# Metformin in Pregnancy: Fetal Consequences & Long-term Offspring Outcomes in a NHP Model

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $1,545,947

## Abstract

Metformin is prescribed to 50 million Americans annually, and is currently in widespread perinatal (pre-pregnancy,
during pregnancy, and post-natal) clinical use. Over the past decade, clinical indications and pragmatic use of metformin
have steadily expanded beyond the treatment of overt diabetes outside of pregnancy, and now include prediabetes and
obesity, polycystic ovary syndrome, type 2 diabetes, and gestational diabetes. With its expanded use, questions of
unintended long-term harm have arisen. The rationale underlying these concerns for metformin exposure during
development as a consequence of expanded maternal use arises from its basic pharmacodynamics and mechanisms of
action, which we and others hypothesize converge to disrupt important metabolic pathways during fetal life, which are
necessary to establish normal birth weight and appropriate early post-natal growth trajectory. When combined with a
maternal Western-style diet (WSD), fetal metformin exposure leads to accelerated early development of a pre-diabetic,
pre-obese phenotype with evidence of obesity and insulin resistance in early adolescence (puberty onset).
 We are inspired by our preliminary data to pursue development of a non-human primate model of maternal
metformin use. Powered as a three-armed mechanistic-based clinical study, we will determine the impact of metformin
or placebo exposure from pre-pregnancy through lactation on the development of obesity and insulin resistance. This
study is adequately powered to test the hypothesis that maternal metformin use in isolation or in conjunction with a
maternal high fat diet renders low birthweight and aberrant catch-up growth, driving obesity and insulin resistance in
the offspring by onset of puberty (approximately 3-4 years of age). In Aim 1, we will determine if early life metformin
exposure in control and/or WSD-fed dams leads to low birthweight and aberrant catch-up growth, resulting in obesity
and insulin resistance in pubertal juvenile offspring. In Aim 2, we will determine what the impact of metformin exposure
in WSD-fed dams is on maternal, fetal (G145) and juvenile (to puberty onset) metabolic physiology. This will include core
measures of maternal and fetal organ metabolism (liver, muscle, gut and pancreas). In Aim 3, we will determine
whether weaning offspring onto a control diet can ameliorate or mitigate the effects of maternal metformin exposure in
WSD-fed dams. Finally, in Aim 4 we will determine how early metformin exposure wields its molecular impact on control
and WSD-induced alterations of core measures of maternal and fetal metabolism in the liver, gut, muscle, and pancreas.
 Considering the recently emerged epidemiologic evidence and known mechanisms of actions of metformin, there is
a rational concern that rather than preventing developmental programming, metformin use during pregnancy may
have unintended consequences of accelerating obesity and the metabolic syndrome epidemic in the next generation.
Th...

## Key facts

- **NIH application ID:** 10364417
- **Project number:** 1R01DK128187-01A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Kjersti Marie Aagaard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,545,947
- **Award type:** 1
- **Project period:** 2021-09-17 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364417

## Citation

> US National Institutes of Health, RePORTER application 10364417, Metformin in Pregnancy: Fetal Consequences & Long-term Offspring Outcomes in a NHP Model (1R01DK128187-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10364417. Licensed CC0.

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