been provided with probiotics (Lactobacillus rhamnosus GG and Bifidobacterium lactis BB12) and placebo capsules free of charge from Christian Hansen Denmark (http://www.chr‐hansen.com/en) for our HUMBA trial (http://humba.ac.nz/). In this randomised controlled double‐blind trial, women are randomised to receive probiotics or placebo capsules with the main aim of reducing pregnancy weight gain and infant birthweight (ANZCTR registration number 12615000400561). In kind: Roche International‐ equipment and consumables for HBA1c for the HUMBA trial. National Heart Foundation assisted by letting us use some of their resources for the study and development of some of the content in the text messages as part of HUMBA trial.

Caroline Crowther ‐ was also involved with the Healthy Mums and Babies (HUMBA) randomised controlled demonstration trial. The HUMBA RCT is not be eligible for inclusion in this review. In kind we have been provided with probiotics (Lactobacillus rhamnosus GG and Bifidobacterium lactis BB12) and placebo capsules free of charge from Christian Hansen Denmark (http://www.chr‐hansen.com/en) for our HUMBA trial (http://humba.ac.nz/). In this randomised controlled double‐blind trial, women are randomised to receive probiotics or placebo capsules with the main aim of reducing pregnancy weight gain and infant birthweight (ANZCTR registration number 12615000400561). In kind: Roche International‐ equipment and consumables for HBA1c for the HUMBA trial. National Heart Foundation assisted by letting us use some of their resources for the study and development of some of the content in the text messages as part of HUMBA trial.