Glucagon-like peptide-1 (GLP-1) receptor agonists

Major congenital malformations

id	Study   Auto Broe (Controls unexposed, general pop), 2025Broe (Controls unexposed, sick), 2025Chou, 2025Kolding - Semaglutide (Controls exposed to insulin), 2025Kolding - Semaglutide (Controls unexposed, general pop), 2025Cesta_Israel, 2024Cesta_Nordic, 2024Cesta_USA, 2024Dao (Controls exposed to metformin/insulin), 2024Dao (Controls unexposed, sick), 2024	Lib. in paper	Exposition period  Auto during pregnancy (anytime or not specified)1st trimester2nd trimester3rd trimester2nd and/or 3rd trimesterthroughout pregnancyearly pregnancydays before deliverylate pregnancypreconception-onlypericonceptionalpreconceptional for kinetic reasonat least 1st trimester3 months (or more) before pregnancy or during pregnancy1st and 2nd trimester3 months or more before pregnancy or1st trimesterPaternal exp. genotoxic window only (0–3 months preconception)Paternal exposure: epigenetic window only (3–xxx months preconception)Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception)Paternal exposure: other window	Study type  All studies Case control excluded Only case control	Control type    Auto unexposed (general population or NOS)unexposed, sickunexposed, disease freeexposed to other treatment, sicknot specifiedsiblingwhatever (meta-analysis)	Tags	OR 95%CI	x1/n1 x0/n0	no cases	no exposed	ROB	Ref.
S18789 R79975	Broe (Controls unexposed, general pop), 2025	Major congenital malformations (exclusion of chromosomal abnormalities (ICD-10 codes Q90– Q99))	1st trimester	population based cohort retrospective	unexposed (general population or NOS) excluded	Adjustment: Yes GLP1-RA indication: Mixed (Diabetes and/or Overweight) or Unspecified	3.46 [1.56;7.66] excluded (control group)	8/56   17,438/482,978	17,446	56		ref
S18790 R79978	Broe (Controls unexposed, sick), 2025	Major congenital malformations (exclusion of chromosomal abnormalities (ICD-10 codes Q90– Q99))	1st trimester	population based cohort retrospective	unexposed, sick	Adjustment: Yes GLP1-RA indication: Mixed (Diabetes and/or Overweight) or Unspecified	0.73 [0.20;2.68]	8/56   9/53	17	56		ref
S18797 R80001	Chou, 2025	Major congenital malformations (MCMs)	1st trimester	population based cohort retrospective	exposed to other treatment, sick	Adjustment: No GLP1-RA indication: Type 2 diabetes (T2D)	1.28 [0.05;31.69] C	0/68   1/260	1	68		ref
S18794 R79983	Kolding - Semaglutide (Controls exposed to insulin), 2025	Major malformations	1st trimester	retrospective cohort	exposed to other treatment, sick excluded	Adjustment: No GLP1-RA indication: Mixed (Diabetes and/or Overweight) or Unspecified	0.64 [0.12;2.15] excluded (control group)	3/32   76/547	79	32		ref
S18796 R79990	Kolding - Semaglutide (Controls unexposed, general pop), 2025	Major malformations	1st trimester	retrospective cohort	unexposed (general population or NOS)	Adjustment: No GLP1-RA indication: Mixed (Diabetes and/or Overweight) or Unspecified	1.24 [0.24;4.01]	3/32   7,985/103,843	7,988	32		ref
S18787 R79957	Cesta_Israel, 2024	Major congenital malformations (excluding fetal chromosomal abnormality)	1st trimester	retrospective cohort (claims database)	exposed to other treatment, sick	Adjustment: No GLP1-RA indication: Type 2 diabetes (T2D)	2.16 [0.72;6.45]	3/20   31/447	34	20		ref
S18785 R79949	Cesta_Nordic, 2024	Major congenital malformations (excluding fetal chromosomal abnormality)	1st trimester	population based cohort retrospective	exposed to other treatment, sick	Adjustment: No GLP1-RA indication: Type 2 diabetes (T2D)	0.59 [0.25;1.40]	5/110   245/3,164	250	110		ref
S18786 R79953	Cesta_USA, 2024	Major congenital malformations (excluding fetal chromosomal abnormality)	1st trimester	retrospective cohort (claims database)	exposed to other treatment, sick	Adjustment: No GLP1-RA indication: Type 2 diabetes (T2D)	1.06 [0.70;1.61]	30/331   136/1,583	166	331		ref
S18768 R79855	Dao (Controls exposed to metformin/insulin), 2024	Major birth defects (excluding genetic or chromosomal anomalies and those associated with intrauterine infections)	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: Yes GLP1-RA indication: Mixed (Diabetes and/or Overweight) or Unspecified	0.98 [0.16;5.82] excluded (control group)	3/117   3/128	6	117		ref
S18806 R80011	Dao (Controls unexposed, sick), 2024	Major birth defects (excluding genetic or chromosomal anomalies and those associated with intrauterine infections)	1st trimester	prospective cohort	unexposed, sick	Adjustment: Yes GLP1-RA indication: Mixed (Diabetes and/or Overweight) or Unspecified	0.54 [0.11;2.75]	3/117   5/127	8	117		ref
					Total	7 studies	1.00 [0.72;1.38]		8,464	734
x1: number of endpoints among exposed, n1: number of exposed; x0: number of endpoints among non exposed, n0: number of non exposed; C: calculated odds ratio from numbers of events and effectives

Forest plot

Sensitivity analysis

Publication bias and p-hacking diagnosis

Sub-groups analysis using all included studies

excluded 18768, 18789, 18794

Umbrella review (other published meta-analyses)