Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2022 Jan 28;17(1):e0262987.
doi: 10.1371/journal.pone.0262987. eCollection 2022.

Metformin exposure, maternal PCOS status and fetal venous liver circulation: A randomized, placebo-controlled study

Sindre Grindheim  1 , Cathrine Ebbing  1   2 , Henriette Odland Karlsen  1 , Svein Magne Skulstad  3 , Francisco Gómez Real  1   2 , Marianne Lønnebotn  3 , Tone Løvvik  4   5 , Eszter Vanky  4   5 , Jørg Kessler  1   2
Affiliations
Randomized Controlled Trial

Metformin exposure, maternal PCOS status and fetal venous liver circulation: A randomized, placebo-controlled study

Sindre Grindheim et al. PLoS One. .

Abstract

Background: Metformin is prescribed to women with polycystic ovary syndrome (PCOS) to prevent pregnancy complications. Children exposed to metformin vs. placebo in utero, have increased head circumference at birth and are more overweight and obese at 8 years of age. Also, maternal PCOS-status seems to alter the long-term cardio-metabolic health of offspring. We hypothesized that the long-term effects of metformin-exposure and/or maternal PCOS may be mediated by circulatory adaptations during fetal life.

Material and methods: This is a sub-study of a larger double-blinded, placebo-controlled trial, where women with PCOS were randomized to metformin (2g/day) or placebo in pregnancy, a total of 487 women. A sub-group of participants (N = 58) took part in this sub-study and had an extended ultrasound examination at gestational week 32, including blood flow velocity and diameter measurements of the umbilical vein (UV), the ductus venosus (DV) and the portal vein (PV). Blood flow volume was calculated and adjusted for estimated fetal weight (EFW) (normalized flow). Metformin exposed fetuses were compared to placebo exposed fetuses. Fetuses of mothers with PCOS (metformin [n = 30] and placebo [n = 28]) were compared to a low-risk reference population (N = 160) by z-score statistics.

Results: There was no difference in fetal liver flow between metformin vs. placebo-exposed fetuses. Fetuses of mothers with PCOS had higher EFW (0.63 [95% CI 0.44-0.83] p<0.001), lower normalized UV, DV, PV, and lower total venous liver blood flows than the reference population.

Conclusion: Metformin during pregnancy did not affect fetal liver blood-flow. In our population, maternal PCOS-status was associated with reduced total venous liver blood-flow, which may explain altered growth and metabolism later in life.

PubMed Disclaimer

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Flow chart of inclusion, randomization and dropout.
Fig 2
Fig 2. Illustration of fetal vessels and their changes in blood flow.
See this image and copyright information in PMC

References

    1. Lauritsen MP, Bentzen JG, Pinborg A, Loft A, Forman JL, Thuesen LL, et al.. The prevalence of polycystic ovary syndrome in a normal population according to the Rotterdam criteria versus revised criteria including anti-Mullerian hormone. Hum Reprod. 2014;29(4):791–801. doi: 10.1093/humrep/det469 - DOI - PubMed
    1. Palomba S, de Wilde MA, Falbo A, Koster MP, La Sala GB, Fauser BC. Pregnancy complications in women with polycystic ovary syndrome. Hum Reprod Update. 2015;21(5):575–92. doi: 10.1093/humupd/dmv029 - DOI - PubMed
    1. Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012;122(6):253–70. doi: 10.1042/CS20110386 - DOI - PMC - PubMed
    1. Bauer PV, Duca FA, Waise TMZ, Rasmussen BA, Abraham MA, Dranse HJ, et al.. Metformin Alters Upper Small Intestinal Microbiota that Impact a Glucose-SGLT1-Sensing Glucoregulatory Pathway. Cell Metab. 2018;27(1):101–17 e5. doi: 10.1016/j.cmet.2017.09.019 - DOI - PubMed
    1. Romero R, Erez O, Huttemann M, Maymon E, Panaitescu B, Conde-Agudelo A, et al.. Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. Am J Obstet Gynecol. 2017;217(3):282–302. doi: 10.1016/j.ajog.2017.06.003 - DOI - PMC - PubMed

Publication types