Metformin + Insulin vs. Insulin for GDM and T2DM during pregnancy: systematic review and meta-analysis

Hallack, Christiano; Nogueira, Bernardo Vieira; Bomfim, Maressa; Meireles, Nathália; Martins, Wellington

doi:10.61622/rbgo/2026rbgo18

Sumário Anterior Atual Seguinte

Sumário

Review article • Rev Bras Ginecol Obstet 48 • 2026 • https://doi.org/10.61622/rbgo/2026rbgo18 linkcopy

Metformin + Insulin vs. Insulin for GDM and T2DM during pregnancy: systematic review and meta-analysis

Authorship SCIMAGO INSTITUTIONS RANKINGS

Objective: Evaluate the effectiveness and safety of adding metformin to insulin (M+I) versus insulin alone for pregnant women with type 2 diabetes mellitus (T2DM) or gestational diabetes mellitus (GDM), focusing on stillbirth as the primary outcome.

Sources of data: PubMed, Embase, and Cochrane Central were searched. No date limits. Last search: January 2025.

Eligibility criteria: Randomized clinical trials including women with T2DM or GDM were eligible. Trials restricted to type 1 diabetes were excluded.

Data collection and synthesis: Two reviewers extracted maternal and neonatal outcomes and assessed risk of bias with the Cochrane RoB 2 tool. Evidence certainty was graded using GRADE. Data were pooled with random-effects models and reported as risk ratios (RRs) or mean differences (MDs) with 95% confidence intervals.

Results: Nine RCTs (2,420 women) were included, most with GDM and some with T2DM. Moderate-quality evidence indicated reduced stillbirth risk with M+I (6 RCTs, 2,196 participants; RR 0.36, 95% CI 0.14–0.90; NNT 111). Low-quality evidence suggested lower risks of gestational hypertension (4 RCTs; RR 0.68, 95% CI 0.48–0.97) and neonatal hypoglycemia (7 RCTs; RR 0.49, 95% CI 0.30–0.80). No significant differences were found for cesarean section, preterm delivery, or other neonatal outcomes. Heterogeneity, baseline imbalances, and small samples limited certainty.

Conclusions: M+I may reduce stillbirth and some adverse outcomes compared with insulin alone, but most evidence remains low certainty. Further high-quality RCTs are needed. Registered in PROSPERO: CRD42024617330

Keywords
Gestational diabetes mellitus; Type 2 diabetes mellitus; Pregnancy complications; Pregnancy outcome; Fetal outcome; Antidiabetic agents; Hypoglycemic agents

Study	Diabetes type	Participants		Inclusion (wk)		BMI		HbA1c
Study	Diabetes type	I+M	Insulin	I+M	Insulin	I+M	Insulin	I+M	Insulin
Studies starting both metformin and Insulin at randomization vs. Insulin only
Boggess et al. (MOMPOD) (2023)(³⁶)	T2DM	397	397	< 23		36.4±8.0	36.3±8.9	7.7±2.0	7.7±2
Ibrahim et al. (2014)*(³⁷)	GDM/T2DM	46	44	28.7±3.71		31.83±3.23		NI	NI
Feig et al. (2020)(³⁸) (MiTy)	T2DM	253	249	16.5±4.0	16.4±3.8	35.0 ± 7.1	35.0 ± 7.1	6.4±1.2	6.4±1.1
Studies starting metformin at randomization, adding insulin if poor glycemic control vs. Insulin only
Ainuddin et al. (2015)(³⁴)	T2DM	90	100	10.1±4.8	9.6±5.2	33.6±3.9	32.9±4.0	NI	NI
Ainuddin et al. (2015)(³⁵)	GDM	32	75	29.7±1,6	29.2±1,5	NI	NI	5.3±0.5	5.2±0.6
Ashoush et al. (2016)(³⁹)	GDM	11	48	NI	27.8±1.4	32.5±1.0	31.4±1.5	6.0±0.5	5.8±0.6
Dasari et al. (2023)(⁴⁰)	GDM	13	80	NI	NI	30.9	29.2±14	NI	NI
Ijäs et al. (2011)(⁴¹)	GDM	15	32	30±4.9	30±4.0	31.5±6.5	30.8±5.4	5.9±0.4	5.9±0.4
Rowan et al. (2008)(¹⁹) (MiG)	GDM	168	370	+ 20 days	30.1±3.2	36.7±9.3	34.6±7.2	5.9±0.7	5.9±0.4

Outcome	Participants	Relative effect	Absolute effects (95% CI)			NNT	Certainty
Outcome	(studies)	(95% CI)	Insulin	M+I	Difference	NNT	Certainty
Hypertension	1573	RR 0.68	90 per 1,000	61 per 1,000	29 fewer per 1,000	34	⨁⨁◯◯
Hypertension	(4 RCTs)	(0.48 to 0.97)		(43 to 87)	(from 47 fewer to 3 fewer)		Low ^a
Preeclampsia	1573	RR 1.07	104 per 1,000	112 per 1,000	7 more per 1,000	143	⨁◯◯◯
Preeclampsia	(4 RCTs)	(0.71 to 1.60)		(74 to 167)	(from 30 fewer to 63 more)		Very low ^f
Severe Maternal Hypoglicemia	1264	RR 1.03	13 per 1,000	13 per 1,000	0 fewer per 1,000		⨁◯◯◯
Severe Maternal Hypoglicemia	(2 RCTs)	(0.39 to 2.76)		(5 to 35)	(from 8 fewer to 22 more)		Very low ^f
Preterm Delivery	1814	RR 1.25	96 per 1,000	120 per 1,000	24 more per 1,000	42	⨁⨁◯◯
Preterm Delivery	(3 RCTs)	(0.95 to 1.64)		(91 to 158)	(from 5 fewer to 62 more)		Low ^b
Caesarean Section	1695	RR 0.88	630 per 1,000	555 per 1,000	76 fewer per 1,000	13	⨁◯◯◯
Caesarean Section	(6 RCTs)	(0.74 to 1.04)		(466 to 655)	(from 164 fewer to 25 more)		Very low ^f
Gestational Age at Delivery	1612				-0.07 weeks		⨁◯◯◯
Gestational Age at Delivery	(5 RCTs)				(-0.31 to 0.17 weeks)		Very low ^d
Stillbirth	2196	RR 0.36	14 per 1,000	5 per 1,000	9 fewer per 1,000	111	⨁⨁⨁◯
Stillbirth	(6 RCTs)	(0.14 to 0.90)		(2 to 13)	(from 12 fewer to 1 fewer)		Moderate ^a
Congenital Malformations	1282	RR 0.94	35 per 1,000	33 per 1,000	2 fewer per 1,000	500	⨁◯◯◯
Congenital Malformations	(3 RCTs)	(0.42 to 2.09)		(15 to 72)	(from 20 fewer to 38 more)		Very low ^f
Birthweight	1672				-0.1 kg		⨁◯◯◯
Birthweight	(6 RCTs)				(-0.25 to 0.04 kg)		Very low ^f
Small for Gestational Age	1559	RR 1.94	60 per 1,000	116 per 1,000	56 more per 1,000	18	⨁⨁◯◯
Small for Gestational Age	(4 RCTs)	(1.07 to 3.51)		(64 to 211)	(from 4 more to 151 more)		Low ^c
Large for Gestational Age	1638	RR 0.82	344 per 1,000	282 per 1,000	62 fewer per 1,000	16	⨁◯◯◯
Large for Gestational Age	(5 RCTs)	(0.65 to 1.04)		(223 to 358)	(from 120 fewer to 14 more)		Very low ^f
Macrossomia	629	RR 0.72	202 per 1,000	146 per 1,000	57 fewer per 1,000	18	⨁⨁◯◯
Macrossomia	(3 RCTs)	(0.51 to 1.03)		(103 to 208)	(from 99 fewer to 6 more)		Low ^b
Neonatal Death	1364	RR 1.72	4 per 1,000	7 per 1,000	3 more per 1,000	333	⨁◯◯◯
Neonatal Death	(3 RCTs)	(0.17 to 17.16)		(1 to 73)	(from 4 fewer to 68 more)		Very low^f
Neonatal Hypoglycemia	2263	RR 0.49	171 per 1,000	84 per 1,000	87 fewer per 1,000	11	⨁⨁◯◯
Neonatal Hypoglycemia	(7 RCTs)	(0.30 to 0.80)		(51 to 137)	(from 119 fewer to 34 fewer)		Low ^c
Respiratory Distress Syndrome	1584	RR 0.71	54 per 1,000	38 per 1,000	16 fewer per 1,000	63	⨁⨁◯◯
Respiratory Distress Syndrome	(5 RCTs)	(0.44 to 1.15)		(24 to 62)	(from 30 fewer to 8 more)		Low ^b
Transient Tachypnea of Newborn	835	RR 0.99	50 per 1,000	49 per 1,000	0 fewer per 1,000		⨁◯◯◯
Transient Tachypnea of Newborn	(3 RCTs)	(0.27 to 3.61)		(13 to 179)	(from 36 fewer to 129 more)		Very low ^e
NICU admission	1694	RR 0.72	377 per 1,000	271 per 1,000	105 fewer per 1,000	10	⨁◯◯◯
NICU admission	(6 RCTs)	(0.47 to 1.10)		(177 to 414)	(from 200 fewer to 38 more)		Very low ^d

location_on

Federação Brasileira das Sociedades de Ginecologia e Obstetrícia Av. Brigadeiro Luís Antônio, 3421, sala 903 - Jardim Paulista, 01401-001 São Paulo SP - Brasil, Tel. (55 11) 5573-4919 - Rio de Janeiro - RJ - Brazil
E-mail: editorial.office@febrasgo.org.br

rss_feed Acompanhe os números deste periódico no seu leitor de RSS

[TFN1] BMI = Body Mass Index (kg/m²); GMD = Gestational Diabetes Mellitus; HbA1c = Glycated Hemoglobin (%); T2DM = Type 2 Diabetes I+M = Insulin + Metformin; I only = Insulin only; NA = not available;

[TFN2] ^*
Trial conducted with patients who failed insulin at a dose of 1.12U/kg