What is the teratogenicity risk of SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors during pregnancy?

SGLT2 Inhibitors Are Contraindicated During Pregnancy

SGLT2 inhibitors must not be administered during pregnancy or in women planning pregnancy due to significant risks of fetal harm, and should be discontinued immediately upon pregnancy recognition. 1

Guideline-Based Contraindications

The 2022 AHA/ACC/HFSA Heart Failure Guidelines explicitly state that SGLT2 inhibitors should not be administered to pregnant women or those planning pregnancy because of significant risks of fetal harm (Class 3 recommendation, Level of Evidence: C-LD). 1 This represents the highest level contraindication in guideline terminology.

Women with heart failure or cardiomyopathy who are of childbearing potential must receive counseling that SGLT2 inhibitors cannot be used during pregnancy and lactation as part of guideline-directed medical therapy discussions. 1

Mechanisms of Fetal Risk

Placental Transfer

• All three major SGLT2 inhibitors (empagliflozin, dapagliflozin, and canagliflozin) cross the placental barrier, achieving fetal-to-maternal concentration ratios of 0.38,0.67, and 0.62 respectively within 6 hours. 2
• This substantial placental transfer means the fetus is directly exposed to these medications at clinically relevant concentrations. 2

Renal Development Concerns

• Animal studies demonstrate that SGLT2 inhibitor exposure during periods corresponding to late second and third trimester human renal development causes renal pelvic and tubular dilatation. 3
• The critical exposure window in rats (postnatal days 21-90) corresponds to the period of human kidney maturation that extends through the second and third trimesters. 3

Placental Hormone Disruption

• SGLT2 inhibitors cause a statistically significant decrease in placental leptin secretion, which plays important roles in fetal growth and development. 2
• This hormonal disruption adds another mechanism of potential fetal harm beyond direct drug effects. 2

Human Pregnancy Outcome Data

Malformation Risk

A 2024 multinational cohort study (Nordic countries, US, Israel) examining periconceptional SGLT2 inhibitor exposure found:

• Standardized prevalence of major congenital malformations was 7.0% in SGLT2 inhibitor-exposed infants (n=335), compared to 3.7% in the general population and 5.3% in infants of mothers with type 2 diabetes. 4
• While the adjusted relative risk compared to insulin was 0.98 (95% CI: 0.65-1.46), the wide confidence interval reflects limited data and cannot exclude clinically meaningful harm. 4

Pharmaceutical Database Findings

• Inadvertent pregnancies during SGLT2 inhibitor use showed increased rates of miscarriages and congenital malformations in pharmaceutical safety databases. 3
• The systematic review identified only 76 human offspring with documented exposure, highlighting the severe paucity of safety data. 3

Clinical Management Algorithm

Preconception Planning

1. Discontinue SGLT2 inhibitors in all women planning pregnancy, regardless of diabetes type or cardiovascular indication. 1
2. Transition to pregnancy-safe alternatives (insulin is the preferred agent for diabetes management during pregnancy). 1
3. Ensure reliable contraception is in place for any woman of childbearing age prescribed SGLT2 inhibitors. 1

Inadvertent Exposure

1. Stop SGLT2 inhibitor immediately upon pregnancy recognition. 1
2. Switch to insulin-based regimen for glycemic control. 1
3. Arrange enhanced fetal monitoring given the documented placental transfer and potential renal effects. 2, 3
4. Consider detailed fetal anatomic ultrasound with attention to renal structures in the second trimester. 3

Lactation

• SGLT2 inhibitors are excreted in breast milk in animal studies and should be avoided during breastfeeding. 3
• No human data exist on breast milk excretion or effects on nursing infants. 3

Comparison to Other Teratogenic Risks

SGLT2 inhibitors fall into the same contraindication category as:

• ACE inhibitors and ARBs (known renal teratogens in second/third trimester). 1
• Mineralocorticoid receptor antagonists (contraindicated due to fetal harm). 1
• Statins (should be avoided in women of childbearing age not using reliable contraception). 1

Unlike thalidomide, which is "one of the most potent human teratogens known" with absolute contraindication, 5 SGLT2 inhibitors have less dramatic but still significant fetal risks that warrant complete avoidance during pregnancy.

Critical Pitfalls to Avoid

1. Do not continue SGLT2 inhibitors for their cardiovascular or renal benefits during pregnancy—the fetal risks outweigh maternal benefits, and pregnancy-safe alternatives exist. 1

2. Do not assume first-trimester-only exposure is safe—renal development concerns extend through the second and third trimesters. 3

3. Do not rely on the relatively reassuring 2024 cohort study as evidence of safety—the sample size was small (n=335), confidence intervals were wide, and the study could not exclude clinically meaningful harm. 4

4. Do not forget preconception counseling—women with diabetes or heart failure of childbearing age must understand SGLT2 inhibitors are incompatible with pregnancy before conception occurs. 1