Progesterone Side Effects in Pregnancy
Progesterone therapy in pregnancy has an excellent safety profile with no significant long-term adverse effects on children or increased risk of major congenital anomalies, though maternal side effects like drowsiness, dizziness, and headaches are common. 1, 2
Safety Profile for the Fetus
Long-term follow-up studies demonstrate no developmental concerns:
- Children exposed to progesterone in utero showed no differences in physical examination, health status, or developmental performance (motor, problem-solving, personal-social skills) at 4-year follow-up compared to placebo 1
- Multiple studies have failed to detect long-term adverse effects from intrauterine progesterone exposure, even when administered in the first trimester 1
Important caveat regarding congenital anomalies:
- The FDA drug label lists rare cases of cleft palate, cleft lip, hypospadias, ventricular septal defect, patent ductus arteriosus, and other congenital heart defects 2
- However, these represent isolated case reports without established causal relationship, and the overall evidence base shows no increased risk in controlled trials 1
Common Maternal Side Effects
Frequent but generally mild side effects include: 2
- Drowsiness and dizziness (most common, particularly with oral formulations)
- Headaches
- Breast pain or tenderness
- Irregular vaginal bleeding or spotting
- Stomach or abdominal cramps and bloating
- Nausea and vomiting
- Fluid retention
- Vaginal yeast infection
- Hair loss
Critical safety warning for oral progesterone: 2
- Some women experience extreme dizziness and/or drowsiness during initial therapy
- In rare cases, symptoms may include blurred vision, difficulty speaking, difficulty walking, and feeling abnormal
- Patients should take oral progesterone at bedtime while standing with a full glass of water
- Caution is required when driving or operating machinery
Serious but Rare Side Effects
Thromboembolic events (very rare): 2
- Stroke
- Heart attack
- Pulmonary embolus
- Visual loss or blindness
Warning signs requiring immediate medical attention: 2
- Changes in vision or speech
- Sudden new severe headaches
- Severe chest or leg pain with or without shortness of breath
- Weakness and fatigue
- Dizziness and faintness
- Vomiting
Route-Specific Considerations
Vaginal progesterone (90-mg gel or 200-mg suppository):
- Generally better tolerated than oral formulations 1
- Lower systemic side effects due to first-uterine-pass effect
- Local side effects may include vaginal discharge or irritation
Intramuscular 17-hydroxyprogesterone caproate (17P):
- Injection site reactions possible 1
- Systemic side effects similar to other formulations but may be less pronounced than oral
Oral micronized progesterone:
- Highest incidence of drowsiness and dizziness 2
- Must be taken at bedtime to minimize impact on daily activities
Contraindications and Precautions
Allergy warning: 2
- Progesterone capsules contain peanut oil
- Contraindicated in patients with peanut allergy
Risk factors requiring closer monitoring: 2
- History of thromboembolic disease
- High blood pressure
- High cholesterol
- Diabetes
- Obesity
- Tobacco use
Clinical Context for Safety
The safety profile supports use in appropriate clinical scenarios:
- Progesterone is recommended for singleton pregnancies with prior preterm birth (17P 250 mg IM weekly from 16-20 weeks until 36 weeks) 1
- Vaginal progesterone is recommended for singleton pregnancies with short cervical length ≤20 mm at 18-24 weeks 1
- Not recommended for multiple gestations, active preterm labor, or preterm premature rupture of membranes, as efficacy has not been demonstrated in these populations 1
Key pitfall to avoid:
The evidence for progesterone safety comes primarily from its use in preterm birth prevention protocols. Extrapolating safety data to other uses (such as threatened miscarriage in women without prior losses) requires caution, as the risk-benefit profile may differ 3, 4.