Metformin in pregnancy and risk of abnormal growth outcomes at birth: a register-based cohort study.

INTRODUCTION: We previously reported an increased risk of being small for gestational age (SGA) and a decreased risk of being large for gestational age (LGA) after in utero exposure to metformin compared with insulin exposure. This follow-up study investigated if these observations remain when metformin exposure (henceforth, metformin cohort) is compared with non-pharmacological antidiabetic treatment of gestational diabetes mellitus (GDM; naïve cohort), instead of insulin. RESEARCH DESIGN AND METHODS : This was a Finnish population register-based cohort study from singleton children born during 2004-2016. Birth outcomes from metformin cohort (n=3964) and the naïve cohort (n=82 675) were used in the main analyses. Additional analyses were conducted in a subcohort, restricting the metformin cohort to children of mothers with GDM only (n=2361). Results were reported as inverse probability of treatment weighted OR (wOR), with the naïve cohort as reference. RESULTS  : No difference was found for the outcome of SGA between the cohorts in the main analyses (wOR 0.97, 95% CI 0.73 to 1.27) or in the additional analyses (wOR 1.01, 95% CI 0.75 to 1.37). No difference between the cohorts was found for the risk of LGA (wOR 0.91, 95% CI 0.75 to 1.11) in the main analyses but a decreased risk was observed in the additional analyses (wOR 0.72, 95% CI 0.56 to 0.92). CONCLUSIONS : This follow-up study found no increase in the risk of SGA or LGA after in utero exposure to metformin, compared with drug-naïve GDM. The decreased risk of LGA in mothers with GDM may suggest residual confounding. The lack of increased SGA risk aligns with findings from studies using metformin in non-diabetic pregnancies. In contrast, lower birth weight and increased SGA birth risk were observed in GDM pregnancies for metformin versus insulin. Metformin should be avoided with emerging growth restriction in utero. The interplay of intrauterine hyperglycemia and pharmacological treatments needs further assessment.

Quality and Characteristics of 4241 Case Reports of Lactic Acidosis in Metformin Users Reported to a Large Pharmacovigilance Database.

Objective: Metformin-associated lactic acidosis (MaLA) occurs rarely and is thus difficult to study. We analysed 4241 individual case safety reports of lactic acidosis (LA) that implicated metformin as a suspected drug reported to the pharmacovigilance database of Merck KGaA, Darmstadt, Germany. The primary objective was to review reports for quality and completeness of data to support diagnoses of MaLA. We also explored the correlations between reported biomarkers, and associations between biomarkers and outcomes. Research Design and Methods: Records were analysed for completeness in supporting diagnoses of LA or metformin-associated LA (MaLA), against commonly used diagnostic criteria. Correlations between indices of exposure to metformin and biomarkers of LA and mortality were investigated. Results: Missing data was common, especially for plasma metformin. Clinical/biomarker evidence supported a diagnosis of LA in only 33% of cases (LA subpopulation) and of MaLA in only 9% (MaLA subpopulation). The metformin plasma level correlated weakly with plasma lactate (positive) and pH (negative). About one-fifth (21.9%) of cases reported a fatal outcome. Metformin exposure (plasma level or dose) was not associated with increased mortality risk (there was a suggestion of decreased risk at higher levels of exposure to metformin). Plasma lactate was the only variable associated with increased risk of mortality. Examination of concomitant risk factors for MaLA identified renal dysfunction (including of iatrogenic origin) as a potential driver of mortality in this population. Conclusion: Despite the high frequency of missing data, this is the largest analysis of cases of MaLA supported by measurements of circulating metformin, and lactate, and pH, to date. Plasma lactate, and not metformin dose or plasma level, appeared to be the main driver of mortality in the setting of LA or MaLA. Further research with more complete case reports is required.

Metformin in pregnancy and risk of adverse long-term outcomes: a register-based cohort study.

INTRODUCTION: This study aimed to investigate if maternal pregnancy exposure to metformin is associated with increased risk of long-term and short-term adverse outcomes in the child. RESEARCH DESIGN AND METHODS : This register-based cohort study from Finland included singleton children born 2004-2016 with maternal pregnancy exposure to metformin or insulin (excluding maternal type 1 diabetes): metformin only (n=3967), insulin only (n=5273) and combination treatment (metformin and insulin; n=889). The primary outcomes were long-term offspring obesity, hypoglycemia, hyperglycemia, diabetes, hypertension, polycystic ovary syndrome, and challenges in motor-social development. In a sensitivity analysis, the primary outcomes were investigated only among children with maternal gestational diabetes. Secondary outcomes were adverse outcomes at birth. Analyses were conducted using inverse- probability of treatment weighting (IPTW), with insulin as reference. RESULTS  : Exposure to metformin or combination treatment versus insulin was not associated with increased risk of long-term outcomes in the main or sensitivity analyses. Among the secondary outcomes, increased risk of small for gestational age (SGA) was observed for metformin (IPTW-weighted OR 1.65, 95% CI 1.16 to 2.34); increased risk of large for gestational age, preterm birth and hypoglycemia was observed for combination treatment. No increased risk was observed for neonatal mortality, hyperglycemia, or major congenital anomalies. CONCLUSIONS : This study found no increased long-term risk associated with pregnancy exposure to metformin (alone or in combination with insulin), compared with insulin. The increased risk of SGA associated with metformin versus insulin suggests caution in pregnancies with at-risk fetal undernutrition. The increased risks of adverse outcomes at birth associated with combination treatment may reflect confounding by indication or severity.