Probiotics to prevent gestational diabetes mellitus

We analysed evidence from randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) investigating probiotic supplements alone or in combination with drug or non-drug interventions for preventing gestational diabetes mellitus (GDM).

What is the issue?

GDM is a condition where the mother develops high blood sugar levels, usually after 13 weeks of pregnancy. GDM is different from type 2 diabetes in that blood sugar levels are normal before pregnancy, and the levels usually return to normal after pregnancy. GDM is associated with an increased risk of developing type 2 diabetes later in life. Women with GDM are at increased risk of high blood pressure with protein in the urine (pre-eclampsia) and instrumental delivery or caesarean section. Their infants are more likely to be born large for their gestational age. Probiotics are 'good bacteria' that are usually taken in the form of capsules or drinks to add to the gut bacteria. We are dependent on our gut bacteria to help digest our food, produce certain vitamins, regulate our immune system and keep us healthy by protecting us against disease-causing bacteria. Probiotics could change a person's metabolism and play a role in the prevention of GDM. 

Why is this important?

Women who are overweight or obese, had GDM in a previous pregnancy or have an immediate family member with diabetes are at increased risk of GDM. Current treatment for GDM includes diet with or without medication but does not always prevent the problems associated with GDM. Probiotics could be a simple method for preventing GDM. This review looked at whether there is evidence to show if this is true. 

What evidence did we find?

We searched for evidence from randomised controlled trials in March 2020 and identified seven studies with 1647 pregnant women comparing probiotics with inactive placebo (pretend treatment). Two studies were in overweight and obese women, two in obese women and three did not exclude women based on their weight. The overall risk of bias was low except for one study where the risk of bias was unclear.

It is unclear how probiotics affect the risk of developing GDM due to the wide variation in the results of six studies (1440 women, low-quality evidence). Probiotics increase the risk of developing pre-eclampsia (4 studies, 955 women; high-quality evidence). Probiotics make little to no difference to the risk of needing a caesarean section (6 studies, 1520 women; high-quality evidence), and probably make little to no difference to weight gain during pregnancy (4 studies, 853 women; moderate-quality evidence) or to the risk of giving birth to a big baby (4 studies, 919 women; moderate-quality evidence). None of the studies reported information about the risk of perineal trauma (tears during vaginal birth or a surgical incision (episiotomy)), postnatal depression or developing subsequent diabetes.

We do not know if probiotics affect the infant having medical problems after birth because of the variation in results between studies (2 studies, 623 infants; low-quality evidence). It is also uncertain how probiotics affect infant death (either before birth or as a newborn) (3 studies, 709 infants; low-certainty evidence), low blood sugar (2 studies, 586 infants; low-certainty evidence) or body fat (2 studies, 320 infants; low-certainty evidence). None of the studies reported information about the risk of infants developing diabetes or long-term conditions that affect brain development.

What does this mean?

Low-quality evidence from six trials has not clearly identified the effect of probiotics on the risk of GDM. However, high-quality evidence suggests that probiotics probably increase the risk of pre-eclampsia. Therefore, there is currently evidence of possible harm with little observed benefit for widespread use of probiotics in pregnancy.

There are eight studies currently ongoing that may help to provide more clarity on the effects of probiotics. It is also important to explore the relationship between probiotics and pre-eclampsia further.

Authors' conclusions: 

Low-certainty evidence from six trials has not clearly identified the effect of probiotics on the risk of GDM. However, high-certainty evidence suggests there is an increased risk of pre-eclampsia with probiotic administration. There were no other clear differences between probiotics and placebo among the other primary outcomes. The certainty of evidence for this review's primary outcomes ranged from low to high, with downgrading due to concerns about substantial heterogeneity between studies, wide CIs and low event rates.

Given the risk of harm and little observed benefit, we urge caution in using probiotics during pregnancy.

The apparent effect of probiotics on pre-eclampsia warrants particular consideration. Eight studies are currently ongoing, and we suggest that these studies take particular care in follow-up and examination of the effect on pre-eclampsia and hypertensive disorders of pregnancy. In addition, the underlying potential physiology of the relationship between probiotics and pre-eclampsia risk should be considered.

Read the full abstract...
Background: 

Gestational diabetes mellitus (GDM) is associated with a range of adverse pregnancy outcomes for mother and infant. The prevention of GDM using lifestyle interventions has proven difficult. The gut microbiome (the composite of bacteria present in the intestines) influences host inflammatory pathways, glucose and lipid metabolism and, in other settings, alteration of the gut microbiome has been shown to impact on these host responses. Probiotics are one way of altering the gut microbiome but little is known about their use in influencing the metabolic environment of pregnancy. This is an update of a review last published in 2014.

Objectives: 

To systematically assess the effects of probiotic supplements used either alone or in combination with pharmacological and non-pharmacological interventions on the prevention of GDM.

Search strategy: 

We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (20 March 2020), and reference lists of retrieved studies.

Selection criteria: 

Randomised and cluster-randomised trials comparing the use of probiotic supplementation with either placebo or diet for the prevention of the development of GDM. Cluster-randomised trials were eligible for inclusion but none were identified. Quasi-randomised and cross-over design studies were not eligible for inclusion in this review. Studies presented only as abstracts with no subsequent full report of study results were only included if study authors confirmed that data in the abstract came from the final analysis. Otherwise, the abstract was left awaiting classification.

Data collection and analysis: 

Two review authors independently assessed study eligibility, extracted data and assessed risk of bias of included studies. Data were checked for accuracy.

Main results: 

In this update, we included seven trials with 1647 participants. Two studies were in overweight and obese women, two in obese women and three did not exclude women based on their weight. All included studies compared probiotics with placebo. The included studies were at low risk of bias overall except for one study that had an unclear risk of bias. We excluded two studies, eight studies were ongoing and three studies are awaiting classification.

Six included studies with 1440 participants evaluated the risk of GDM. It is uncertain if probiotics have any effect on the risk of GDM compared to placebo (mean risk ratio (RR) 0.80, 95% confidence interval (CI) 0.54 to 1.20; 6 studies, 1440 women; low-certainty evidence). The evidence was low certainty due to substantial heterogeneity and wide CIs that included both appreciable benefit and appreciable harm.

Probiotics increase the risk of pre-eclampsia compared to placebo (RR 1.85, 95% CI 1.04 to 3.29; 4 studies, 955 women; high-certainty evidence) and may increase the risk of hypertensive disorders of pregnancy (RR 1.39, 95% CI 0.96 to 2.01, 4 studies, 955 women), although the CIs for hypertensive disorders of pregnancy also indicated probiotics may have no effect.

There were few differences between groups for other primary outcomes. Probiotics make little to no difference in the risk of caesarean section (RR 1.00, 95% CI 0.86 to 1.17; 6 studies, 1520 women; high-certainty evidence), and probably make little to no difference in maternal weight gain during pregnancy (MD 0.30 kg, 95% CI –0.67 to 1.26; 4 studies, 853 women; moderate-certainty evidence). Probiotics probably make little to no difference in the incidence of large-for-gestational age infants (RR 0.99, 95% CI 0.72 to 1.36; 4 studies, 919 infants; moderate-certainty evidence) and may make little to no difference in neonatal adiposity (2 studies, 320 infants; data not pooled; low-certainty evidence). One study reported adiposity as fat mass (MD –0.04 kg, 95% CI –0.12 to 0.04), and one study reported adiposity as percentage fat (MD –0.10%, 95% CI –1.19 to 0.99). We do not know the effect of probiotics on perinatal mortality (RR 0.33, 95% CI 0.01 to 8.02; 3 studies, 709 infants; low-certainty evidence), a composite measure of neonatal morbidity (RR 0.69, 95% CI 0.36 to 1.35; 2 studies, 623 infants; low-certainty evidence), or neonatal hypoglycaemia (mean RR 1.15, 95% CI 0.69 to 1.92; 2 studies, 586 infants; low-certainty evidence). No included studies reported on perineal trauma, postnatal depression, maternal and infant development of diabetes or neurosensory disability.

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