Metformin

in Pregnancy
Gestational Diabetes Mellitus

• Gestational diabetes mellitus (GDM), defined as glucose intolerance with onset or

first recognition during pregnancy, is a common pregnancy complication.

• During the past 20 years, its prevalence has increased substantially across a range
of multi-ethnic populations and is expected to continue to rise along with the
increase in prevalence of obesity.

Diabetes Care 2016;39:16–23

 Global estimates of hyperglycaemia in pregnancy in 2019

IDF 9th Edition 2019

Management of GDM
by Metformin:
Evidence in Science
 Metformin: A Wonder Drug

Maniar K, etal. Pharmacol Res. 2017 Mar;117:103-128.

 Metformin in Women's Health

• Mild Anti androgen

• Reduced weight gain
effect
• Reduced risk of
PCOS • Safety and efficacy
miscarriage GDM comparable to Insulin
• Second-Line ovulation • Reduced risk of
induction agent miscarriage
• Decreased OHSS with • Decreased neonatal
IVF hypoglycemia

Obstet Gynecol Surv. 2016 May;71(5):307-17.

Evidence
goes way
back in
Year 1994
science....

Seven women were treated with metformin during the first

trimester.
Study found NO major congenital
malformations in infants of diabetic women
treated with metformin at the time of
conception and during the first 8 weeks of
pregnancy

NO obvious indication for therapeutic

abortions in patients who have taken
metformin during embryogenesis
• Several RCTs, meta-analysis and observational studies have largely supported the
outcome with metformin.

• Ease of its use, acceptability by the patients, significantly less maternal weight
gain and less maternal hypoglycemia, as evident from these studies, appears a lot
encouraging

IJEM Mar-Apr 2015 / Vol 19 | Issue 2

 42 clinical trials 8956 patients with GDM
Estimated probability (%) of a treatment being the most effective in reducing the risk of
outcomes

Metformin found to be most effective in reducing the risk of complications

compared with Insulin or Glibenclamide
BMJ Open. 2017 Jun 24;7(6):e015557
Glycemic control with metformin vs insulin in the management of
gestational diabetes

Table 1:Mean capillary blood glucose levels in the different periods of the day

21% of women using insulin and 27% of women using metformin achieved
adequate glycemic control in the first week of treatment
Am J Obstet Gynecol 2013;209:34.e1-7.
Comparison of Newborn Outcomes in Women with Gestational
Diabetes Mellitus Treated with Metformin or Insulin

Figure 1:Neonatal outcomes in trial groups

Metformin can be an excellent alternative for insulin in the treatment of GDM with
fewer complications for fetuses and better maternal acceptance
Int J Prev Med. Mar 2013; 4(3): 327–333
Metformin treatment in the first trimester was associated with a statistically
significant 57% protective effect.

On the basis of the data in this analysis, there is no evidence of an increased risk for
major malformations when metformin is taken during the first trimester of pregnancy.

Gilbert, C., Valois, M. and Koren, G., 2006. Pregnancy outcome after first-trimester exposure to metformin: a meta-analysis. Fertility and sterility, 86(3), pp.658-
663.
First-trimester exposure to metformin was not associated
with an increased rate of major malformations.
Metformin can Cross the Placenta: Yes, so What!

Metformin was shown to be able to significantly cross the

placenta, with fetal concentrations in the range of half of
maternal concentrations.
Hague WM, et al: Metformin crosses the placenta: a modulator for fetal insulin resistance?
(Letter) Br Med J. 4 December 2003.

However, it does not stimulate insulin

secretion or release, and does not cause
hypoglycemia.
Metformin enhances insulin action,
stimulating glucose uptake in the liver
and in the periphery and also
suppressing hepatic glucose output.

Nguyen L, Chan SY, Teo AK. Metformin from mother to unborn child–Are there unwarranted effects?. EBioMedicine. 2018 Sep 1;35:394-404.
 Metformin: Helping in Getting Pregnant
Metformin useful in the insulin resistance syndrome and constitute an increasingly
popular treatment for polycystic ovarian syndrome, often inducing ovulation and
resulting in pregnancy.

Metformin Prevents Early

Pregnancy Loss
Metformin administration during
pregnancy reduces 1st trimester
pregnancy losses in women with
Polycystic ovary syndrome. 

Jakubowicz DJ et al. J Clin Endocrinol Metab 2002 Feb;87(2):524-9  

 The MiG Trial: 2008

• The Metformin in Gestational Diabetes (MiG) trial is a prospective randomized multicenter trial in
women with gestational diabetes mellitus (GDM).
• It includes 750 women with GDM from Australia and New Zealand.
• The trial started in October 2002.

In women with gestational diabetes mellitus, metformin (alone or with supplemental

insulin) is not associated with increased perinatal complications as compared with
insulin.
The women preferred metformin to insulin treatment.
 MiTy Study: 2020

• A Large study done at 25 Centres from Canada and Australia.

• Metformin Vs Placebo trial
• 502 Women randomized to metformin or placebo

Metformin has several maternal glycaemic and neonatal adiposity benefits.

MiTy Study: Results
Women in the metformin group achieved better glycaemic control and
required less insulin dose.

Women in the metformin group gained less overall weight and less weight
per week

Fewer women in the metformin group had caesarean sections

Fewer women reported serious adverse events in the metformin group than
in the placebo group

No difference between women who received metformin and those receiving

placebo in a composite of neonatal morbidity and mortality. 
 In a large international, population based database, no evidence was
found of an overall increased risk of congenital anomalies after first
trimester metformin exposure

Given JE, Loane M, Garne E, et al. Metformin exposure in first trimester of pregnancy and risk of all or specific congenital anomalies: exploratory case-control
study. BMJ. 2018;361:k2477. Published 2018 Jun 25. doi:10.1136/bmj.k2477
• Without metformin the 40 women had 100
pregnancies with 34 (34%) live births and 62 (62%)
first trimester spontaneous abortions (SAB).
• On metformin, the 40 women had 46 pregnancies,
47 fetuses (one twin pregnancy, six women with
two singleton pregnancies, 33 women with one
singleton pregnancy).
• Metformin reduced first trimester SAB from 62 to
26%.
• A register-based cohort study
• A total of 10129 children with maternal exposure to
metformin, insulin or both fulfilled the criteria for inclusion.

This study found no increased long-term risk associated with pregnancy exposure
to metformin (alone or in combination with insulin), compared with insulin.

Brand KMG, Saarelainen L, Sonajalg J, et al.. BMJ Open Diab Res Care 2022;10:e002363. doi:10.1136/bmjdrc-2021-002363
Guidelines: What do They Say?

• The National Institute for Health and Clinical Excellence suggests metformin as the
first-line drug in GDM.
• The World Health Organization, Australian Obstetrics and Gynecological Society,
International Diabetes Federation (2009) and Canadian Diabetes Association
guidelines currently recommend the use of metformin in settings where insulin
administration has logistic or compliance issues.

Guidelines are being modified to include Metformin in GDM, as more and

more data is being made available.
• Women with diabetes may be advised to use metformin as an adjunct or alternative to
insulin in the preconception period and during pregnancy, when the likely benefits from
improved blood glucose control outweigh the potential for harm.
• Offer metformin to women with gestational diabetes if blood glucose targets are not met
using changes in diet and exercise within 1–2 weeks.
• Offer addition of insulin to the treatments of changes in diet, exercise and metformin for
women with gestational diabetes if blood glucose targets are not met.
GDM: Management During Pregnancy 2018

• Insulin first-line
• May use aspart, lispro, glulisine: perinatal outcomes similar
• Metformin may be used as an alternative to insulin
• Good safety data in pregnancy
• Evidence of less maternal weight gain, less large-for-gestational-age, less
neonatal hypoglycemia
• Women should be informed that it crosses the placenta
• Safety data in offspring postpartum up to 2 years
• Insulin necessary in 40% on metformin

2018 Diabetes Canada CPG – Chapter 36. Diabetes and Pregnancy

FIGO Guidelines 2017

Dahiya, Krishna. "New FIGO Guidelines on Gestational Diabetes [24P]." Obstetrics & Gynecology 129.5 (2017): S170.
Metformin in GDM according to ADA 2021

• Metformin as compared to insulin was associated with:

 Lower risk of neonatal hypoglycemia

 Less maternal weight gain

• Metformin readily crosses the placenta

 Resulting in umbilical cord blood levels of metformin as high or higher than simultaneous maternal
levels
Metformin
• Safe and no risks of hypolygemia
• Compliant with patients for oral therapy
• Benefits and protective effects in
pregnancy
Insulin
• Associated with hypoglycemia and
weight gain
• Sometimes, fear of injections
• Uncontrolled low blood glucose levels

Choices???
?
Advantages of Metformin as Oral Therapy

• Insulin therapy is associated with:

• - The fear of injections (particularly when multiple).
• - The issue of compliance.
• - The risks of hypoglycemia.
• - The increase in appetite and weight.

Metformin Successfully overcomes all the drawbacks

with injectable therapy
Summary of evidence

GDM
• Good safety profile in mothers
• Reduced rates of severe hypoglycaemia (< 1.6 mmol/l) vs other agents
• Reduced pregnancy weight gain vs insulin
• Similar effects on newborn health vs insulin

Long-term • No differences in BP
effects in
• No differences in motor, social and linguistic development at 18 months
offspring

Fetal • No convincing evidence for increase in congenital malformations or miscarriage

effects • Longterm effects on health or metabolism during adulthood not known
Thank You