Metformin In Pregnancy

Author: Dr. Om J Lakhani

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Corresponding patient information Metformin in Pregnancy- What You Need to Know

Video Lecture:

• Q. What are the rationales for the use of metformin in pregnancy?

  • Treatment of Gestational Diabetes Mellitus (GDM)
  • Treatment of pregestational diabetes
  • Patients with PCOS becoming pregnant
  • Gestational obesity

• Q. What is the category for metformin in pregnancy?

  • Metformin is in pregnancy category B
  • This is the same as insulin
  • Category B is defined as:
    • "Either animal-reproduction studies have not demonstrated a fetal risk, but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters)."

• Q. Does first-trimester exposure to metformin produce congenital abnormalities?

  • No
  • Case-control study by Given et al. found no congenital abnormalities
  • There was the chance finding of increased pulmonary atresia, but this was more likely to be a chance finding
  • "No evidence was found for an increased risk of all non-genetic congenital anomalies combined following exposure to metformin during the first trimester, and the one significant association was no more than would be expected by chance. Further surveillance is needed to increase sample size and follow up the cardiac signal, but these findings are reassuring given the increasing use of metformin in pregnancy" ^[1]

• Q. Can metformin be used in the management of gestational obesity?

  • Rationale: Metformin can potentially prevent maternal weight gain and reduce the risk of GDM in pregnancy
  • RCT has shown that metformin does prevent maternal weight gain
  • Reduces the risk of preeclampsia
  • Also reduces the risk of neonatal ICU admission
  • However, it does not prevent GDM
  • It also does not reduce the risk for large for gestational age babies

Use of Metformin in Pregestational Diabetes

• Q. What is the MITY study?

  • This is the study done to see the effect of metformin in women with type 2 diabetes and pregnancy
  • This is an RCT
  • Women were already on insulin
  • Women were randomized to receive metformin 1 gram BD versus placebo added to insulin
  • The results were encouraging
  • The study found better glycemic control with the use of metformin and fewer large for gestational age infants
  • However, the risk of small for gestational age was increased

• Q. Overall, what is the understanding of metformin with regards to the size of infants?

  • Clearly, metformin produces smaller infants
  • But there might be a post-natal growth acceleration leading to large children at a later date

• Q. Which guidelines support the use of metformin for hyperglycemia in pregnancy?

  • NICE guidelines
  • Society for Maternal-Fetal Medicine

• Q. What are the benefits of the use of metformin in hyperglycemia in pregnancy?

  • Less pregnancy weight gain
  • Less hypoglycemia
  • Better patient acceptability
  • Reduces the risk of preeclampsia
  • Reduces the risk of preterm delivery

• Q. What are the benefits of metformin over insulin in hyperglycemia in pregnancy?

  • Lower large for gestational age babies
  • Less neonatal hypoglycemia
  • Less neonatal ICU admission

• Q. What are the biggest challenges with the use of metformin in pregnancy?

  • High rate of ineffectiveness as a form of treatment for hyperglycemia in pregnancy
    • 46% of women on metformin required insulin (Rowan et al. 2008)
  • Metformin does cross the placenta (however, it does not seem to have any adverse fetal effects)
  • Long-term impact is NOT known

• Q. Is metformin in pregnancy safe?

  • Yes
  • Conclusion from a meta-analysis of 6 RCTs has concluded that the use of metformin in pregnancy is safe

• Q. Does the metformin use in the first trimester of pregnancy associate with an increased risk of fetal teratogenicity?

  • No
  • Several studies and meta-analyses have been reassuring of this

• Q. What are the issues with PCOS women becoming pregnant?

  • The odds of several complications in pregnancy are more with women having PCOS compared to normal women
  • This makes continuing metformin in these women an attractive option

• Q. Does continuing or starting metformin in women with PCOS have any benefit?

  • The conclusion comes from an RCT by Vanky et al.
  • They found:
    • No effect of prevention of GDM in these women with metformin use (some other studies have shown that it does prevent GDM)
    • The main benefit was a reduction of preterm delivery
      • This is in contrast to other situations where the use of metformin is associated with higher preterm birth

• Q. What are the long-term impacts of the use of metformin in pregnancy when used in the context of hyperglycemia in pregnancy?

  • 18 months:
    • Children exposed to metformin are taller and heavier compared to their counterparts not exposed to metformin
    • No neurodevelopmental issues
  • 2 years:
    • Large skinfold thickness in children exposed to metformin in fetal life
    • But DEXA did not show a difference in fat percentage
  • 9 years:
    • Meta-analysis clearly shows that in utero exposure leads to heavier and taller children
    • Also, DEXA fat mass is more
    • Hence, since they are heavier and taller, the BMI z-scores were not different compared to the control
    • Main data from this meta-analysis comes from the MIG-TOFU study

• Q. Is metformin secreted in breast milk?

  • Yes

• Q. What is the MiG trial?

  • This is the most important trial comparing the use of metformin and insulin in GDM patients
  • 46% of patients on metformin did require insulin
  • However, the composite endpoint of perinatal outcomes was the same in the metformin and the insulin group
  • There was no adverse effect with the use of metformin
  • 70% of the women preferred using metformin over insulin

Metformin in Pregnancy - Summary and Conclusions

• Treatment of Gestational Diabetes Mellitus (GDM):

  • Use insulin as the first line of therapy
  • Metformin can be add-on therapy
  • This is as per guidelines
  • MiG trial may be useful here

• Treatment of Pregestational Diabetes:

  • MITY study
  • Found benefit of using insulin + metformin versus insulin + placebo
  • Must be used

• Patients with PCOS Becoming Pregnant:

  • Vanky et al. found no major benefit for the prevention of GDM and other parameters
  • In some parameters, it was useful
  • Can be used till the end of the first trimester then stopped

• Gestational Obesity:

  • There is no indication for use
  • Does not prevent GDM
  • No major benefit
  • Don't use

Recent updates 2024

Article Metformin Use in the First Trimester of Pregnancy

### Title of the Article

Metformin Use in the First Trimester of Pregnancy and Risk for Nonlive Birth and Congenital Malformations: Emulating a Target Trial Using Real-World Data

Authors

Yu-Han Chiu, MD, ScD; Krista F. Huybrechts, MS, PhD, et al.

One Line Summary

This study assesses the risks associated with the use of Metformin during the first trimester of pregnancy compared to switching to insulin, using observational data to emulate a target trial.

Key Points

1. The study utilized U.S. Medicaid healthcare administration data from 2000 to 2018, focusing on pregnant women with pregestational type 2 diabetes.

2. Women were assigned to either continue Metformin and initiate insulin or switch to insulin only within 90 days of their last menstrual period.

3. The risk for nonlive birth was slightly higher in the Metformin plus insulin group compared to insulin only, but within a statistically insignificant range.

4. The risk of congenital malformations was lower in the Metformin plus insulin group compared to the insulin-only group.

5. The study noted potential residual confounding due to variables like glycemic control and body mass index that could affect outcomes.

6. The findings suggest that continuing Metformin with added insulin in early pregnancy does not significantly increase the risk for nonlive births or congenital malformations.

Practical Take Home Message

For pregnant women with type 2 diabetes, continuing Metformin in addition to insulin in the first trimester may not increase the risk of nonlive births or congenital malformations significantly, challenging existing guidelines that recommend switching to insulin only.

Citation

Chiu YH, Huybrechts KF, Patorno E, et al. Metformin Use in the First Trimester of Pregnancy and Risk for Nonlive Birth and Congenital Malformations: Emulating a Target Trial Using Real-World Data. Ann Intern Med. [Epub ahead of print 18 June 2024] doi:10.7326/M23-2038.

Multiple-Choice Questions

1. Question: What is the pregnancy category for metformin, and what does it signify?
   A. Category A: No risk in human studies
   B. Category B: No fetal risk in animal studies, but no controlled studies in pregnant women
   C. Category C: Risk cannot be ruled out due to limited human studies
   D. Category D: Positive evidence of fetal risk
   Correct Answer: B

   Explanation: Metformin is classified as pregnancy category B, which means animal reproduction studies have not demonstrated a fetal risk, but there are no controlled studies in pregnant women. This classification is reassuring for its use in pregnancy.

2. Question: What does the MITY study reveal about the use of metformin in women with type 2 diabetes during pregnancy?
   A. Metformin increases the risk of large for gestational age infants
   B. Metformin improves glycemic control and reduces the risk of large for gestational age infants
   C. Metformin has no effect on glycemic control or infant size
   D. Metformin increases the risk of preterm delivery
   Correct Answer: B
   Explanation: The MITY study found that adding metformin to insulin in women with type 2 diabetes during pregnancy resulted in better glycemic control and fewer large for gestational age infants, although it increased the risk of small for gestational age infants.

3. Question: What is the primary benefit of continuing metformin in women with PCOS during pregnancy, according to the RCT by Vanky et al.?
   A. Prevention of gestational diabetes mellitus (GDM)
   B. Reduction in preterm delivery
   C. Prevention of preeclampsia
   D. Reduction in neonatal ICU admissions
   Correct Answer: B
   Explanation: The RCT by Vanky et al. found that the primary benefit of continuing metformin in women with PCOS during pregnancy was a reduction in preterm delivery, although it did not prevent GDM.