Oral hypoglycaemic agents and pregnancy

There is evidence relating to maternal and neonatal complications in pregnancies of diabetic women treated with oral hypoglycaemic agents (1):

• a cohort study including all consecutively registered, orally treated pregnant diabetic patients set in a diabetic obstetrical service at a university hospital
  • 50 women treated with metformin, 68 women treated with sulphonylurea during pregnancy and a reference group of 42 diabetic women treated with insulin during pregnancy
  • the prevalence of pre-eclampsia was significantly increased in the group of women treated with metformin compared to women treated with sulphonylurea or insulin (32 vs. 7 vs. 10%, P < 0.001)
  • no difference in neonatal morbidity was observed between the orally treated and insulin-treated groups; no cases of severe hypoglycaemia or jaundice were seen in the orally treated groups. However, in the group of women treated with metformin in the third trimester, the perinatal mortality was significantly increased compared to women not treated with metformin (11.6 vs. 1.3%, P < 0.02)
    • the authors concluded that treatment with metformin during pregnancy was associated with an increased prevalence of pre-eclampsia and a high perinatal mortality
      
      
• however, a more recent systematic review concluded that there were no substantial maternal or neonatal outcome differences found with the use of glyburide or metformin compared with the use of insulin in women with gestational diabetes (2)
  
  
• a population-based case-control study found there was no evidence for an increased risk of all non-genetic congenital anomalies combined following exposure to metformin during the first trimester (3)
  
  
• NICE guidance states (4):
  • with respect to the use of metformin and glibenclamide in pregnancy:
    • metformin
      • although metformin is commonly used in UK clinical practice in the management of diabetes in pregnancy and lactation, and there is strong evidence for its effectiveness and safety (presented in the full version of the guideline), at the time of publication (February 2015) metformin did not have a UK marketing authorisation for this indication. The summary of product characteristics advises that when a patient plans to become pregnant and during pregnancy, diabetes should not be treated with metformin but insulin should be used to maintain blood glucose levels. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented
        
    • glibenclamide
      • at the time of publication (February 2015) glibenclamide was contraindicated for use up to gestational week 11 and did not have UK marketing authorisation for use during the second and third trimesters of pregnancy in women with gestational diabetes. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented

NICE has given guidance regarding the safety of diabetic medication pre-conceptually and during pregnancy and breastfeeding (4):

• oral hypoglycaemic agents
  • women with diabetes may be advised to use metformin as an adjunct or alternative to insulin in the pre-conception period and during pregnancy, when the likely benefits from improved glycaemic control outweigh the potential for harm. Glibenclamide may also be used during pregnancy (4). All other oral hypoglycaemic agents should be discontinued before pregnancy and insulin substituted
• insulin
  • the rapid-acting insulin analogues (aspart and lispro) are safe to use during pregnancy
    • healthcare professionals should be aware that data from clinical trials and other sources do not suggest that the rapid-acting insulin analogues (aspart and lispro) adversely affect the pregnancy or the health of the fetus or newborn baby (3)
  • women with insulin-treated diabetes who are planning to become pregnant should be informed that there is insufficient evidence about the use of long-acting insulin analogues during pregnancy. Therefore isophane insulin (also known as NPH insulin) remains the first choice for long-acting insulin during pregnancy. Consider continuing treatment with long-acting insulin analogues (insulin detemir or insulin glargine) in women with diabetes who have established good blood glucose control before pregnancy
• advice specific to gestational diabetes management:
  • hypoglycaemic therapy for women with gestational diabetes (which may include regular insulin, rapid-acting insulin analogues [aspart and lispro] and/or oral hypoglycaemic agents [metformin and glibenclamide]) should be tailored to the glycaemic profile of, and acceptability to, the individual woman
• breastfeeding
  • women with pre-existing type 2 diabetes who are breastfeeding can resume or continue to take metformin and glibenclamide immediately following birth but other oral hypoglycaemic agents should be avoided while breastfeeding
• angiotensin-converting enzyme inhibitors and angiotensin-II receptor antagonists
  • should be discontinued before conception or as soon as pregnancy is confirmed. Alternative antihypertensive agents suitable for use during pregnancy should be substituted
• statins
  • should be discontinued before pregnancy or as soon as pregnancy is confirmed

Metformin in pregnancy - evidence review (5)

• a systematic review/meta-analysis was undertaken
  • review (35 studies;n=8033 pregnancies) noted
    • lower gestational weight gain in pregnancies randomised to metformin (MF) vs. other treatments (p <0.0001)
      
      
    • lower likelihood of pre-eclampsia in MF (OR 0.69, 95% CI 0.50-0.95;p =0.02)
      
      
    • increased risk of GI side effects was greater in the MF group

Following a European review of data from a non-interventional cohort study of population registries in Finland (the CLUE study), the product information for metformin is being updated to permit the use of metformin during pregnancy and the periconceptional phase as an addition or an alternative to insulin, if clinically needed (6):

• results of the study were reassuring, with no safety signals of concern identified for the use of metformin in pregnancy relating either to those who were pregnant or their baby
• among secondary outcomes, similar rates of births that were small (low weight) for gestational age were observed with exposure to metformin and within the group of patients with untreated gestational diabetes
  • by contrast, an increased risk of small for gestational age was observed with exposure to metformin compared with insulin, which may relate to an overall increase in body weight due to the use of insulin

Reference:

1. Diabet Med. 2000 Jul;17(7):507-11
2. Nicholson W et al. Benefits and risks of oral diabetes agents compared with insulin in women with gestational diabetes: a systematic review.Obstet Gynecol. 2009 Jan;113(1):193-205
3. Given JE et al. Metformin exposure in first trimester of pregnancy and risk of all or specific congenital anomalies: exploratory case-control study.BMJ 2018; 361
4. NICE (February 2015). Diabetes in pregnancy Management of diabetes and its complications from pre-conception to the postnatal period
5. Tarry-Adkins JL, Ozanne SE, Aiken CE. Impact of metformin treatment during pregnancy on maternal outcomes: a systematic review/meta-analysis. Sci Rep. 2021 Apr 29;11(1):9240. doi: 10.1038/s41598-021-88650-5. PMID: 33927270; PMCID: PMC8085032
6. MHRA (March 2022). Metformin in pregnancy: study shows no safety concerns Drug Safety Update volume 15, issue 8: March 2022: 3.