Participant attrition and perinatal outcomes in prenatal vitamin D-supplemented gestational diabetes mellitus patients in Asia: A meta-analysis

Table 1 Salient features of the reviewed trials

Ref.	Design	Participants	Interventions	Outcomes
Jamilian et al[37], 2016	Randomized, double-blind, placebo-controlled clinical trial; Intervention arms: Two; Single-centered trialTrial duration: 6 wk. Trial conducted in: Iran; Obtained ethical clearance and participant consent. Funding information provided. Clinical trial registration number: IRCT201509115623N52	Participants diagnosed with GDM (used ADA criteria); 60 participants randomized into different treatment arms (vitamin D3 and evening primrose oil: n = 30, placebo: n = 30); Mean age of participants: -Vitamin D3 and evening primrose oil receiving group: 28.4 ± 6.2 yr; -Placebo receiving group: 29.6 ± 4.3 yr	Two intervention arms: (1) 1000 IU of vitamin D and 1000 mg of evening primrose oil daily for 6 wk; and (2) Placebo	Attrition from vitamin D supplemented arm: n = 3; Other outcomes reported: Fasting plasma glucose
Jamilian et al[17], 2017	Randomized, double blinded, placebo-controlled clinical trial; Intervention arms: four; Single centered trial; Trial duration: 6 wk. Trial conducted in: Iran; Obtained ethical clearance and participant consent. Funding information provided. Clinical trial registration number: IRCT201605135623N78	Participants diagnosed with GDM (used ADA criteria); 140 participants randomized into different treatment arms (vitamin D and omega-3 fatty acid receiving group: n = 35, vitamin D receiving arm: n = 35, omeag-3 fatty acid receiving arm: n = 35, placebo receiving arm: n = 35); Mean age of participants: -Vitamin D and omega-3 fatty acid receiving group: 31.2 ± 4.3 yr; -Vitamin D receiving group: 31.5 ± 7.0 yr; -Omega-3 receiving group: 30.7 ± 3.5 yr; -Placebo receiving group: 30.7 ± 4.1 yr	Four intervention arms: (1) Vitamin D and omega-3 fatty acid: 50000 IU of vitamin D two weekly and 1000 mg omega-3 fatty acid twice daily; (2) Vitamin D: 50000 IU vitamin D every 2 wk; (3) Omega-3 fatty acid: 1000 mg omega-3 fatty acids two times a day; and (4) Placebo	No attrition from vitamin D supplemented arm; Other outcomes reported: Fasting plasma glucose
Jamilian et al[33], 2019a	Randomized, double-blind, placebo-controlled; Intervention arms: 3; Trial conducted in: Iran; Single centered trial; Trial duration: 6 wk; Obtained ethical clearance and participant consent. Funding information provided. Trial ID: IRCT201706075623N119	Participants diagnosed with GDM (used ADA criteria); 90 participants randomized into different treatment arms (probiotic arm: n = 30, vitamin D and probiotic arm: n = 30, placebo arm: n = 30); Mean age of participants: -Probiotic arm: 31.2 ± 5.9 yr; -Vitamin D and probiotic arm: 28.9 ± 6.1 yr; -Placebo arm: 29.9 ± 3.7 yr	Three intervention arms: (1) Probiotic: 8 × 109 CFU/g; (2) Vitamin D3 (50,000 IU) every 2 wk plus 8 × 109 CFU/g probiotic; Placebo	No attrition from vitamin D supplemented arm; Other outcomes reported: (1) Newborn hyperbilirubinemia; (2) Newborn hospitalization; (3) Macrosomia; and (4) Cesarean section. Fasting plasma glucose
Jamilian et al[36], 2019b	Randomized, double-blind, placebo-controlled. Intervention arms: 2; Trial conducted in: IranSingle centered trialTrial duration: 6 wkObtained ethical clearance and participant consent. Funding information provided.Trial ID: IRCT201704225623N109	Participants diagnosed with GDM (used ADA criteria); 60 participants randomized into different treatment arms (vitamin D-magnesium-zinc-calcium arm: n = 30, placebo arm: n = 30). Mean age of participants: -Vitamin D-magnesium-zinc-calcium arm: 27.7 ± 4.0 yr; -Placebo arm: 29.1 ± 4.1 yr	Two intervention arms: (1) Vitamin D (200 IU) along with 100 mg magnesium, 4 mg zinc, 400 mg calcium twice daily; and (2) Placebo	No attrition from vitamin D supplemented armOther outcomes reported: (1) Newborn hyperbilirubinemia; (2) Newborn hospitalization; (3) Macrosomia; and (4) Cesarean section. Fasting plasma glucose
Asemi et al[31], 2014a	Randomized, double-blind, placebo-controlled trial. Intervention arms: 2; Trial conducted in: Iran; Single centered trial; Trial duration: 6 wk; Obtained ethical clearance and participant consent. Funding information provided.Trial ID: IRCT201305115623N7	Participants diagnosed with GDM (used ADA criteria); 50 participants randomized into different treatment arms (vitamin D arm: n = 25, placebo arm: n = 25). Mean age of participants: -Vitamin D arm: 31.1 ± 5.5 yr; -Placebo arm: 30.8 ± 6.2 yr	Two intervention arms: (1) Vitamin D: 50,000 IU vitamin D3 pearl two times during the trial period (at baseline and day 21); and (2) Placebo	Attrition from vitamin D supplemented arm: n = 3; Other outcomes reported: (1) Newborn hyperbilirubinemia; (2) Newborn hospitalization; (3) Macrosomia; and (4) Cesarean section
Asemi et al[16], 2014b	Randomized, placebo-controlled clinical trial. Intervention arms: TwoMulti-centric trial. Trial duration: 6 wk. Trial conducted in: IranObtained ethical clearance and participant consent. Funding information provided. Clinical trial registration number: IRCT201311205623N11	Participants diagnosed with GDM (used ADA criteria); 56 participants randomized into different treatment arms (vitamin D and calcium: n = 28, placebo receiving group: n = 28). Mean age of participants: -Vitamin D and calcium receiving arm: 28.7 ± 6.0 yr; -Placebo receiving arm: 30.8 ± 6.6 yr	Two intervention arms: (1) 1000 mg calcium carbonate daily and 50000 U vitamin D3 at the baseline and day 21 of the study; and (2) Placebo	Attrition from vitamin D supplemented arm: n = 3. Other outcomes reported: Fasting plasma glucose
Karamali et al[32], 2016	Randomized, double-blind, placebo-controlled trial; Intervention arms: 2; Trial conducted in: Iran; Multicentric trialTrial duration: 6 wk; Obtained ethical clearance and participant consent. Funding information provided. Trial ID: IRCT201407115623N23	Participants diagnosed with GDM (used ADA criteria); 60 participants randomized into different treatment arms (vitamin D and calcium arm: n = 30; placebo arm: n = 30). Mean age of participants: -Vitamin D and calcium arm: 28·7 ± 6·1 yr; -Placebo arm: 31·6 ± 6·3 yr	Two intervention arms: (1) Vitamin D3 (50000 IU) at baseline and day 21 along with 1000 mg calcium carbonate daily; and (2) Placebo	No attrition from vitamin D supplemented arm; Other outcomes reported: (1) Newborn hyperbilirubinemia; (2) Newborn hospitalization; (3) Macrosomia; and (4) Cesarean section
Karamali et al[14], 2018	Randomized, double-blind, placebo-controlled trial; Intervention arms: 2; Single centered trial. Trial duration: 6 wk; Trial conducted in: Iran; Obtained ethical clearance (participant consent information unclear). Funding information provided. Trial registration details: Unclear	Participants diagnosed with GDM (used ADA criteria); 60 participants randomized into different treatment arms; (Magnesium, zinc, calcium and vitamin D supplements arm: n = 30; Placebo arm: n = 30); Mean age of participants: -Magnesium, zinc, calcium and vitamin D: 30.0 ± 4.5 yr; -Placebo arm: 31.1 ± 4.2 yr	Two intervention arms: (1) 100 mg magnesium, 4 mg zinc, 400 mg calcium and 200 IU vitamin D two times a day for 6 wk; and (2) Placebo	No attrition from vitamin D supplemented arm; Other outcomes reported: Fasting plasma glucose
Razavi et al[35], 2017	Randomized, double-blind, placebo-controlled, Intervention arms: 4; Trial conducted in: Iran. Single centered trial. Trial duration: 6 wk; Obtained ethical clearance and participant consent. Funding information provided. Trial ID: IRCT201701305623N106	Participants diagnosed with GDM (used ADA criteria); 120 participants randomized into different treatment arms (vitamin D and omega-3 arm: n = 30; omega-3 arm: n = 30; vitamin D arm: n = 30; placebo: n = 30); Mean age of participants: -Vitamin D and omega-3 arm: 29.9 ± 4.0 yr; -Omega-3 arm: 29.7 ± 3.6 yr; -Vitamin D arm: 29.9 ± 5.0 yr; -Placebo: 29.2 ± 3.4 yr	Four intervention arms: (1) Vitamin D (50000 IU): Two weekly two times a day; (2) Vitamin D (50000 IU) two weekly plus 1000 mg omega-3 fatty acids two times a day; (3) 1000 mg omega-3 fatty acids two times a day; and (4) Placebo	No attrition from vitamin D supplemented arm; Other outcomes reported: (1) Newborn hyperbilirubinemia; (2) Newborn hospitalization; (3) Macrosomia; and (4) Cesarean section
Valizadeh et al[34], 2016	Randomized controlled trial. Investigators and patients were not blinded. Intervention arms: 2; Single centered trial; Trial conducted in: Iran; Trial duration: Until delivery; Obtained ethical clearance and participant consent. Funding information provided. Trial ID: IRCT2012101611144N1	Participants diagnosed with GDM (used ADA criteria); 96 participants randomized into different treatment arms (vitamin D arm: n = 48; no supplement arm: n = 48); Mean age of participants: -Vitamin D arm: 32.0 ± 5.5 yr; -No supplement arm: 32.4 ± 4.7 yr	Two intervention arms: (1) 700000 IU vitamin D3 in total (regimen differed by gestational age of GDM patients); and (2) Comparison group did not receive any supplementation	Attrition from vitamin D supplemented arm: n = 4; Other outcomes reported: (1) Newborn hyperbilirubinemia; (2) Macrosomia; (3) Cesarean section; and (4) Fasting plasma glucose
Yazdchi et al[15], 2016	Randomized, double-blinded placebo-controlled clinical trial; Intervention arms: 2; Multi-center trial; Trial duration: 8 wk. Trial conducted in: Iran; Obtained ethical clearance and participant consent. Funding information provided. Clinical trial registration number: IRCT201306253140N11	Participants diagnosed with GDM (used International Association of Diabetes and Pregnancy Study Groups criteria); 76 participants randomized into different treatment arms: Vitamin D arm: n = 38; placebo arm: n = 38; Mean age of participants: -Vitamin D arm: 31.64 ± 4.40 yr; -Placebo arm: 32.11 ± 3.61 yr	Two intervention arms:(1) 50000 IU vitamin D3 oral capsules two weekly for 8 wk; and (2) Placebo	Attrition from vitamin D supplemented arm: n = 4; Other outcomes reported: Fasting plasma glucose
Zhang et al[38], 2016	Randomized, double-blind, placebo-controlled trial. Intervention arms: 4; Single centered trial. Trial duration: 24-28 wk of pregnancy to delivery; Trial conducted in: China; Obtained ethical clearance and participant consent. Funding information provided. Clinical trial registration details: Unclear	Participants diagnosed with GDM (criteria unclear). 133 participants randomized into different treatment arms (low dose vitamin D: n = 38; medium dose vitamin D: n = 38; high dose vitamin D: n = 37; placebo: n = 23); Mean age of participants: -Placebo arm: 29.8 ± 4.7; -Low dose vitamin D arm: 30.3 ± 5.1; -Medium dose vitamin D arm: 29.4 ± 4.9; -High dose vitamin D arm: 30.1 ± 4.5	Four intervention arms: (1) Low dose vitamin D: 200 IU daily; (2) Medium dose vitamin D: 2000 IU monthly; and (3) High dose vitamin D: 50000 IU every 2 wk. Placebo	Attrition from vitamin D supplemented arm: n = 4
Li and Xing[13], 2016	Randomized, double-blinded clinical trial. Intervention arms: 2. Multi-centric trial. Trial duration: 16 wk. Trial conducted in: China; Obtained ethical clearance and participant consent. Funding information provided. Clinical trial registration details: Unclear	Participants diagnosed with GDM (used ADA criteria)103 participants randomized into different treatment arms (yoghurt with vitamin D: n = 52, plain yoghurt: n = 51); Mean age of participants: -Yoghurt supplemented with vitamin D receiving arm: 29.0 ± 5.3 yr; -Plain yoghurt arm: 28.3 ± 4.1 yr	Two intervention arms: (1) Yoghurt was supplemented with 500 IU of vitamin D3 twice daily for 16 wk; and (2) plain yoghurt: Twice daily for 16 wk	Attrition from vitamin D supplemented arm: n = 4. Other outcomes reported: Fasting plasma glucose

ADA: American diabetes association.

Table 2 Risk of bias assessment of respective trial included in the review[23]

Ref.	Random sequence generation (selection bias)	Allocation concealment (selection bias)	Blinding of participants and personnel (performance bias); All outcomes	Blinding of outcome assessment (detection bias); All outcomes	Incomplete outcome data (attrition bias); All outcomes	Selective reporting (reporting bias)	Other bias
Jamilian et al[37], 2016	Low	Unclear; Comment: Precise mechanism unclear	Unclear; Comment: Precise mechanism unclear	Low	Low	Low	Low
Jamilian et al[17], 2017	Low	Unclear; Comment: Precise mechanism unclear	Unclear; Comment: Precise mechanism unclear	Unclear	Low	Low	Low
Jamilian et al[33], 2019a	Low risk	Unclear risk; Comment: Precise mechanism unclear	Low risk	Low risk	Low risk	Low risk	Low risk
Jamilian et al[36], 2019b	Low risk	Unclear risk; Comment: Precise mechanism unclear	Low risk	Low risk	Low risk	Low risk	Low risk
Asemi et al[31], 2014a	Low risk	Unclear risk; Comment: Precise mechanism unclear	Low risk	Low risk	Low risk	Low risk	Low risk
Asemi et al[16], 2014b	Low	Low	Low	Low	Low	Low	Low
Karamali et al[32], 2016	Low risk	Unclear risk; Comment: Precise mechanism unclear	Low risk	Low risk	Low risk	Low risk	Low risk
Karamali et al[14], 2018	Low	Unclear; Comment: Precise mechanism unclear	Unclear; Comment: Precise mechanism unclear	Low	Low	Low	Low
Razavi et al[35], 2017	Low risk	Unclear risk; Comment: It’s unclear if the bottles were sequentially numbered and identical in appearance	Low risk	Low risk	Low risk	Low risk	Low risk
Valizadeh et al[34], 2016	Low risk	Unclear risk	High risk; Comment: Both investigators and participants were not blinded		Low risk	Low risk	Low risk
Yazdchi et al[15], 2016	Low	Unclear	Unclear	Low	Low	Low	Low
Zhang et al[38], 2016	Low	Unclear; Comment: Precise mechanism unclear	Unclear; Comment: Precise mechanism unclear	Unclear; Comment: Precise mechanism unclear	Low	Low	Low
Li and Xing[13], 2016	Low	Unclear; Comment: Precise mechanism unclear	Unclear; Comment: Precise mechanism unclear	Low	Low	Low	Low

Table 3 League table. Outcomes: cesarean section (left lower triangle) and newborn hyperbilirubinemia (right upper triangle). Interventions of interest: represented in diagonal cells

Interventions and effect sizes
Vitamin D and probiotic	1.14 (0.22, 5.92)1	0.79 (0.19, 3.27)	0.59 (0.16, 2.20)	0.73 (0.18, 2.96)	0.28 (0.09, 0.91)2	0.34 (0.09, 1.32)	0.42 (0.10, 1.69)
0.76 (0.27, 2.19)	Vitamin D and omega-3 fatty acid	0.70 (0.17, 2.79)	0.52 (0.16, 1.75)	0.64 (0.14, 2.99)	0.25 (0.08, 0.77)	0.30 (0.09, 0.98)	0.37 (0.09, 1.44)
1.48 (0.52, 4.21)	1.94 (0.71, 5.28)	Vitamin D and calcium	0.75 (0.29, 1.96)	0.91 (0.25, 3.35)	0.35 (0.16, 0.77)	0.43 (0.16, 1.19)	0.53 (0.18, 1.55)
0.69 (0.29, 1.68)	0.91 (0.44, 1.90)	0.47 (0.21, 1.07)	Vitamin D	1.22 (0.37, 3.96)	0.47 (0.27, 0.83)	0.57 (0.27, 1.22)	0.71 (0.28, 1.78)
0.68 (0.30, 1.54)	0.89 (0.34, 2.35)	0.46 (0.17, 1.20)	0.97 (0.45, 2.13)	Probiotic	0.39 (0.14, 1.09)	0.47 (0.14, 1.60)	0.58 (0.16, 2.07)
0.54 (0.25, 1.18)	0.71 (0.35, 1.46)	0.37 (0.18, 0.74)	0.78 (0.52, 1.19)	0.80 (0.42, 1.56)	Placebo	1.22 (0.64, 2.33)	1.50 (0.72, 3.14)
0.68 (0.24, 1.90)	0.89 (0.40, 1.99)	0.46 (0.17, 1.22)	0.98 (0.49, 1.96)	1.00 (0.39, 2.58)	1.24 (0.63, 2.45)	Omega-3 fatty acid	1.23 (0.46, 3.28)
1.23 (0.33, 4.57)	1.61 (0.45, 5.79)	0.83 (0.23, 2.97)	1.76 (0.56, 5.53)	1.81 (0.52, 6.33)	2.25 (0.78, 6.52)	1.81 (0.51, 6.37)	Magnesium, zinc, calcium, and vitamin D

¹Effect sizes in risk ratio with its 95% confidence interval in parenthesis.

²Cells with bold-faced values depict a statistically significant decrease in effect size.

In the right upper and the left lower triangle, the columns and rows depict the reference treatment, respectively.

Table 4 League table: Outcomes: Macrosomia (left lower triangle) and newborn hospitalization (right upper triangle). Interventions of interest: Represented in diagonal cells

Interventions and effect sizes
Vitamin D and probiotic	1.27 (0.24, 6.66)1	0.88 (0.21, 3.69)	0.66 (0.18, 2.49)	0.97 (0.21, 4.41)	0.31 (0.09, 1.03)	0.38 (0.10, 1.49)	0.47 (0.11, 1.91)
0.94 (0.11, 8.45)	Vitamin D and omega-3 fatty acid	0.70 (0.17, 2.79)	0.52 (0.16, 1.75)	0.76 (0.15, 4.02)	0.25 (0.08, 0.77)2	0.30 (0.09, 0.98)	0.37 (0.09, 1.44)
3.36 (0.13, 88.67)	3.56 (0.14, 93.17)	Vitamin D and calcium	0.75 (0.29, 1.96)	1.10 (0.26, 4.59)	0.35 (0.16, 0.77)	0.43 (0.16, 1.19)	0.53 (0.18, 1.55)
0.98 (0.13, 7.29)	1.03 (0.18, 6.09)	0.29 (0.01, 6.77)	Vitamin D	1.46 (0.39, 5.50)	0.47 (0.27, 0.83)	0.57 (0.27, 1.22)	0.71 (0.28, 1.78)
1.93 (0.19, 20.18)	2.05 (0.15, 27.32)	0.58 (0.02, 20.11)	1.98 (0.17, 22.68)	Probiotic	0.32 (0.10, 1.07)	0.39 (0.10, 1.53)	0.48 (0.12, 1.97)
0.37 (0.08, 1.77)	0.40 (0.08, 1.85)	0.11 (0.01, 1.98)	0.38 (0.11, 1.36)	0.19 (0.02, 1.55)	Placebo	1.22 (0.64, 2.33)	1.50 (0.72, 3.14)
0.63 (0.08, 4.84)	0.67 (0.12, 3.71)	0.19 (0.01, 4.45)	0.64 (0.13, 3.13)	0.33 (0.03, 3.83)	1.69 (0.45, 6.30)	Omega-3 fatty acid	1.23 (0.46, 3.28)
1.87 (0.14, 25.22)	1.98 (0.15, 26.45)	0.56 (0.02, 19.45)	1.91 (0.17, 21.96)	0.97 (0.05, 18.42)	5.00 (0.62, 40.28)	2.96 (0.25, 34.96)	Magnesium, zinc, calcium, and vitamin D

¹Effect sizes in risk ratio with its 95% confidence interval in parenthesis.

²Cells with bold-faced values depict a statistically significant decrease in effect size.

In the right upper and the left lower triangle, the columns and rows depict the reference treatment, respectively.

Table 5 The surface under the cumulative ranking curve values. Outcomes: Newborn hyperbilirubinemia, newborn hospitalization, and cesarean section

Intervention	Outcomes
	Newborn hyperbilirubinemia		Newborn hospitalization		Cesarean section
	SUCRA	Mean rank	SUCRA	Mean rank	SUCRA	Mean Rank
Vitamin D and omega-3 fatty acid	81.8	2.31	81.1	2.31	46.4	4.8
Vitamin D and probiotic	76.2	2.7	70.7	3.0	66.3	3.4
Probiotic	62.2	3.6	69.5	3.1	36.6	5.4
Vitamin D and calcium	67.9	3.3	67.2	3.3	87.6	1.91
Vitamin D	52.8	4.3	52.4	4.3	39.0	5.3
Magnesium, zinc, calcium, and vitamin D	32.4	5.7	32.2	5.7	73.8	2.8

¹The best rank corresponding to the highest SUCRA value. SUCRA: Surface under the cumulative ranking curve.