TABLE 2.

The outcomes of different clinical trials assessing the probiotics efficacy on gestational diabetes among pregnant women

First author year	Origin	Sample size T C	Mean age (SD)	Mean weight (g) (SD)	Study design	Time of intervention	Probiotics	Probiotics Dose (CFU)	Duration of intervention	Controls used and duration of therapy	Outcomes	Certainty of the evidence (GRADE)
Allen, 2010	UK	454, 220 T 234 C	29 ± 5.6	NR	RCT DB prospective	36 wks of gestation	L. salivarius CUL61	6.25 × 109	D 4wks	Placebo group Mothers during the last month of pregnancy Infants during the first 6 MO of life	The safe use of this consortium of organisms was suggested during pregnancy and early infancy	⊕ ⊕ ⊕ ⊕
							L. paracaseiCUL08/	1.25 × 109
							B. animalis subsp. lactisCUL34	1.25 × 109
							B. bifidum CUL20	1.25 × 109
Jafarnejad, 2016	Iran	82, 41 T 41 C	32.4 ± 3.1	70.4 ± 7.3	RCT	GDM	VSL#3 lactic acid bacteria: S. thermophilus, Bifidobacterium breve, B. longum, B. infantis, L. acidophilus, L. plantarum L. Paracasei L. delbrueckii subsp. Bulgaricus	112.5 × 109	27–36 wks of gestation	Placebo group, 9 wks	1. Supplementation with probiotics may help modulate some inflammatory markers and may have benefits on glycemic control. 2. There were significant increase/decrease? in insulin levels and HOMA IR and a significant decrease in levels of IL−6 and hs‐CRP following probiotic consumption	⊕ ⊕ ⊕ ⊕
Mehri Jamilian, 2018	Iran	87, D + probiotic n = 30 Probiotic = 2 placebo n = 28	31.2 ± 5.9	71.7 ± 12.4	RCT DB	24–28 wks of gestation	L. acidophilus, B. bifidum, L. reuteri L. fermentum	8 × 109 (each 2 × 109)	D 6 wks	Not specified 24–28 wks of gestation	1. Vitamin D and probiotics resulted in a significant reduction in the levels of TG, VLDL, hsCRP, MDA, and HDL‐total cholesterol ratio 2. A significant rise in the levels of HDL‐cholesterol, total antioxidant capacity, TAC and total GSH	⊕ ⊕ ⊕ ⊕
Shahnaz Ahmadi, 2016	Iran	70, 35 T 35 C	28·5	77·7	RCT DB	24–28 wks of gestation	Symbiotic: L. acidophilus, L. casei,B.ium bifidum	2 × 109 each	D 6 wks	Not specified 6 wks	1. Taking synbiotic supplements among patients with GDM had beneficial effects 2. Significant decrease in serum insulin levels and serum TAG and VLDL‐cholesterol concentrations	⊕ ⊕ ⊕ ⊕
Z Asemi, 2012	Iran	70, 37 T 33 C	24.2 ± 3.3	Not report	RCT DB	6–9 MO of pregnancy	S. thermophilus, L. bulgaricus, L. acidophilus LA5, B. animalis BB12	1 × 107	D 9wks	Not specified 9 wks	1. Consumption of probiotic yogurt maintains serum insulin levels and HOMA‐IR score, which might help pregnant women prevent developing insulin resistance	⊕ ⊕ ⊕ 〇
Bita Badehnoosh, 2017	Iran	60, 30T 30C	28.8 ± 5.4	74.2 ± 9.5	RCT DB SC	24–28 wks of gestation	L. acidophilus L. casei B. bifidum	2 × 109 each	D 6 wks	Not specified 6 wks	Significant decreases in the FPG, hs‐CRP levels and MDA/TAC ratio, as well as a significant increase in TAC level	⊕ ⊕ ⊕ 〇
Leonie K. Callaway, 2019	Australia	411, 207 T 204 C	31.3 ± 4.7	169	RCT DB	Second trimester pregnancy	L. rhamnosus, B.animalis subsps lactis [BB−12]	1 × 109	D	Not specified 1 MO	Probiotics did not prevent GDM among overweight and obese pregnant women.	⊕ ⊕ 〇 〇
Neda Dolatkhah, 2015	Iran	64, 29 T 27 C	28.14 ± 6.24	83.27 ± 12.06	RCT DB	24–28wks of gestation	L. acidophilus LA−5, B. BB−12 S. thermophilus STY−31, L. delbrueckii bulgaricus LBY−27	4 biocap>4 × 109	8 wks	Not specified 8 wks	1. The probiotic supplement appeared to affect glucose metabolism and weight gain among pregnant women with GDM. 2. A decrease in the FBS level and insulin resistance index and an increase in insulin sensitivity index following probiotic consumption	⊕ ⊕ ⊕ 〇
Majid Hajifaraji, 2017	Iran	64, 29 T 27 C	28.1 ± 6.25	83.3 ± 12.1	RCT DB	24–28 wks of gestation	L. acidophilus LA−5, B. BB−12, S. Thermophilus STY−31, L. delbrueckii bulgaricus LBY−27	4 biocap>4 × 109	D 8 wks	Not specified 8 wks	1. The probiotic supplement improved several inflammation and oxidative stress biomarkers in women with GDM 2. Sh‐ CRP, TNF‐α, malondialdehyde, glutathione reductase, and erythrocyte glutathione peroxidase levels were improved, while serum IL−6 levels was decreased	⊕ ⊕ ⊕ ⊕
Maryam Karamali, 2017	Iran	60, 30 T 30 C	27.2 ± 5.9	74.7 ± 10.5	RCT DB	NR	Symbiotic: L. acidophilus strain T16(IBRCM10785), L. casei strain T2 (IBRC‐M10783), B. bifidum strain T1 (IBRC‐M10771)	2 × 109	6 wks	Not specified 6 wks	Probiotic consumption increased serum hs‐CRP, plasma malondialdehyde, cesarean section rate, and incidence of hyperbilirubinemic newborns while decreased the levels of TAC and GSH	⊕ ⊕ ⊕ 〇
Athasit Kijmanawat, 2019	USA	57, 28 T 29 C	32.50 ± 5.02	63.49 ± 10.75	RCT DB	6–7 MO of gestation	Bifidobacterium	109	D 4 wks	Not specified 4 wks	Probiotic consumption increased the fasting plasma glucose, fasting plasma insulin, insulin sensitivity, and homeostatic model assessment for insulin resistance and decreased fasting glucose	⊕ ⊕ ⊕ 〇
							Lactobacillus	109
Karen L. Lindsay, 2015	Ireland	149, 74 T 75 C	>18 y	33.5 ± 5.0	RCT DB	<34 wks gestation	L. salivarius UCC118	109	D 4 wks	Not specified 4 wks	Probiotic consumption had no impacts on glycemic control	⊕ ⊕ ⊕ 〇 ⊕ ⊕ ⊕ 〇
Zohoor Nabhani, 2018	Iran	90, 45 T 45 C	Synbiotic 29.4 ± 5.8	69 ± 12.8	RCT DB	24–28 wks of gestation	L.acidophilus	5 × 1010	6 wks	Not specified 6 wks	1. Probiotic consumption may prevent any increments in LDL‐C levels as well as having positive effects on HDL‐C and TAC status. 2. Positive effect of synbiotics on SBP and DBP was noticeable.
							L.plantarum	1.5 × 1010
							L.fermentum	7 × 109
							L. Gasseri	2 × 1010
Marloes Dekker Nitert1, 2013	Australia	540, 270 T 270 C	>18.0	NR	RCT DB MC prospective	GDM at 28 wks gestation	L.rhamnosus GG, B. lactis BB−12	1 × 109 each	D	Not specified > 2 y	Probiotics prevented gestational diabetes in the high‐risk group of overweight and obese pregnant women.	⊕ ⊕ ⊕ ⊕
Outi Pellonperä, 2019	Finland	439, Probiotic n = 109 probiotic/fish oil n = 110 fish oil/placebo n = 109 placebo/placebo n = 110	Fish oil + probiotics 30.8 ± 4.6	83.6 ± 14.9	RCT DB	mean 13.9 ± 2.1 gestational wks	Lactobacillus rhamnosus HN001, Bifidobacterium animalis ssp. lactis 420	1010 each	D	Throughout the pregnancy, until 6 MO postpartum.	Intervention with fish oil and probiotics did not lower the incidence of GDM, fasting glucose concentration, or insulin resistance in overweight and obese pregnant women	⊕ ⊕ ⊕ 〇
Kristin L. Wickens, 2017	New Zealand	423, 212 T 211 C	30 36	63–80	RCT DB TC	Earliest first‐trimester, 14–16 wks of gestation	L. rhamnosus HN001	6 × 1010	D	Throughout pregnancy until 6 MO post birth if still breast‐feeding	Probiotics may reduce GDM prevalence particularly among older women and those with previous GDM.	⊕ ⊕ ⊕ 〇
Hanieh Asgharian, 2019	Iran	130, 65 T 65 C	29.5 ± 6.2	Birth weight (g) 3270 ± 495	RCT	BMI ≥25, FPG<92 mg/dl, 22 wks of gestation	L. acidophilus La5, B. lactis Bb12	5 × 108 each	D 12wks	Until 1 MO after birth	The probiotics supplementation had some beneficial effects on glucose metabolism of overweight and obese pregnant women	⊕ ⊕ ⊕ ⊕
Mahtab Babadi, 2018	Iran	48, 24 T 24 C	28.8 ± 4.3	70.1 ± 5.2 kg	RCT DB PCCT	GDM at 24–28 wks of gestation	L. acidophilus, L. casei, B. bifidum, L. fermentum	2 × 109 each	D 6 wks	1 y	1. Probiotic had beneficial effects on gene expressions related to insulin, inflammation, and glycemic control 2. Probiotics decreased lipid profiles, inflammatory markers, and oxidative stress	⊕ ⊕ ⊕ ⊕
Christine Barthow, 2016	New Zealand	400	NR	NR	RCT DB TC	14–16 wks of gestation	L. rhamnosus HN001	6 × 109	D	12–16 wks, until 6 MO post‐partum	Probiotics alleviated the severity of eczema and atopic sensitisation in the first year of life of neonates.	⊕ ⊕ ⊕ ⊕
Luisa F. Go mez‐Arango, 2016	Australia	205	Overweight 36 33 , 34 , 35 , 36 , 37 , 38 Obese 36 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40	BMI: Overweight 27.5 (26.4–28.4) Obese 34.9 (32.1–38.5)	RCT	16 wks of gestation	L. rhamnosus GG B. lactis BB−12	2 × 109 each	NR	NR	1. The abundance of butyrate‐producing bacteria in the gut microbiota was negatively associated with BP and with PAI−1 levels. 2. Increasing butyrate‐producing capacity may contribute to maintenance of normal BP in obese pregnant women	⊕ ⊕ 〇 〇
Luisa F. Gomez‐Arango, 2017	Australia	57 overweight 73 obese	Overweight: 32.0 (29.0 –34.0) Obese: 30.5 (28.0–34.0)	BMI (kg/m) Overweight: 27.9 (27.0 –29.1) Obese 34.3 (31.8–41.3)	RCT	16 wks of gestation	L. rhamnosus GG B. lactis BB−12	2 × 109	D	1–16 wks gestation	1. Low dietary fiber may enable overgrowth of Collinsella spp.and alter the overall fermentation pattern in the gut microbiota 2. That dietary choices during pregnancy can modify the nutritional ecology of the gut microbiota, with potential deleterious effects on the metabolic and inflammatory health of the host.	⊕ ⊕ 〇 〇
Sofie Ingdam Halkjaer, 2016	Denmark	50, 25 T 25 C	> 18 y	BMI of between 30–35 kg/m2	DB SC RPCT	14–20 wks of gestation	S. thermophilus DSM 24731, B. breve DSM 24732, B. longum DSM 24736, B. infantis DSM 24737, L. acidophilus DSM 24735, L. plantarum DSM 24730, L. paracasei DSM 24733, L. delbrueckii, bulgaricus DSM 24734)	450 billion each	12–16 wks	12–16 wks infants until 9 MO	1. Probiotics could control weight gain and reduce complications during pregnancy by inducing changes in the gut microbiota 2. Probiotics could influence the infant's microbiota, which could have important implications on infant's development and health	⊕ ⊕ ⊕ ⊕
Karen L Lindsay, 2014	Ireland	138, 63 T 75 C	31.4 ± 5.0	89.5 ± 9.1	DB RPCT	24–28 wks of gestation	L. salivarius UCC118	109	D 4wks	<20 wks of gestation	Probiotics did not influence the maternal fasting glucose, the metabolic profile, or pregnancy outcomes in obese women	⊕ ⊕ ⊕ 〇
Raakel Luoto, 2012	Finland	256, Diet/probiotics n = 64 Diet/placebo (n = 59) Placebo/control (n = 58)	29.7 (4.3)	Infants (g) 3468 (3360–3577)	RPCT Prospective	every trimester of pregnancy infant age of 6 MO	L. rhamnosus GG, B. lactis	1010 each	D every trimester of pregnancy	2002–2005	The dietary intervention increased the colostrum adiponectin concentration	⊕ ⊕ ⊕ 〇
Farnaz Sahhaf Ebrahimi, 2019	Iran	84, 42 T 42 C	31.64 ± 5.97	79.5 ± 17.31	DB RPCT	3–6 MO	L. acidophilus B. lactis	300 g/day 106	D 8 wks	2 MO	Probiotics increased fasting and post prandial blood glucose and decreased the level of HbA1c, in lower weight and fewer macrosome neonates	⊕ ⊕ ⊕ ⊕
Lihui Si, 2019	China	226 113+113	34.32 ± 6.47	58.48 ± 7.36	Parallel RCT	12.14 ± 2.46 wk of gestation	L. bulgaricus	108	7 d	40 wks	L. bulgaricus improved the antioxidant capacity of black garlic in the prevention of GDM	⊕ ⊕ ⊕ ⊕
Shaun Sabico, 2017	UK	78, 39 T 39 C	48.0 ± 8.3	75.6 ± 11.0 kg	RCT DB SC	T2DM patients	B. bifidum W23, B.lactis W52, L. acidophilus W37, L. brevis W63, L. casei W56, L. salivarius W24, L. lactis W19, L. lactis W58	2.5 × 109 each	12 wks	12/13 wks	Probiotics significantly improved HOMA‐IR and modestly reduced abdominal adiposity among medication naïve T2DM patients	⊕ ⊕ ⊕ ⊕
Maryam Karamali, 2018	Iran	60 30 T 30 C	P: 27.2 ± 4.6 C: 27.7 ± 4.7	62.9 ± 7.8 63.7 ± 8.0	RCT DB	women with PCOS	L. acidophilus, L. casei and B. bifidum	2 × 109 each	12 wks	12 wks	Probiotic supplementation of PCOS had beneficial effects on total testosterone, SHBG, mFG scores, hs‐CRP, TAC, and MDA levels but did not affect other metabolic profiles.	⊕ ⊕ ⊕ ⊕

Abbreviations: BP, blood pressure; C, control; CFU, colony‐forming units; Chol, cholesterol; C‐peptide, connecting peptide; D, daily; d, days; DB, double‐blind; FBS, fasting blood sugar; GDM, gestational diabetes mellitus; GSH, total glutathione; HDL‐cholesterol, high‐density lipoprotein‐cholesterol; HOMA‐IR, homeostatic model assessment of insulin resistance; HOMA‐β, homeostasis model assessment of β‐cell function; hs‐CRP, high‐sensitivity C‐reactive protein; IL, interleukin; INS, insulin; LDL‐cholesterol, low‐density lipoprotein‐cholesterol; MC, multi‐center; MDA, malondialdehyde; mF‐G, modified Ferriman‐Gallwey; MO, month; NO, nitric oxide; NR, not report; PAI‐1, plasminogen activator inhibitor‐1; PCCT, placebo‐controlled clinical trial; PCOS, Polycystic ovary syndrome; QUICKI, quantitative insulin sensitivity check index; RCT, randomized controlled trials; RPCT, randomized placebo‐controlled study; SC, single‐center; SHBG, sex hormone‐binding globulin; T, test; T2DM, Type 2 diabetes mellitus; TAC, total antioxidant capacity; TC, two‐center; TG, triglyceride; TNF‐α, tumor necrosis factor alpha; VLDL‐cholesterol, very low‐density lipoprotein‐cholesterol; wks, weak(s); y, year.