What are the risks of using Cox-2 (cyclooxygenase-2) inhibitors, such as celecoxib (Celebrex), during pregnancy?

COX-2 Inhibitors in Pregnancy: Risks and Recommendations

COX-2 inhibitors, such as celecoxib (Celebrex), are contraindicated during pregnancy, especially after 30 weeks gestation due to significant risks of premature closure of the fetal ductus arteriosus and should be avoided throughout pregnancy whenever possible. 1

Classification and Pregnancy Risk Category

• COX-2 inhibitors are classified as FDA Pregnancy Category C for the first and second trimesters, changing to Category D from 30 weeks of gestation onward 1
• These medications lack adequate well-controlled studies in pregnant women, with animal reproduction studies showing potential embryo-fetal risks 1

Specific Risks During Pregnancy

First and Second Trimester Risks:

• While not proven to be major teratogens, animal studies show COX-2 inhibitors can cause:
  • Embryo-fetal deaths 1
  • Diaphragmatic hernias in rats at doses approximately 6 times the maximum recommended human dose 1
  • Structural abnormalities including septal defects and skeletal malformations in rabbits 1
• COX-2 inhibitors may interfere with implantation and increase risk of early pregnancy loss by inhibiting prostaglandin synthesis 1, 2
• Limited human data from a prospective observational cohort study of 174 women exposed to coxibs in the first trimester did not show a significantly increased rate of major birth defects compared to unexposed women (2.9% vs. 2.7%) 3

Third Trimester Risks:

• Premature closure of the fetal ductus arteriosus, which can lead to pulmonary hypertension in the newborn 4, 1
• Reduced fetal renal blood flow potentially causing oligohydramnios and renal dysfunction 2, 5
• Prolongation of pregnancy and labor 2, 5
• Increased risk of bleeding due to antiplatelet effects 4, 6

Timing Considerations

• COX-2 inhibitors should be absolutely avoided after 30 weeks gestation due to FDA Category D classification 1
• The 2020 American College of Rheumatology guidelines conditionally recommend against using cyclooxygenase-2 specific inhibitors in the first two trimesters, suggesting nonselective NSAIDs if anti-inflammatory treatment is necessary 4
• If NSAIDs are required during pregnancy, they should be discontinued by gestational week 32 to prevent fetal complications 6

Alternative Approaches

• For pregnant women requiring anti-inflammatory treatment:
  • Low-dose glucocorticoids (≤10 mg daily of prednisone or equivalent) are conditionally recommended if clinically indicated 4
  • For rheumatic diseases, pregnancy-compatible DMARDs such as hydroxychloroquine, sulfasalazine, azathioprine, and certain biologics may be safer alternatives 4
  • Acetaminophen (paracetamol) is generally considered safer for pain and fever during pregnancy 7

Special Considerations

• COX-2 inhibitors may interfere with female fertility by delaying or preventing rupture of ovarian follicles 1
• Women planning pregnancy who are taking COX-2 inhibitors should discuss medication changes with their healthcare provider before conception 4
• In cases of inadvertent exposure during pregnancy, immediate consultation with maternal-fetal medicine specialists is strongly recommended 4

Clinical Decision-Making Algorithm

1. For women planning pregnancy:

   • Discontinue COX-2 inhibitors before conception 4
   • Transition to pregnancy-compatible medications if anti-inflammatory treatment is needed 4

2. For pregnant women currently taking COX-2 inhibitors:

   • Discontinue immediately and consult with maternal-fetal medicine specialist 4
   • Consider alternative medications based on indication and trimester 4

3. For pregnant women with inflammatory conditions requiring treatment:

   • First choice: Use pregnancy-compatible DMARDs if appropriate for the condition 4
   • Second choice: If NSAIDs are necessary, use nonselective NSAIDs rather than COX-2 inhibitors 4
   • Third choice: Low-dose glucocorticoids if other options are insufficient 4
   • Regardless of choice, all anti-inflammatory medications should be discontinued by 32 weeks gestation 6