AC Dibbets,1,2,3 DTA Hiensch,1 VE Bukkems,1 HCJ Scheepers,2,3 SN de Wildt1,4,5 on behalf of Project MADAM working group
1. Department of Pharmacy, Pharmacology & Toxicology, Radboud University Medical Center, Nijmegen
2. Department of Gynecology and Obstetrics, Maastricht University Medical Center, Maastricht
3. GROW, Institute of Oncology and Reproduction, Maastricht University, Maastricht
4. Department of Paediatric and Neonatal Intensive Care, Erasmus MC Sophia Children’s Hospital, Rotterdam, The Netherlands
5. Department of Intensive Care, Radboud University Medical Center, Nijmegen, The Netherlands
caroline.dibbets@radboudumc.nl
Background: Metformin is used for the treatment of gestational diabetes and diabetes type 2 in pregnancy. Currently, pregnant patients receive a lower maximum daily dose (2000 mg) compared to nonpregnant individuals (3000 mg). Notably, physiological changes in pregnancy might result in antenatal exposure falling below therapeutic levels, which may necessitate (higher) dose adjustments. Project MADAM aims to develop an evidence-based dosing recommendation for metformin during pregnancy through a combination of evidence review and expert consensus.
Methods: Data on the safety and efficacy of metformin during pregnancy was collected, along pharmacokinetic data from existing literature, to develop antenatal doses using our previously developed Framework for Dose Selection in Pregnancy (FDSP). The FDSP and the proposed doses were reviewed by a multidisciplinary working committee of project MADAM, including various medical specialists, experts from other disciplines including pharmacology, reproductive toxicology and medical ethics, alongside patient representatives.
Results: Published pharmacokinetic studies, modeling and simulation show decreased metformin concentrations (20-35%) in the second and third trimester compared to non-pregnant individuals, mainly due to an increase in renal clearance. Safety studies show no significant risks associated with metformin use in pregnancy, although a possible risk of small-for-gestational-age infants cannot be ruled out. Aligning pregnancy dosing with nonpregnant adult dosing, which is already implemented in American guidelines, may enhance glycemic control. At the same time, titrating the metformin dosage to this maximum dose should not cause unnecessary delays in achieving glycemic control. The proposed doses were endorsed by the working committee and will be published on the Moeders van Morgen Lareb website and Farmacotherapeutisch Kompas.
Discussion/conclusion: Increasing the current maximum dosage of metformin during pregnancy may improve antenatal diabetes care by providing greater flexibility in diabetes management. This could potentially reduce the need for adjunct insulin therapy and offer an alternative when insulin is contraindicated or otherwise undesirable.