What caused the fetal demise in a patient with polycystic ovary syndrome (PCOS) and dyslipidemia who was taking metformin?

Fetal Demise in PCOS Patient on Metformin: Likely Causes

The fetus most likely died from complications related to PCOS itself—particularly placental insufficiency, intrauterine growth restriction, or stillbirth—rather than from metformin exposure, though metformin should have been discontinued by the end of the first trimester and its continuation may have contributed to adverse outcomes.

Primary Risk Factors from PCOS

Women with PCOS face substantially elevated risks of pregnancy complications that can lead to fetal demise:

• Stillbirth risk is approximately 2-fold higher in women with underlying metabolic conditions similar to PCOS 1
• Placental abruption occurs at 2-2.6 times the rate of healthy pregnancies, which can cause acute fetal death 1
• Fetal distress is 1.35-3.55 times more common, depending on pregnancy characteristics 1
• Small for gestational age occurs 1.5-1.7 times more frequently, indicating chronic placental insufficiency 1

The combination of PCOS with dyslipidemia (hypertriglyceridemia and hypercholesterolemia) compounds these risks through vascular and placental dysfunction 2.

Metformin's Role and Contraindications

Metformin should have been discontinued by the end of the first trimester (12-13 weeks) when used solely for PCOS and ovulation induction 1, 3, 4.

Critical Contraindications That May Apply

If this patient developed any of the following conditions during pregnancy, continued metformin use was absolutely contraindicated and could have contributed to fetal demise:

• Hypertension or preeclampsia: Metformin should not be used due to potential for growth restriction or acidosis with placental insufficiency 1, 3, 4
• Risk factors for intrauterine growth restriction: Metformin is contraindicated 1, 3, 4
• Placental insufficiency: Metformin can worsen acidosis in this setting 1

Lack of Protective Benefit

Metformin does not prevent the pregnancy complications that lead to fetal demise in PCOS:

• No benefit in preventing gestational diabetes in high-risk women with PCOS, obesity, or insulin resistance 1, 4
• No benefit in preventing spontaneous abortion when used for ovulation induction 1, 3, 4
• Inconsistent evidence for preventing preeclampsia, with mixed results across studies 2, 5

Altered Fetal Circulation in PCOS

Recent evidence reveals that maternal PCOS status itself causes significant alterations in fetal liver blood flow that may predispose to adverse outcomes:

• Reduced total venous liver blood flow in fetuses of PCOS mothers compared to reference populations 6
• Lower normalized umbilical vein, ductus venosus, and portal vein flows 6
• These circulatory changes may explain altered fetal growth and metabolism, potentially contributing to fetal compromise 6

Importantly, metformin exposure did not affect these fetal liver blood flow parameters, suggesting the underlying PCOS pathophysiology—not metformin—drives these circulatory abnormalities 6.

Metformin's Fetal Effects

While metformin crosses the placenta freely (umbilical cord levels equal to or exceed maternal levels), it has not been directly linked to fetal demise 1, 3, 7:

• Metformin-exposed fetuses have larger head circumference at birth, particularly in offspring of overweight mothers 1, 8
• Smaller neonates with accelerated postnatal growth leading to higher childhood BMI 1
• No significant impact on placental or cerebral pulsatility indices that would indicate acute fetal compromise 9

Most Likely Sequence of Events

Based on the evidence hierarchy, the most probable causes of fetal demise in descending order are:

1. Placental abruption (2-2.6× increased risk in metabolic conditions) 1
2. Stillbirth from chronic placental insufficiency (2× increased risk, compounded by dyslipidemia) 1, 2
3. Severe fetal growth restriction leading to intrauterine demise (1.5-1.7× increased risk of SGA) 1
4. Acute fetal distress from PCOS-related complications (1.35-3.55× increased risk) 1
5. Worsening of placental insufficiency by continued metformin use if hypertension or preeclampsia developed 1, 3, 4

Critical Clinical Pitfall

The most common error is continuing metformin throughout pregnancy in PCOS patients when it was used solely for ovulation induction 3, 4. Randomized controlled trials demonstrate no benefit in preventing spontaneous abortion or gestational diabetes when metformin is continued beyond the first trimester 1, 3, 4, yet it exposes the fetus to a medication with concerning long-term metabolic effects 1.

The American Diabetes Association explicitly states there is no evidence-based need to continue metformin in PCOS patients once pregnancy is confirmed unless the patient has type 2 diabetes requiring ongoing treatment 1, 3.