Letters
COMMENT & RESPONSE 5. Lautatzis ME, Goulis DG, Vrontakis M. Efficacy and safety of metformin
Metformin Plus Insulin for Preexisting Diabetes
or Gestational Diabetes in Pregnancy
To the Editor The MOMPOD study1 revealed that for pregnant
individuals with preexisting type 2 or early gestational diabe-
tes, metformin, 1000 mg twice daily, starting before 23 weeks’
gestation and taken until delivery, did not reduce a compos-
ite adverse neonatal outcome but resulted in reduced num-
bers of large-for-gestational-age infants. However, we be-
lieve that safety issues regarding the long-term effects of
metformin on male infant fertility should also be considered.
Metformin is classified as US Food and Drug Administra-
tion pregnancy category B. However, prenatal exposure
of human fetal testicular cells to metformin may significantly
decrease testosterone secretion.2 Metformin concentration
in umbilical cord blood has been shown to be equal to the
concentration in maternal venous blood.3 The level of sex
hormone–binding globulin was increased in newborns fol-
lowing metformin exposure in the first trimester of preg-
nancy, which could result in lower free androgen indexes.3
The production of fetal androgen is critical for masculiniza-
tion of the fetal reproductive system and maintaining
gonocyte integrity.3 Therefore, metformin exposure during
fetal and neonatal periods could result in a reduction in tes-
ticular size, Sertoli cell numbers, and sperm count, and
may result in hypospadias and subinfertility. 4 Based on
available data, use of metformin during pregnancy is still
controversial,5 and further data are required to identify the
long-term effects of metformin on fetal testicular cells and
determine infertility rates among male infants who were
exposed to metformin during pregnancy. Therefore, in the
MOMPOD study, long-term monitoring of fertility in male
infants is highly recommended for the possible effects of
fetal exposure to metformin.
Fariba Pourkarim, PharmD
Taher Entezari-Maleki, PharmD
Author Affiliations: Faculty of Pharmacy, Tabriz University of Medical Sciences,
Tabriz, Iran (Pourkarim); Cardiovascular Research Center, Tabriz University of
Medical Sciences, Tabriz, Iran (Entezari-Maleki).
Corresponding Author: Taher Entezari-Maleki, PharmD, Department of
Clinical Pharmacy, Faculty of Pharmacy, Tabriz University of Medical Sciences,
PO Box 51664-14766, Tabriz 516567-9555, Iran (tentezari@gmail.com;
entezrim@tbzmed.ac.ir).
Published Online: April 3, 2024. doi:10.1001/jama.2024.1380
Conflict of Interest Disclosures: None reported.
1. Boggess KA, Valint A, Refuerzo JS, et al. Metformin plus insulin for
preexisting diabetes or gestational diabetes in early pregnancy: the MOMPOD
randomized clinical trial. JAMA. 2023;330(22):2182-2190. doi:10.1001/jama.
2023.22949
2. Tartarin P, Moison D, Guibert E, et al. Metformin exposure affects human and
mouse fetal testicular cells. Hum Reprod. 2012;27(11):3304-3314. doi:10.1093/
humrep/des264
3. Bertoldo MJ, Faure M, Dupont J, Froment P. Impact of metformin on
reproductive tissues: an overview from gametogenesis to gestation. Ann Transl
Med. 2014;2(6):55.
4. Nguyen L, Chan SY, Teo AKK. Metformin from mother to unborn child—are
there unwarranted effects? EBioMedicine. 2018;35:394-404. doi:10.1016/j.
ebiom.2018.08.047
1502 JAMA May 7, 2024 Volume 331, Number 17 (Reprinted)
© 2024 American Medical Association. All rights reserved.
Downloaded from jamanetwork.com by Royal College of Physicians, sangram Biradar on 05/08/2024
during pregnancy in women with gestational diabetes mellitus or polycystic
ovary syndrome: a systematic review. Metabolism. 2013;62(11):1522-1534.
doi:10.1016/j.metabol.2013.06.006
In Reply We thank Drs Pourkarim and Entezari-Maleki for
their thoughtful comment about our recent study 1 that
described outcomes following metformin plus insulin for the
treatment of early gestational and preexisting type 2 diabetes
in pregnancy. We agree that based on available data, the use
of metformin during pregnancy remains controversial and
that long-term health data following in utero exposure
should be collected prior to asserting that there are no unin-
tended negative health consequences in childhood or adult-
hood. About reproductive health in males, a 2022 review
article2 summarized the published data on the effect of met-
formin on male reproductive function, demonstrating that in
preclinical models, metformin appears to have a beneficial
effect on spermatogenesis and sperm motility. Whether this
translates in benefit or harm in young males will need to be
determined in long-term follow-up studies.
Kim A. Boggess, MD
for the MOMPOD Study PIs
Author Affiliation: Department of Obstetrics and Gynecology, University of
North Carolina at Chapel Hill School of Medicine, Chapel Hill.
Corresponding Author: Kim A. Boggess, MD, Department of Obstetrics and
Gynecology, University of North Carolina at Chapel Hill School of Medicine,
3010 Old Clinic Bldg/CB 7570, Chapel Hill, NC 27599-7570 (kboggess@med.
unc.edu).
Published Online: April 3, 2024. doi:10.1001/jama.2024.1383
Conflict of Interest Disclosures: None reported.
1. Boggess KA, Valint A, Refuerzo JS, et al. Metformin plus insulin for
preexisting diabetes or gestational diabetes in early pregnancy: the MOMPOD
randomized clinical trial. JAMA. 2023;330(22):2182-2190. doi:10.1001/jama.
2023.22949
2. Tseng CH. The effect of metformin on male reproductive function and
prostate: an updated review. World J Mens Health. 2022;40(1):11-29. doi:10.
5534/wjmh.210001
Noninvasive Airway Management of Comatose
Patients With Acute Poisoning
To the Editor A recent study1 suggested clinical benefits of non-
invasive airway management in comatose patients with acute
poisoning. An accompanying editorial lauded the study as a
practice-changing trial providing rigorous evidence.2 Al-
though we have recommended against indiscriminate intu-
bation of patients based on a low Glasgow Coma Scale (GCS)
score,3,4 we are concerned about the ability of this study1 to
provide conclusive evidence allowing a paradigm shift in clini-
cal practice.
The clinical benefit reported for the primary outcome was
driven by a reduced intensive care unit (ICU) admission rate and
consequently shorter ICU length of stay in the intervention
group.1,2 Given that patients receiving intubation typically re-
quire ICU care, the study’s design inevitably resulted in shorter
ICU stays for the intervention group. This finding, therefore,
does not justify avoiding intubation of intoxicated patients. It
would have been important to show that withholding intuba-
tion is safe and improves clinically relevant patient outcomes.
jama.com