A systematic review

Archives of Gynecology and Obstetrics https://doi.org/10.1007/s00404-018-4809-2

REVIEW

Do probiotics effectively ameliorate glycemic control during gestational diabetes? A systematic review Suelen Dallanora1,2 · Yasmin Medeiros de Souza1 · Rúbia Garcia Deon1 · Clare A. Tracey5,6 · Ana Amélia Freitas‑Vilela3 · Luiz Fernando Wurdig Roesch4 · Roberta Hack Mendes1,5 Received: 24 November 2017 / Accepted: 30 April 2018 © Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract Background Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. The aim of this work was to systematically review all studies in which probiotic supplements were used during pregnancy and analyse the effects on GDM. Methods The data were collected using the medical subheading (MeSH) terms: (“diabetes, gestational”[MeSH Terms] OR (“diabetes”[All Fields] AND “gestational”[All Fields]) OR “gestational diabetes”[All Fields] OR (“gestational”[All Fields] AND “diabetes”[All Fields])) AND (“probiotics”[MeSH Terms] OR “probiotics”[All Fields]). The search included original articles written in English/Portuguese and published between 2012 and 2017. Results Of the 31 articles identified, seven met the inclusion criteria and were included in this review. In these studies, the sample size ranged from 60 to 373 women with GDM, which was between 24 and 40 weeks of pregnancy (second and third trimesters). Results demonstrated that probiotics used during pregnancy in women with GDM may improve glycaemic control and reduce VDL cholesterol, triglycerides, and inflammatory markers. Conclusions The present systematic review highlights the importance of probiotics for glycemic control and decrease of inflammatory markers in GDM. Further long-term studies should be conducted to elucidate this interaction. Keywords Gestational diabetes · Gut microbiome · Lactobacillus · Bifidobacterium

Introduction Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance, with onset or first recognition during the pregnancy [1]. In Brazil, GDM is the most

* Roberta Hack Mendes [email protected] 1

Universidade Regional Integrada do Alto Uruguai e das Missões-URI, Frederico Westphalen, Brazil

2

Instituto de Cardiologia do Rio Grande do Sul, Porto Alegre, Brazil

3

Unidade Acadêmica Especial de Ciências da Saúde, Curso de Medicina, Universidade Federal de Goiás/Regional Jataí, Jataí, Brazil

4

Universidade Federal do Pampa, São Gabriel, Brazil

5

University College Dublin, Science Centre South, Dublin, Ireland

6

Maastricht University, Maastricht, The Netherlands

common metabolic disorder during pregnancy with a prevalence of 3–25% [2]. The problem of GDM is very pertinent worldwide, and according to the International Diabetes Federation [3], 7% of pregnancies in the world are affected by GDM. In Canada and China, the prevalence of GDM ranges from 8 to 18% [4] and 6.8–10.4%, respectively [5], and in India, more than 5 million women are affected each year [3]. GDM is of major concern, because it is associated with significant health risks for both the pregnant woman and developing fetus. In terms of the health risks posed to the pregnant woman, GDM increases the likelihood of a caesarean section delivery, whereby complications such as infection and excessive bleeding can sometimes ensue. Furthermore, a woman with GDM may develop pre-eclampsia, and following childbirth, they may acquire diabetes mellitus type 2 (DM2). For the infant, the risks include macrosomia and neonatal hypoglycaemia [6, 7]. In addition, the infants are more likely to be obese with increased insulin resistance in early adulthood [8].

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The maternal insulin resistance observed in GDM leads to inflammation, resulting in increased concentrations of inflammatory markers, such as C-reactive protein (CRP) and fibrinogen. In addition, the influence of gut microbiome diversity improvement during pregnancy has been studied. The use of probiotics may be useful as an efficient therapy to maintain the healthy gut microbiome [9]. Recent evidences show that GDM is related to maternal gut microbiome during the pregnancy. This relationship is possibly associated with the gut microbiome effects on insulin metabolism [10]. The gastrointestinal tract (GIT) is inhabited by numerous microorganisms, known as a microbiota, which have been shown to have protective functions beneficial to host health [11, 12]. The human microbiome consists of 1:1 microbial to human cells. In terms of number of genes, this proportion is even higher, with one human gene for each 100 microbial genes [13, 14]. Pregnancy, type of delivery, gestation period (term/preterm), infant feeding (maternal milk/infant formula), use of antiobiotics among other factors are all correlated with the human microbial community composition [8, 15–17]. Moreover, the use of probiotics, that are live microorganisms that when administered in appropriate dosages provide numerous health benefits to the host [15], might help to regulate the microbiota to promote favourable metabolic activity, produce beneficial metabolites, and regulate the diversity of gut microbiota [18]. The mechanisms of interaction between gut microbiota and glycemic control during pregnancy are similar to those found in obese individuals with increased insulin resistance. The modulation of bacterial composition of pregnant women affects the development and function of the gastrointestinal tract (GIT) of the babies [19]. However, there are not enough studies about modifications in maternal microbial diversity during pregnancy. For this reason, future studies concerning distinct populations and ethnicities should be considered, as they present different microbiota compositions, so metagenomics sequencing can be used to better examine the different microbial assemblages [20]. There is evidence of increased Proteobacteria and Actinobacteria in pregnant women in the third trimester when compared to the first trimester of pregnancy. This dysbiosis is similar to that occurring in obesity, where Proteobacteria are accompanied by inflammatory cytokines, such as interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α), suggesting an association between dysbiosis and insulin resistance and inflammatory processes [20]. Moreover, to ensure the beneficial action of probiotics in relation with GDM, they must be consumed in adequate quantities [21] must be able to survive in the passage of GIT and multiply in the intestine [22]. For this reason, probiotic

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Archives of Gynecology and Obstetrics

bacteria must be resistant to gastric and bile secretions [21, 22]. The aim of this article is to systematically review all studies which probiotic supplements were used during pregnancy and analyse the effects on GDM.

Methods Protocol and selection of studies This study was conducted according to Cochrane Handbook methods produced by Collaboration of Cochrane and Competency Demonstrations Report published by Centre for Reviews and Disseminations [23] and followed the recommendations of Preferred Reporting Items for Systematic Reviews and Meta Analysis (PRISMA) guidelines [24]. A protocol for the present review was registered with PROSPERO (https://www.crd.york.ac.uk/PROSPERO/CRD42 017065785). Two independent investigators conducted a literature search on the following databases: Scientific Electronic Library Online (SCIELO), PUBMED, and CLINICAL TRIALS. The search included terms such as “gestational diabetes” and “probiotics” and related entry terms associated with a high-sensitivity strategy search. Specifically, with regard to the PubMed database, we used the following: (“diabetes, gestational”[MeSH Terms] OR (“diabetes”[All Fields] AND “gestational”[All Fields]) OR “gestational diabetes”[All Fields] OR (“gestational”[All Fields] AND “diabetes”[All Fields])) AND (“probiotics”[MeSH Terms] OR “probiotics”[All Fields]). An additional search on GOOGLE SCHOLAR database was also performed. Our extensive search ensures that this systematic review includes all relevant studies, so as to build a comprehensive picture of the role of probiotics as an effective preventative measure for GDM. For elaboration of the analysis question, the PICO method was used: population (pregnant), intervention (probiotics), compare (glycaemia), and outcome (GDM). The search on databases was conducted during December 2016 until April 2017. We included studies which met the following criteria: (1) randomized controlled trials comparing any type of probiotic by placebo; (2) that included diabetic pregnant women, at any age and any stage of pregnancy; (3) evaluating any probiotic supplementation, irrespective of the microbial formulation, supplement composition (single vs. multiple strains) or dose, was included; and (4) published in Portuguese or English. We excluded review studies, systematic reviews, book chapters, and abstracts presented at national or international meetings, besides studies using experimental models.


Results Of the 31 articles found, 7 original articles met our selection criteria and were ultimately selected and reviewed. The articles were published between 2012 and 2017 (Table 2). The studies were randomized, double blind, placebo-controlled clinical trials, written in English and conducted in Asia, Europe, and Oceania and the duration of the studies included was between 4 and 9 weeks. The sample size ranged of 60–373 women with GDM, between 24 and 40 weeks of pregnancy (second and third trimesters). The risk of bias evaluated by Cochrane Collaboration tools [23] for randomized clinical trials (RCTs) is presented

Records identified through database searching (n = 31)

Records excluded by title

Records screened (n = 15)

Full text excluded

Eligibility

Screening

(n = 16)

Included

Fig. 1 Flow diagram of trials for inclusion in the systematic review

Identification

Two reviewer’s independently extracted data from the studies sourced (S. D. and Y. M.). An initial screening was done to exclude duplicated data and irrelevant records. The reviewers independently screened the remaining records to identify which potentially relevant records met inclusion/exclusion criteria. Full papers were obtained from these records, and were independently evaluated for relevance by two reviewers. Any discrepancies were resolved through discussion and by consulting a third reviewer. A flow diagram of search and selection is shown in Fig. 1. The diagram follows the recommendations of PRISMA statement [23].

(n = 8)

Records included in qualitative synthesis (n = 7)

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Table 1 Characteristics of included randomized clinical trial ECRs (Cochrane Collaboration) Estudo

Random sequence generation

Allocation concealment

Blinding participants/personnel

Blinding outcome assessment

Incomplete outcome data

Selective reporting

Asemi et al. [26] Lindsay et al. [27] Dolatkhah et al. [28] Lindsay et al. [29] Karamali et al. [30] Jafarnejad et al. [9] Wickens et al. [31]

↓ ↓ ↓ ↓ ↓ ↓ ↓

? ↓ ↓ ↓ ↓ ↓ ↓

? ↓ ↓ ↓ ↓ ↓ ↓

? ↓ ↓ ↓ ↓ ↓ ↓

↓ ↓ ↓ ↓ ↓ ↓ ↓

? ↓ ↓ ↓ ↓ ↓ ↓

↑ high risk, ↓ low risk, ? unclear

in Table 1. All manuscripts evaluated in this systematic review reported randomization and dropout rates appropriately. Furthermore, the generation of allocation sequences was adequate and explicit mention of the intention-to-treat was evident in 6/7 manuscripts. In one of the studies, a yogurt enriched with probiotics was ingested [25], in another article, two probiotic capsules were given daily [8], and in the remaining five studies, one probiotic capsule was ingested daily [26–30]. The microorganisms used belong mainly to the genus Lactobacillus (100% of the studies) and Bifidobacterium (80% of the studies). Asemi et al. found that there were differences in insulin concentrations and HOMA-IR (homeostatic model assessment-insulin resistance) between probiotic and traditional yogurts, among pregnant women consumers (baseline test on serum insulin levels: + 1.2 ± 1.2 vs. + 5.0 ± 1.1 U/mL, respectively, p = 0.02 and in the score HOMA-IR: − 0.2 ± 0.3 vs. 0.7 ± 0.2, respectively, p = 0.01) [25]. The exact mechanism by which probiotics might be able to modulate insulin concentrate is not clear, but we already know that glucose is the first energy source for probiotics. Dolatkhah et al. [28] conducted a study with women between 18 and 45 years of age with GDM between 24 and 28 weeks of pregnancy. The study was based on the daily consumption of probiotic capsules containing four bacterial strains (4 biocap > 4 × 109 CFU) in lyophilised culture including Lactobacillus acidophilus LA-5, Bifidobacterium BB-12, Streptococcus thermophilus STY-31 and Lactobacillus delbrueckii bulgaricus LBY-27, or placebo. The aim of the study was to evaluate the effect of a probiotic supplement capsule containing four bacterial strains on glucose metabolism and weight changes in pregnant women with newly diagnosed GDM. During the first 6 weeks of study, the trend of weight gain was similar between the groups. The probiotic supplement appeared to improve glucose metabolism and weight gain among pregnant women with GDM. Jafarnejad et al. tested the effects of VSL#3 in glycemic status and inflammatory markers in 82 pregnant women

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with GDM for 8 weeks. There was a significant decrease in levels of IL-6 (3.81 ± 0.7), TNF-α (3.10 ± 1.1), and hs-CRP (4927.4 ± 924.6). The studies included, in our systematic review, evaluated biochemical markers related to lipid and glucose metabolism. After 6-week intervention, probiotics vs. placebo, Karamali et al. [28] demonstrated that glycaemia (− 9.2 ± 9.2 vs. + 1.1 ± 12.2 mg/dL, p