Table 1 Characteristics of the studies included in the meta-analysis

Bartal et al. (2021) [28]

RCT

USA

Women with singleton gestation and type 2 diabetes; gestational diabetes mellitus (GDM) diagnosed before 20 weeks gestation; mean age of 32 years and 88% multiparous; pre-pregnancy BMI of > 30 kg/m2 (83%); mean gestational age at randomization (13 wks)

Detemir

108 (57-Detemir; 51- neutral protamine Hagedorn)

Maternal outcomes

Symptomatic hypoglycaemia: RR 0.33 (95% CI 0.13, 0.76)

Hypertensive disorder: RR 0.81 (95% CI 0.54, 1.16)

Mean (SD) gestational weight gain (kg): 7 (1.83) vs. 9 (1.78)

Caesarean section: RR 0.99 (95% CI 0.73, 1.34)

Postpartum haemorrhage: RR 1.25 (95% CI 0.50, 3.26)

Endometritis: RR 0.80 (95% CI 0.22, 2.91)

Wound infection or dehiscence: RR 0.83 (95% CI 0.26, 2.64)

Postpartum readmission: RR 1.71 (95% CI 0.63, 5.01)

Hospitalization for glucose control: RR 0.89 (95% CI 0.42, 1.87)

Induction of labour: RR 0.96 (95% CI 0.66, 1.37)

Foetal/neonatal outcomes

Mean (SD) gestational age (wks): 37.10 (0.23) vs. 37 (0.55)

Preterm (< 37 wks): RR 0.93 (95% CI 0.60, 1.39)

Large for gestational age (LGA): RR 1.75 (95% CI 0.92, 3.60)

Shoulder dystocia: RR 0.98 (95% CI 0.33, 3.00)

Admission to NICU: RR 0.91 (95% CI 0.63, 1.21)

Respiratory distress: RR 0.69 (95% CI 0.40, 1.13)

Need for mechanical ventilation: RR 0.47 (95% CI 0.17, 1.20)

Neonatal hypoglycemia: RR 1.02 (95% CI 0.69, 1.54)

Need for I/v glucose: RR 1.24 (95% CI 0.78, 2.10)

Mean (SD) birth weight (gm): 3158 (660.2) vs. 2707 (812.7)

APGAR < 7 (at 5 min): RR 1.13 (95% CI 0.40, 3.33)

Small for gestational age (SGA): RR 0.77 (95% CI 0.32, 1.83)

Neonatal hyperbilirubinemia: RR 1.20 (95% CI 0.68, 2.22)

Chico et al. (2016) [29]

Retrospective cohort

Spain

Women with singleton gestation and type 1 diabetes; Median age of 31 years; Mean pre-pregnancy BMI of 23.9 kg/m2

Glargine

1210 (356-glargine; 854- neutral protamine Hagedorn)

Maternal outcomes

Symptomatic hypoglycaemia: RR 0.89 (95% CI 0.64, 1.25)

Hypertensive disorder: RR 0.93 (95% CI 0.66, 1.30)

Mean (SD) gestational weight gain (kg): 12 (1.63) vs. 12.5 (1.47)

Caesarean section: RR 1.10 (95% CI 0.97, 1.26)

Hb A1c (%) (mean, SD):

1^st trimester: 6.16 (0.34) vs. 6.33 (0.39)

2^nd trimester: 5.70 (0.24) vs. 5.79 (0.27)

3^rd trimester: 5.70 (0.25) vs. 5.83 (0.27)

Foetal/neonatal outcomes

Mean (SD) gestational age (wks): 38 (0.25) vs. 38 (0.24)

Preterm (< 37 wks): RR 0.97 (95% CI 0.75, 1.24)

Large for gestational age (LGA): RR 0.99 (95% CI 0.85, 1.14)

Small for gestational age (SGA): RR 1.21 (95% CI 0.53, 2.81)

Shoulder dystocia: RR 0.78 (95% CI 0.31, 1.94)

Respiratory distress: RR 0.78 (95% CI 0.52, 1.17)

Neonatal hypoglycemia: RR 1.14 (95% CI 0.89, 1.46)

Mean (SD) birth weight (gm): 3495 (196.2) vs. 3495 (205.7)

APGAR < 7 (at 5 min): RR 0.79 (95% CI 0.35, 1.76)

Neonatal sepsis: RR 1.40 (95% CI 0.63, 1.53)

Stillbirth: RR 0.37 (95% CI 0.08, 1.65)

Perinatal mortality: RR 0.61 (95% CI 0.20, 1.80)

Spontaneous abortion: RR 1.25 (95% CI 0.84, 1.86)

Congenital malformation: RR 0.83 (95% CI 0.45, 1.55)

Bartal et al. (2020) [30]

Retrospective cohort

USA

Women with singleton gestation and type 2 diabetes; gestational diabetes mellitus (GDM) diagnosed before 20 weeks gestation; majority aged 20–34 yrs (55%); BMI ≥ 30 kg/m2 (> 75%); 80% multiparous

Insulin analogues (glargine and detemir)

233 (114-basal insulin analogues; 119- neutral protamine Hagedorn)

Maternal outcomes

Symptomatic hypoglycaemia: RR 0.72 (95% CI 0.35, 1.45)

Hypertensive disorder: RR 0.99 (95% CI 0.63, 1.55)

Caesarean section: RR 0.93 (95% CI 0.75, 1.15)

Endometritis: RR 2.09 (95% CI 0.39, 11.2)

Wound infection or dehiscence: RR 0.10 (95% CI 0.02, 0.80)

Hospitalization for glucose control: RR 1.26 (95% CI 0.76, 2.08)

Induction of labour: RR 0.89 (95% CI 0.57, 1.37)

Hospitalization during pregnancy: RR 1.37 (95% CI 0.92, 2.05)

Foetal/neonatal outcomes

Mean (SD) gestational age (wks): 36.2 (2.1) vs. 36.1 (2.5)

Preterm (< 37 wks): RR 0.93 (95% CI 0.68, 1.26)

Large for gestational age (LGA): RR 1.56 (95% CI 0.89, 2.73)

Shoulder dystocia: RR 1.39 (95% CI 0.32, 6.08)

Admission to NICU: RR 1.06 (95% CI 0.77, 1.46)

Respiratory distress: RR 0.58 (95% CI 0.22, 1.55)

Need for mechanical ventilation: RR 0.68 (95% CI 0.14, 3.24)

Neonatal hypoglycemia: RR 1.30 (95% CI 0.88, 1.92)

Mean (SD) birth weight (gm): 3186.1 (751.9) vs. 2993.9 (800.6)

APGAR < 7 (at 5 min): RR 3.24 (95% CI 0.43, 24.53)

Neonatal sepsis: RR 0.42 (95% CI 0.08, 2.11)

Perinatal mortality: RR 1.89 (95% CI 0.27, 13.32)

Neonatal hyperbilirubinemia: RR 0.59 (95% CI 0.34, 1.05)

Herrera et al. (2015) [31]

RCT

USA

Women with singleton gestation; type 2 diabetes (16%), remaining with type 1 diabetes (84%); in majority, GDM diagnosed after 24 weeks gestation (68%); median age of 35 years; Median BMI of 28 kg/m2

Detemir

87 (42-Detemir; 45- neutral protamine Hagedorn)

Maternal outcomes

Symptomatic hypoglycaemia: RR 0.74 (95% CI 0.39, 1.40)

Mean (SD) gestational weight gain (kg): 12.6 (6.9) vs. 12.9 (5.3)

Foetal/neonatal outcomes

Mean (SD) gestational age (wks): 38.9 (0.43) vs. 38.8 (0.25)

Mean (SD) birth weight (gm): 3230 (167.5) vs. 3235 (237.5)

Neonatal hypoglycemia: RR 0.21 (95% CI 0.01, 4.33)

Admission to NICU: RR 0.54 (95% CI 0.14, 2.00)

APGAR < 7 (at 5 min): RR 3.21 (95% CI 0.13, 76.6)

Hod et al. (2014) [32]

RCT

Multicentric

Women with singleton gestation and type 1 diabetes; mean age of 30 years; Mean BMI of 25 kg/m2

Detemir

310 (152-Detemir; 158- neutral protamine Hagedorn)

Maternal outcomes

Hypertensive disorder: RR 1.49 (95% CI 0.71, 3.09)

Caesarean section: RR 0.90 (95% CI 0.74, 1.11)

Foetal/neonatal outcomes

Mean (SD) gestational age (wks): 38.2 (1.9) vs. 37.8 (1.5)

Preterm (< 37 wks): RR 0.71 (95% CI 0.40, 1.26)

Large for gestational age (LGA): RR 0.74 (95% CI 0.46, 1.21)

SGA: RR 3.06 (95% CI 0.32, 29.1)

Neonatal hypoglycemia: RR 0.65 (95% CI 0.32, 1.30)

Mean (SD) birth weight (gm): 3504 (645) vs. 3571 (601)

Spontaneous abortion: RR 1.27 (95% CI 0.52, 3.14)

Perinatal mortality: RR 2.04 (95% CI 0.19, 22.3)

Congenital malformation: RR 1.02 (95% CI 0.39, 2.65)

Ji et al. (2020) [33]

RCT

China

Women with singleton gestation and type 1 diabetes; mean age of 31 years; Mean BMI of 25 kg/m2; mean gestational age at enrolment- 28 wks; type of diabetes (?)

Detemir

240 (120-Detemir; 120- neutral protamine Hagedorn)

Maternal outcomes

Symptomatic hypoglycaemia: RR 0.50 (95% CI 0.28, 0.90)

HbA1c in 3^rd trimester (Mean, SD): 5.66 (0.83) vs. 5.80 (0.81)

Hypertensive disorder: RR 0.61 (95% CI 0.33, 1.13)

Mean (SD) gestational weight gain (kg): 12.21 (3.84) vs. 11.99 (4.11)

Caesarean section: RR 1.05 (95% CI 0.87, 1.28)

Wound infection or dehiscence: RR 0.83 (95% CI 0.44, 1.57)

Foetal/neonatal outcomes

Mean (SD) gestational age (wks): 38.64 (2.19) vs. 38.15 (3.05)

Preterm (< 37 wks): RR 0.83 (95% CI 0.44, 1.58)

Large for gestational age (LGA): RR 1.00 (95% CI 0.43, 2.31)

Admission to NICU: RR 0.92 (95% CI 0.63, 1.35)

Respiratory distress: RR 1.00 (95% CI 0.21, 4.85)

Neonatal hypoglycemia: RR 0.50 (95% CI 0.18, 1.42)

Mean (SD) birth weight (gm): 3257.6 (496.6) vs. 3179.7 (671.8)

Congenital malformation: RR 1.00 (95% CI 0.21, 4.85)

Neonatal hyperbilirubinemia: RR 0.91 (95% CI 0.69, 1.21)

Mathiesen et al. (2012) [34]

RCT

Multicentric

Women with singleton gestation and type 1 diabetes; mean age of 30 years; Mean BMI of 25 kg/m2; women with type 1 diabetes

Detemir

310 (152-Detemir; 158- neutral protamine Hagedorn)

Maternal outcomes

Symptomatic hypoglycaemia: RR 1.11 (95% CI 0.89, 1.38)

HbA1c in 3rd trimester (Mean, SD): 6.39 (0.71) vs. 6.44 (0.68)

Mean (SD) gestational weight gain (kg): 11.5 (2.5) vs. 11.0 (2.84)

Sleeman et al. (2019) [35]

Retrospective cohort

USA

Women with singleton gestation and type 2 diabetes (65%); mean age of 31 years; Mean HbA1c at enrolment of 8.0%

Insulin analogues (glargine and detemir)

63 (44-basal insulin analogues; 19- neutral protamine Hagedorn)

Maternal outcomes

Symptomatic hypoglycaemia: RR 1.73 (95% CI 0.21, 14.5)

HbA1c in 3rd trimester (Mean, SD): 6.3 (1.2) vs. 6.5 (1.3)

Hypertensive disorder: RR 0.37 (95% CI 0.08, 1.62)

Caesarean section: RR 0.96 (95% CI 0.65, 1.42)

Foetal/neonatal outcomes

Preterm (< 37 wks): RR 0.95 (95% CI 0.51, 1.76)

Large for gestational age (LGA): RR 0.74 (95% CI 0.21, 2.55)

Admission to NICU: RR 0.74 (95% CI 0.44, 1.23)

Respiratory distress: RR 0.66 (95% CI 0.27, 1.64)

Neonatal hypoglycemia: RR 1.72 (95% CI 0.91, 3.24)

Spontaneous abortion: RR 1.84 (95% CI 0.24, 14.4)

Neonatal hyperbilirubinemia: RR 0.66 (95% CI 0.27, 1.64)

Cianni et al. (2008) [36]

Retrospective cohort

Italy

Women with singleton gestation and type 1 diabetes; mean age of 30.5 years; Mean BMI at enrolment of 24 kg/m2

Glargine

101 (43-glargine; 58- neutral protamine Hagedorn)

Maternal outcomes

Symptomatic hypoglycaemia: RR 0.77 (95% CI 0.24, 2.47)

HbA1c in 1st trimester (Mean, SD): 6.77 (1.32) vs. 7.6 (1.09)

HbA1c in 3rd trimester (Mean, SD): 6.5 (0.79) vs. 6.5 (0.91)

Hypertensive disorder: RR 0.67 (95% CI 0.06, 7.2)

Caesarean section: RR 0.99 (95% CI 0.81, 1.22)

Mean (SD) gestational weight gain (kg): 14.1 (4.1) vs. 13.3 (4.4)

Foetal/neonatal outcomes

Large for gestational age (LGA): RR 1.07 (95% CI 0.68, 1.68)

Admission to NICU: RR 1.14 (95% CI 0.57, 2.30)

Neonatal hypoglycemia: RR 0.81 (95% CI 0.32, 2.05)

Congenital malformation: RR 0.87 (95% CI 0.15, 4.97)

Neonatal hyperbilirubinemia: RR 0.93 (95% CI 0.44, 1.98)

Egerman et al. (2009) [37]

Retrospective cohort

USA

Women with singleton gestation; type of diabetes not reported; mean age of 29 years; Mean BMI at enrolment of > 30 kg/m2; mean gestational age at enrolment (19 weeks); majority were multigravida

Glargine

114 (65-glargine; 49- neutral protamine Hagedorn)

Maternal outcomes

Hypertensive disorder: RR 2.01 (95% CI 0.85, 4.76)

HbA1c in 3rd trimester (Mean, SD): 7.04 (1.4) vs. 7.48 (2.09)

Caesarean section: RR 1.08 (95% CI 0.84, 1.40)

Mean (SD) gestational weight gain (kg): 13.06 (9.1) vs. 13.69 (10.6)

Foetal/neonatal outcomes

Admission to NICU: RR 0.98 (95% CI 0.93, 1.05)

Neonatal hypoglycemia: RR 1.19 (95% CI 0.64, 2.22)

Congenital malformation: RR 1.08 (95% CI 0.44, 2.63)

Respiratory distress: RR 0.75 (95% CI 0.23, 2.46)

Shoulder dystocia: RR 0.08 (95% CI 0.01, 1.53)

Mean (SD) gestational age (wks): 37.3 (2.8) vs. 37.7 (3.3)

Mean (SD) birth weight (gm): 3415 (1231) vs. 3351 (1083)

Neonatal hyperbilirubinemia: RR 1.68 (95% CI 0.98, 2.88)

Fang et al. (2009) [38]

Retrospective cohort

USA

Women with singleton gestation; type of diabetes not reported; mean age of 30 years; majority were multigravida

Glargine

112 (52-glargine; 60- neutral protamine Hagedorn)

Maternal outcomes

Symptomatic hypoglycaemia: RR 3.45 (95% CI 0.14, 82.9)

Hypertensive disorder: RR 0.29 (95% CI 0.03, 2.50)

Mean (SD) gestational weight gain (kg): 10.8 (8.1) vs. 11.6 (7.7)

Caesarean section: RR 0.87 (95% CI 0.63, 1.20)

HbA1c (%), third trimester: 6.55 (0.30) vs. 6.70 (0.21)

Foetal/neonatal outcomes

Mean (SD) gestational age (wks): 38 (1.0) vs. 37.5 (1.2)

Preterm (< 37 wks): RR 0.62 (95% CI 0.27, 1.44)

Large for gestational age (LGA): RR 0.77 (95% CI 0.38, 1.56)

Admission to NICU: RR 0.32 (95% CI 0.09, 1.07)

Respiratory distress: RR 3.45 (95% CI 0.14, 82.9)

Neonatal hypoglycemia: RR 0.19 (95% CI 0.02, 1.55)

Mean (SD) birth weight (gm): 3501.3 (473.1) vs. 3296.4 (525.6)

APGAR < 7 (at 5 min): RR 0.38 (95% CI 0.04, 3.59)

Neonatal hyperbilirubinemia: RR 0.48 (95% CI 0.18, 1.27)

Imbergamo et al. (2008) [39]

Case–control

Italy

Women with singleton gestation; type 1 diabetes; mean age of around 27.5 years

Glargine

30 (15-glargine; 15- neutral protamine Hagedorn)

Maternal outcomes

Symptomatic hypoglycaemia: RR 0.71 (95% CI 0.29, 1.75)

Hypertensive disorder: RR 1.25 (95% CI 0.41, 3.77)

Mean (SD) gestational weight gain (kg): 12.4 (3.8) vs. 13.5 (3.9)

Caesarean section: RR 1.00 (95% CI 0.60, 1.66)

HbA1c (%), first trimester: 6.86 (0.95) vs. 7.79 (1.13)

HbA1c (%), second trimester: 6.16 (0.67) vs. 6.62 (0.80)

HbA1c (%), third trimester: 6.23 (0.86) vs. 6.47 (0.95)

Foetal/neonatal outcomes

Mean (SD) gestational age (wks): 36.42 (2.21) vs. 37.04 (1.27)

Large for gestational age (LGA): RR 1.75 (95% CI 0.64, 4.74)

Respiratory distress: RR 7.00 (95% CI 0.39, 124.8)

Neonatal hypoglycemia: RR 4.00 (95% CI 0.50, 31.7)

Mean (SD) birth weight (gm): 3278 (756) vs. 3503 (455)

APGAR < 7 (at 5 min): RR 9.00 (95% CI 0.53, 153.8)

Neonatal hyperbilirubinemia: RR 5.00 (95% CI 0.26, 96.1)

Negrato et al. (2010) [40]

Prospective cohort

Brazil

Women with singleton gestation; gestational diabetes mellitus (GDM) diagnosed between 24–28 weeks gestation; mean age of 30 years; women with both pregestational (n = 56) and gestational diabetes (n = 82); type of diabetes not specified

Glargine

138 (55-glargine; 83- neutral protamine Hagedorn)

Maternal outcomes

Symptomatic hypoglycaemia: RR 0.12 (95% CI 0.01, 2.00)

Hypertensive disorder: RR 0.28 (95% CI 0.09, 0.93)

Mean (SD) gestational weight gain (kg): 11.2 (9.4) vs. 10.6 (6.8)

Caesarean section: RR 0.99 (95% CI 0.92, 1.08)

HbA1c (%), third trimester: 6.1 (0.8) vs. 6.1 (0.8)

Foetal/neonatal outcomes

Mean (SD) gestational age (wks): 37.7 (1.43) vs. 36.6 (4.85)

Large for gestational age (LGA): RR 1.04 (95% CI 0.68, 1.58)

Small for gestational age (SGA): RR 0.30 (95% CI 0.02, 6.13)

Respiratory distress: RR 1.26 (95% CI 0.40, 3.92)

Neonatal hypoglycemia: RR 0.57 (95% CI 0.16, 2.04)

Mean (SD) birth weight (gm): 3450 (640) vs. 3300 (520)

APGAR < 7 (at 5 min): RR 0.50 (95% CI 0.02, 12.06)

Neonatal hyperbilirubinemia: RR 0.30 (95% CI 0.04, 2.51)

Preterm (< 37 wks): RR 0.78 (95% CI 0.46, 1.32)

Admission to NICU: RR 0.41 (95% CI 0.12, 1.41)

Congenital malformation: RR 0.30 (95% CI 0.07, 1.33)

Perinatal mortality: RR 0.30 (95% CI 0.02, 6.13)

Poyhonen-Alho et al. (2007) [41]

Retrospective chart review

Finland

Pregnant women with singleton pregnancy and type 1 diabetes; women in both groups did not differ in age, parity, age at

diagnosis or duration of diabetes, or occurrence

of retinopathy or nephropathy before pregnancy

Glargine

91 (42-glargine; 49- neutral protamine Hagedorn)

Maternal outcomes

Symptomatic hypoglycaemia: RR 2.33 (95% CI 0.45, 12.1)

Hypertensive disorder: RR 0.58 (95% CI 0.19, 1.80)

Caesarean section: RR 1.03 (95% CI 0.69, 1.53)

HbA1c (%), first trimester: 7.6 (0.2) vs. 7.2 (0.3)

HbA1c (%), second trimester: 6.7 (0.1) vs. 6.8 (0.3)

HbA1c (%), third trimester: 6.9 (0.1) vs. 6.9 (0.2)

Foetal/neonatal outcomes

Mean (SD) gestational age (wks): 36.0 (0.85) vs. 37.0 (0.50)

Respiratory distress: RR 2.04 (95% CI 0.64, 6.49)

Neonatal hypoglycemia: RR 0.82 (95% CI 0.45, 1.52)

Mean (SD) birth weight (gm): 3796 (101) vs. 3789 (68)

Neonatal hyperbilirubinemia: RR 0.89 (95% CI 0.49, 1.61)

Preterm: RR 2.33 (95% CI 0.22, 24.8)

Congenital malformation: RR 3.49 (95% CI 0.15, 83.4)

Perinatal mortality: RR 1.17 (95% CI 0.08, 18.1)

Shoulder dystocia: RR 0.39 (95% CI 0.04, 3.60)

Neonatal sepsis: RR 1.16 (95% CI 0.17, 7.93)

Price et al. (2007) [42]

Case-control

UK

Women with singleton gestation with type 1 diabetes; mean age of around 32 years; Majority were pre-obese or obese (BMI > 25 kg/m2; majority were multigravida

Glargine

64 (32-glargine; 32- neutral protamine Hagedorn)

Maternal outcomes

HbA1c (%), third trimester: 6.2 (0.85) vs. 6.1 (0.60)

Foetal/neonatal outcomes

Mean (SD) gestational age (wks): 38.1 (0.47) vs. 38.1 (0.52)

Large for gestational age (LGA): RR 0.92 (95% CI 0.50, 1.70)

Respiratory distress: RR 7.00 (95% CI 0.38, 130.3)

Neonatal hypoglycemia: RR 1.33 (95% CI 0.65, 2.72)

Mean (SD) birth weight (gm): 3537 (520) vs. 3594 (429)

Congenital malformation: RR 0.67 (95% CI 0.12, 3.73)

Admission to NICU: RR 1.40 (95% CI 0.50, 3.95)

Smith et al. (2009) [43]

Retrospective chart review

USA

Women with singleton gestation; both type 1 and type 2 diabetes; age range of 25–35 years; majority were multigravida

Glargine

52 (27-glargine; 25- neutral protamine Hagedorn)

Maternal outcomes

Hypertensive disorder: RR 0.37 (95% CI 0.08, 1.74)

Caesarean section: RR 1.21 (95% CI 0.75, 1.95)

Foetal/neonatal outcomes

Mean (SD) gestational age (wks): 36.3 (0.96) vs. 37.0 (0.7)

Mean (SD) birth weight (gm): 3294 (189) vs. 3274 (137)

Admission to NICU: RR 1.08 (95% CI 0.42, 2.78)

APGAR < 7 (at 5 min): RR 2.78 (95% CI 0.12, 65.4)

Imbergamo et al. (2012) [44]

Case-control

Italy

Women with singleton gestation; type 1 diabetes; mean age of around 29 years

Detemir

16 (8-detemir; 8- neutral protamine Hagedorn)

Maternal outcomes

HbA1c (%), first trimester: 7.38 (0.99) vs. 7.60 (1.33)

HbA1c (%), second trimester: 6.58 (0.66) vs. 6.43 (0.77)

HbA1c (%), third trimester: 6.77 (1.24) vs. 6.32 (1.15)

Mean (SD) gestational weight gain (kg): 14 (3.8) vs. 14.46 (4.5)

Symptomatic hypoglycaemia: RR 3.00 (95% CI 0.39, 23.1)

Hypertensive disorder: RR 0.14 (95% CI 0.01, 2.38)

Foetal/neonatal outcomes

Mean (SD) gestational age (wks): 36.50 (0.92) vs. 37.35 (1.55)

Large for gestational age (LGA): RR 0.50 (95% CI 0.06, 4.47)

Mean (SD) birth weight (gm): 3326 (401) vs. 3489 (572)

Neonatal hyperbilirubinemia: RR 5.00 (95% CI 0.28, 90.2)