NSAIDs in Pregnancy: A Clinical Decision-Making Framework for  Physician

Dr Neeraj Manikath , claude.ai  

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) represent one of the most commonly prescribed medication classes worldwide, yet their use during pregnancy presents significant clinical challenges. This review provides an evidence-based framework for internal medicine physicians managing pregnant patients who may require NSAID therapy, emphasizing gestational age-specific risks, alternative management strategies, and practical clinical pearls for optimizing maternal and fetal outcomes.

Introduction

The prescription of NSAIDs during pregnancy demands careful consideration of both maternal therapeutic needs and potential fetal harm. Approximately 30% of pregnant women report NSAID exposure during gestation, often before pregnancy recognition. Internal medicine physicians frequently encounter scenarios requiring NSAID consideration: the pregnant patient with rheumatoid arthritis flare, acute gout, or refractory migraine. Understanding the nuanced risk-benefit calculus is essential for contemporary practice.

Mechanism of Action and Pregnancy-Specific Concerns

NSAIDs exert their therapeutic effects through inhibition of cyclooxygenase (COX) enzymes, reducing prostaglandin synthesis. During pregnancy, prostaglandins play critical roles in maintaining uterine blood flow, regulating fetal renal function, and facilitating labor onset. COX-1 inhibition affects platelet function and gastric protection, while COX-2 inhibition influences inflammation, pain, and critically—ductus arteriosus patency and fetal renal perfusion.

The gestational age at exposure fundamentally determines the risk profile, creating distinct clinical windows requiring different management approaches.

Trimester-Specific Risk Assessment

First Trimester (Weeks 0-13)

Current Evidence: The teratogenic potential of NSAIDs during organogenesis remains controversial. Large epidemiological studies have shown conflicting results regarding cardiac malformations and orofacial clefts. A 2011 Danish cohort study of over 800,000 pregnancies found no increased risk of major malformations with first-trimester NSAID exposure. However, a Canadian case-control study suggested modest associations with cardiac septal defects (adjusted OR 1.86, 95% CI 1.32-2.62).

Clinical Pearl: The absolute risk increase, if present, remains small (background risk ~1%, potentially increased to 1.5-2%). Short-term exposure (fewer than 7 days) shows minimal association with adverse outcomes.

Miscarriage Risk: Meta-analyses suggest a 2.4-fold increased risk of spontaneous abortion with periconceptional NSAID use, though confounding by indication (pain or fever suggesting underlying pathology) complicates interpretation. This association appears strongest with indomethacin and least evident with low-dose aspirin.

Second Trimester (Weeks 14-27)

Relative Safety Window: The second trimester represents the least problematic period for NSAID exposure if clinically necessary. Organogenesis is complete, and the gestational age-dependent renal and cardiovascular complications of late pregnancy have not yet emerged.

Duration Matters: Short courses (less than 48 hours) for acute conditions carry minimal documented risk. Chronic use should still be avoided due to cumulative effects on amniotic fluid volume.

Hack for Practice: If an NSAID is absolutely necessary during pregnancy, the second trimester offers the optimal risk-benefit window. Document clear medical indication and plan for discontinuation by week 28.

Third Trimester: The High-Risk Period

After 30 Weeks: Contraindication Territory

FDA guidance (updated 2020) strengthens previous warnings, recommending NSAID avoidance after 20 weeks' gestation due to three principal concerns:

1. Premature Ductus Arteriosus Constriction

The ductus arteriosus becomes increasingly sensitive to prostaglandin inhibition with advancing gestation. Ductal constriction can occur within 48 hours of exposure, leading to right ventricular hypertrophy, tricuspid regurgitation, and potentially fetal death. Risk increases dramatically after 32 weeks.

A 2017 systematic review documented ductal constriction in 15% of fetuses exposed beyond 32 weeks, with most cases associated with indomethacin use exceeding 48 hours.

Oyster: Not all NSAIDs carry equal ductal risk. Indomethacin shows the highest association, while ibuprofen and naproxen carry moderate risk. COX-2 selective inhibitors (celecoxib) show similar ductus effects despite selective mechanism.

2. Oligohydramnios and Fetal Renal Dysfunction

Fetal kidneys become primary producers of amniotic fluid in the second half of pregnancy. NSAID-induced reduction in fetal renal blood flow can precipitate oligohydramnios, sometimes within 48-72 hours of exposure. This effect is usually reversible upon discontinuation but may lead to pulmonary hypoplasia if prolonged.

Clinical Hack: If oligohydramnios develops with NSAID exposure, discontinuation typically restores amniotic fluid within 1-2 weeks. Consider ultrasound monitoring if exposure exceeded 48 hours after 28 weeks.

3. Bleeding Risk and Labor Complications

Antiplatelet effects increase peripartum hemorrhage risk for both mother and neonate. NSAIDs can also delay labor onset and prolong gestation, occasionally necessitating this property for tocolysis in specific protocols (though safer alternatives now dominate).

NSAID Selection: When Truly Necessary

The Risk Hierarchy

When clinical circumstances demand NSAID consideration, understanding relative safety profiles guides selection:

Lowest Risk:

• Acetaminophen (paracetamol): Not an NSAID but the first-line analgesic/antipyretic throughout pregnancy. Maximum 4g daily, chronic use >28 days requires consideration of recent data suggesting possible neurodevelopmental effects, though evidence remains inconclusive.

Low-Moderate Risk (First/Second Trimester Only):

• Ibuprofen: Most extensively studied, preferable for short-term use. Dose 200-400mg every 6-8 hours, maximum 2400mg/day, discontinue by 28 weeks.
• Low-dose aspirin (81mg): Specifically indicated for preeclampsia prevention in high-risk patients, continued throughout pregnancy. Does not carry the same risks as therapeutic doses.

Moderate-High Risk:

• Naproxen: Longer half-life increases exposure duration, less preferred than ibuprofen.
• Ketorolac: Potent prostaglandin inhibition, avoid during pregnancy.
• Celecoxib: COX-2 selectivity does not confer fetal safety advantage.

Highest Risk/Avoid:

• Indomethacin: Most potent ductal effects, reserve only for specific indications (polyhydramnios, rarely for tocolysis) under specialist supervision with fetal monitoring.
• Aspirin (therapeutic doses >150mg): Increased bleeding risk without clear benefit in pregnancy.

Clinical Decision Algorithm

Step 1: Is the NSAID truly necessary?

• Consider acetaminophen adequacy
• Evaluate non-pharmacologic interventions
• Assess whether condition can be managed with pregnancy-safe alternatives

Step 2: What is the gestational age?

• <13 weeks: Avoid if possible; if essential, shortest duration, prefer ibuprofen
• 14-27 weeks: Use cautiously if medically necessary, shortest effective duration
• ≥28 weeks: Contraindicated (exceptions require maternal-fetal medicine consultation)

Step 3: What is the indication?

• Acute pain/inflammation: Consider 48-72 hour course in second trimester
• Chronic inflammatory disease: Explore alternative immunosuppression
• Acute migraine: Consider pregnancy-safe alternatives (metoclopramide, diphenhydramine)
• Fever: Acetaminophen preferred

Step 4: Document and monitor

• Clear documentation of risk-benefit discussion
• Lowest effective dose, shortest duration
• Consider ultrasound assessment if used >48 hours after 28 weeks

Disease-Specific Considerations

Rheumatoid Arthritis

Pregnancy often induces RA remission (70% of patients), attributed to immunological tolerance mechanisms. When disease control is inadequate:

• Preferred: Sulfasalazine, hydroxychloroquine, low-dose prednisone, certolizumab (pregnancy-compatible TNF inhibitor)
• NSAIDs: Discontinue preconception or by positive pregnancy test; bridge with prednisone if needed

Pearl: TNF inhibitors (particularly certolizumab) are safer in pregnancy than continuing NSAIDs beyond the first trimester.

Ankylosing Spondylitis

Disease activity often worsens during pregnancy. Management requires proactive transitioning:

• Pre-pregnancy counseling essential
• Transition to sulfasalazine, consider TNF inhibitor continuation
• Physical therapy optimization
• Short-course NSAIDs in second trimester only if severe exacerbation

Acute Gout

Gout flares during pregnancy are uncommon but challenging to manage:

• First-line: Colchicine (compatible with pregnancy in inflammatory doses)
• Second-line: Corticosteroids (oral or intra-articular)
• Avoid: NSAIDs after first trimester, allopurinol/febuxostat

Hack: Colchicine 0.6mg twice daily for 3-5 days effectively treats acute gout without NSAID risks.

Migraine

Pregnancy alters migraine patterns unpredictably:

• Acute treatment: Acetaminophen, metoclopramide, diphenhydramine, magnesium sulfate, nerve blocks
• Preventive: Magnesium supplementation, propranolol, amitriptyline
• Avoid: NSAIDs (especially in third trimester), triptans (limited data, generally avoided), ergotamines (contraindicated)

Special Considerations

Inadvertent Exposure

When patients present after unintended NSAID use:

Reassurance Framework:

• First trimester: Brief exposure (<5 days) carries minimal risk; counsel regarding small potential increase in miscarriage risk but note absolute risk remains low
• Second trimester: Generally reassuring; no specific monitoring required for brief exposure
• Third trimester: Assess timing, duration, and dose
  • <28 weeks, <3 days: Likely low risk

  • 32 weeks, >3 days: Consider fetal echocardiography to assess ductal patency; monitor amniotic fluid volume

Documentation Pearl: Frame discussions using absolute risk (e.g., "background miscarriage risk 15%, possibly increased to 18% with exposure") rather than relative risk to reduce anxiety.

Preterm Labor and Tocolysis

Historical NSAID use for tocolysis (particularly indomethacin) has largely been supplanted by safer agents (nifedipine, atosiban). When used:

• Limited to <48 hours
• Before 32 weeks only
• Requires fetal echocardiographic monitoring
• Reserved for cases where other tocolytics are contraindicated

Alternatives to NSAIDs in Pregnancy

Pain Management

Mild-Moderate Pain:

• Acetaminophen (up to 4g/day)
• Physical therapy, heat/cold application
• Acupuncture
• Transcutaneous electrical nerve stimulation (TENS)

Moderate-Severe Pain:

• Short-term opioids (caution regarding neonatal abstinence syndrome with prolonged use)
• Epidural steroid injections (lumbar, without fluoroscopy)
• Regional nerve blocks

Inflammatory Conditions:

• Corticosteroids (prednisone ≤20mg/day preferred over dexamethasone/betamethasone which cross placenta)
• Sulfasalazine
• Hydroxychloroquine
• Selected biologics (certolizumab, infliximab in severe cases)

Fever Reduction

Maternal hyperthermia (>39°C) carries teratogenic risk, particularly in the first trimester. Aggressive fever control is important:

• Acetaminophen 650-1000mg every 4-6 hours
• Physical cooling measures
• Treatment of underlying infection

Practical Clinical Pearls

1. The 28-Week Rule: Strict NSAID avoidance after 28 weeks minimizes ductal and renal complications while acknowledging the second-trimester safety window when medically necessary.

2. The 48-Hour Principle: Most pregnancy-compatible NSAID use should be limited to 48-72 hours, sufficient for acute inflammatory conditions while minimizing cumulative exposure.

3. Aspirin is Different: Low-dose aspirin (81mg) for preeclampsia prevention represents a distinct pharmacologic scenario from therapeutic NSAID dosing and is explicitly recommended in high-risk pregnancies.

4. Document the Conversation: Shared decision-making documentation protects both patient and physician, ensuring informed consent and acknowledgment of alternatives.

5. COX-2 Selectivity Doesn't Help: Despite theoretical advantages, COX-2 selective agents show similar fetal risks, offering no safety benefit in pregnancy.

6. Lactation is Generally Safe: Most NSAIDs (ibuprofen, naproxen) transfer minimally into breast milk and are compatible with breastfeeding, providing a postpartum option for mothers requiring anti-inflammatory therapy.

Medicolegal Considerations

The 2020 FDA strengthening of NSAID warnings after 20 weeks establishes a clear regulatory standard. Prescribing NSAIDs after 30 weeks requires:

• Documented medical necessity
• Consideration and documentation of alternatives
• Informed consent discussion
• Fetal monitoring plan
• Shortest possible duration

Conclusion

NSAID prescribing in pregnancy demands individualized risk-benefit assessment incorporating gestational age, indication, alternative options, and patient preferences. While first-trimester risks appear modest with brief exposure, third-trimester use carries well-established fetal risks warranting strict avoidance after 28-30 weeks. The internal medicine physician must balance maternal therapeutic needs against fetal safety, leveraging pregnancy-compatible alternatives whenever possible. When NSAIDs are truly necessary, second-trimester use with the shortest effective duration represents the optimal compromise. Multidisciplinary collaboration with obstetrics and maternal-fetal medicine optimizes outcomes for complex cases.

Key Takeaways for Clinical Practice

• Acetaminophen first: Adequate for most pain/fever scenarios
• Avoid after 28 weeks: Non-negotiable except under specialist care
• Second trimester safest: If NSAID truly needed, this is the window
• Document thoroughly: Risk-benefit discussions and alternatives considered
• Prefer ibuprofen: When NSAID selected, best-studied option
• Consider alternatives: Corticosteroids, colchicine, biologics often safer for chronic conditions
• Brief exposure okay: Short first-trimester exposure rarely catastrophic; counsel with perspective

References

1. Daniel S, Koren G, Lunenfeld E, et al. Fetal exposure to nonsteroidal anti-inflammatory drugs and spontaneous abortions. CMAJ. 2014;186(5):E177-E182.

2. Food and Drug Administration. FDA recommends avoiding use of NSAIDs in pregnancy at 20 weeks or later because they can result in low amniotic fluid. FDA Drug Safety Communication. October 2020.

3. Antonucci R, Zaffanello M, Puxeddu E, et al. Use of non-steroidal anti-inflammatory drugs in pregnancy: impact on the fetus and newborn. Curr Drug Metab. 2012;13(4):474-490.

4. Østensen ME, Skomsvoll JF. Anti-inflammatory pharmacotherapy during pregnancy. Expert Opin Pharmacother. 2004;5(3):571-580.

5. Koren G, Florescu A, Costei AM, et al. Nonsteroidal antiinflammatory drugs during third trimester and the risk of premature closure of the ductus arteriosus: a meta-analysis. Ann Pharmacother. 2006;40(5):824-829.

6. Edwards DR, Aldridge T, Baird DD, et al. Periconceptional over-the-counter nonsteroidal anti-inflammatory drug exposure and risk for spontaneous abortion. Obstet Gynecol. 2012;120(1):113-122.

7. Dathe K, Hultzsch S, Pritchard LW, et al. Risk estimation of fetal adverse effects after short-term second 

   NSAIDs in Pregnancy: A Clinical Decision-Making Framework for the Internal Medicine Physician

   Abstract

   Non-steroidal anti-inflammatory drugs (NSAIDs) represent one of the most commonly prescribed medication classes worldwide, yet their use during pregnancy presents significant clinical challenges. This review provides an evidence-based framework for internal medicine physicians managing pregnant patients who may require NSAID therapy, emphasizing gestational age-specific risks, alternative management strategies, and practical clinical pearls for optimizing maternal and fetal outcomes.

   Introduction

   The prescription of NSAIDs during pregnancy demands careful consideration of both maternal therapeutic needs and potential fetal harm. Approximately 30% of pregnant women report NSAID exposure during gestation, often before pregnancy recognition. Internal medicine physicians frequently encounter scenarios requiring NSAID consideration: the pregnant patient with rheumatoid arthritis flare, acute gout, or refractory migraine. Understanding the nuanced risk-benefit calculus is essential for contemporary practice.

   Mechanism of Action and Pregnancy-Specific Concerns

   NSAIDs exert their therapeutic effects through inhibition of cyclooxygenase (COX) enzymes, reducing prostaglandin synthesis. During pregnancy, prostaglandins play critical roles in maintaining uterine blood flow, regulating fetal renal function, and facilitating labor onset. COX-1 inhibition affects platelet function and gastric protection, while COX-2 inhibition influences inflammation, pain, and critically—ductus arteriosus patency and fetal renal perfusion.

   The gestational age at exposure fundamentally determines the risk profile, creating distinct clinical windows requiring different management approaches.

   Trimester-Specific Risk Assessment

   First Trimester (Weeks 0-13)

   Current Evidence: The teratogenic potential of NSAIDs during organogenesis remains controversial. Large epidemiological studies have shown conflicting results regarding cardiac malformations and orofacial clefts. A 2011 Danish cohort study of over 800,000 pregnancies found no increased risk of major malformations with first-trimester NSAID exposure. However, a Canadian case-control study suggested modest associations with cardiac septal defects (adjusted OR 1.86, 95% CI 1.32-2.62).

   Clinical Pearl: The absolute risk increase, if present, remains small (background risk ~1%, potentially increased to 1.5-2%). Short-term exposure (fewer than 7 days) shows minimal association with adverse outcomes.

   Miscarriage Risk: Meta-analyses suggest a 2.4-fold increased risk of spontaneous abortion with periconceptional NSAID use, though confounding by indication (pain or fever suggesting underlying pathology) complicates interpretation. This association appears strongest with indomethacin and least evident with low-dose aspirin.

   Second Trimester (Weeks 14-27)

   Relative Safety Window: The second trimester represents the least problematic period for NSAID exposure if clinically necessary. Organogenesis is complete, and the gestational age-dependent renal and cardiovascular complications of late pregnancy have not yet emerged.

   Duration Matters: Short courses (less than 48 hours) for acute conditions carry minimal documented risk. Chronic use should still be avoided due to cumulative effects on amniotic fluid volume.

   Hack for Practice: If an NSAID is absolutely necessary during pregnancy, the second trimester offers the optimal risk-benefit window. Document clear medical indication and plan for discontinuation by week 28.

   Third Trimester: The High-Risk Period

   After 30 Weeks: Contraindication Territory

   FDA guidance (updated 2020) strengthens previous warnings, recommending NSAID avoidance after 20 weeks' gestation due to three principal concerns:

   1. Premature Ductus Arteriosus Constriction

   The ductus arteriosus becomes increasingly sensitive to prostaglandin inhibition with advancing gestation. Ductal constriction can occur within 48 hours of exposure, leading to right ventricular hypertrophy, tricuspid regurgitation, and potentially fetal death. Risk increases dramatically after 32 weeks.

   A 2017 systematic review documented ductal constriction in 15% of fetuses exposed beyond 32 weeks, with most cases associated with indomethacin use exceeding 48 hours.

   Oyster: Not all NSAIDs carry equal ductal risk. Indomethacin shows the highest association, while ibuprofen and naproxen carry moderate risk. COX-2 selective inhibitors (celecoxib) show similar ductus effects despite selective mechanism.

   2. Oligohydramnios and Fetal Renal Dysfunction

   Fetal kidneys become primary producers of amniotic fluid in the second half of pregnancy. NSAID-induced reduction in fetal renal blood flow can precipitate oligohydramnios, sometimes within 48-72 hours of exposure. This effect is usually reversible upon discontinuation but may lead to pulmonary hypoplasia if prolonged.

   Clinical Hack: If oligohydramnios develops with NSAID exposure, discontinuation typically restores amniotic fluid within 1-2 weeks. Consider ultrasound monitoring if exposure exceeded 48 hours after 28 weeks.

   3. Bleeding Risk and Labor Complications

   Antiplatelet effects increase peripartum hemorrhage risk for both mother and neonate. NSAIDs can also delay labor onset and prolong gestation, occasionally necessitating this property for tocolysis in specific protocols (though safer alternatives now dominate).

   NSAID Selection: When Truly Necessary

   The Risk Hierarchy

   When clinical circumstances demand NSAID consideration, understanding relative safety profiles guides selection:

   Lowest Risk:

   • Acetaminophen (paracetamol): Not an NSAID but the first-line analgesic/antipyretic throughout pregnancy. Maximum 4g daily, chronic use >28 days requires consideration of recent data suggesting possible neurodevelopmental effects, though evidence remains inconclusive.

   Low-Moderate Risk (First/Second Trimester Only):

   • Ibuprofen: Most extensively studied, preferable for short-term use. Dose 200-400mg every 6-8 hours, maximum 2400mg/day, discontinue by 28 weeks.
   • Low-dose aspirin (81mg): Specifically indicated for preeclampsia prevention in high-risk patients, continued throughout pregnancy. Does not carry the same risks as therapeutic doses.

   Moderate-High Risk:

   • Naproxen: Longer half-life increases exposure duration, less preferred than ibuprofen.
   • Ketorolac: Potent prostaglandin inhibition, avoid during pregnancy.
   • Celecoxib: COX-2 selectivity does not confer fetal safety advantage.

   Highest Risk/Avoid:

   • Indomethacin: Most potent ductal effects, reserve only for specific indications (polyhydramnios, rarely for tocolysis) under specialist supervision with fetal monitoring.
   • Aspirin (therapeutic doses >150mg): Increased bleeding risk without clear benefit in pregnancy.

   Clinical Decision Algorithm

   Step 1: Is the NSAID truly necessary?

   • Consider acetaminophen adequacy
   • Evaluate non-pharmacologic interventions
   • Assess whether condition can be managed with pregnancy-safe alternatives

   Step 2: What is the gestational age?

   • <13 weeks: Avoid if possible; if essential, shortest duration, prefer ibuprofen
   • 14-27 weeks: Use cautiously if medically necessary, shortest effective duration
   • ≥28 weeks: Contraindicated (exceptions require maternal-fetal medicine consultation)

   Step 3: What is the indication?

   • Acute pain/inflammation: Consider 48-72 hour course in second trimester
   • Chronic inflammatory disease: Explore alternative immunosuppression
   • Acute migraine: Consider pregnancy-safe alternatives (metoclopramide, diphenhydramine)
   • Fever: Acetaminophen preferred

   Step 4: Document and monitor

   • Clear documentation of risk-benefit discussion
   • Lowest effective dose, shortest duration
   • Consider ultrasound assessment if used >48 hours after 28 weeks

   Disease-Specific Considerations

   Rheumatoid Arthritis

   Pregnancy often induces RA remission (70% of patients), attributed to immunological tolerance mechanisms. When disease control is inadequate:

   • Preferred: Sulfasalazine, hydroxychloroquine, low-dose prednisone, certolizumab (pregnancy-compatible TNF inhibitor)
   • NSAIDs: Discontinue preconception or by positive pregnancy test; bridge with prednisone if needed

   Pearl: TNF inhibitors (particularly certolizumab) are safer in pregnancy than continuing NSAIDs beyond the first trimester.

   Ankylosing Spondylitis

   Disease activity often worsens during pregnancy. Management requires proactive transitioning:

   • Pre-pregnancy counseling essential
   • Transition to sulfasalazine, consider TNF inhibitor continuation
   • Physical therapy optimization
   • Short-course NSAIDs in second trimester only if severe exacerbation

   Acute Gout

   Gout flares during pregnancy are uncommon but challenging to manage:

   • First-line: Colchicine (compatible with pregnancy in inflammatory doses)
   • Second-line: Corticosteroids (oral or intra-articular)
   • Avoid: NSAIDs after first trimester, allopurinol/febuxostat

   Hack: Colchicine 0.6mg twice daily for 3-5 days effectively treats acute gout without NSAID risks.

   Migraine

   Pregnancy alters migraine patterns unpredictably:

   • Acute treatment: Acetaminophen, metoclopramide, diphenhydramine, magnesium sulfate, nerve blocks
   • Preventive: Magnesium supplementation, propranolol, amitriptyline
   • Avoid: NSAIDs (especially in third trimester), triptans (limited data, generally avoided), ergotamines (contraindicated)

   Special Considerations

   Inadvertent Exposure

   When patients present after unintended NSAID use:

   Reassurance Framework:

   • First trimester: Brief exposure (<5 days) carries minimal risk; counsel regarding small potential increase in miscarriage risk but note absolute risk remains low
   • Second trimester: Generally reassuring; no specific monitoring required for brief exposure
   • Third trimester: Assess timing, duration, and dose
     • <28 weeks, <3 days: Likely low risk

     • 32 weeks, >3 days: Consider fetal echocardiography to assess ductal patency; monitor amniotic fluid volume

   Documentation Pearl: Frame discussions using absolute risk (e.g., "background miscarriage risk 15%, possibly increased to 18% with exposure") rather than relative risk to reduce anxiety.

   Preterm Labor and Tocolysis

   Historical NSAID use for tocolysis (particularly indomethacin) has largely been supplanted by safer agents (nifedipine, atosiban). When used:

   • Limited to <48 hours
   • Before 32 weeks only
   • Requires fetal echocardiographic monitoring
   • Reserved for cases where other tocolytics are contraindicated

   Alternatives to NSAIDs in Pregnancy

   Pain Management

   Mild-Moderate Pain:

   • Acetaminophen (up to 4g/day)
   • Physical therapy, heat/cold application
   • Acupuncture
   • Transcutaneous electrical nerve stimulation (TENS)

   Moderate-Severe Pain:

   • Short-term opioids (caution regarding neonatal abstinence syndrome with prolonged use)
   • Epidural steroid injections (lumbar, without fluoroscopy)
   • Regional nerve blocks

   Inflammatory Conditions:

   • Corticosteroids (prednisone ≤20mg/day preferred over dexamethasone/betamethasone which cross placenta)
   • Sulfasalazine
   • Hydroxychloroquine
   • Selected biologics (certolizumab, infliximab in severe cases)

   Fever Reduction

   Maternal hyperthermia (>39°C) carries teratogenic risk, particularly in the first trimester. Aggressive fever control is important:

   • Acetaminophen 650-1000mg every 4-6 hours
   • Physical cooling measures
   • Treatment of underlying infection

   Practical Clinical Pearls

   1. The 28-Week Rule: Strict NSAID avoidance after 28 weeks minimizes ductal and renal complications while acknowledging the second-trimester safety window when medically necessary.

   2. The 48-Hour Principle: Most pregnancy-compatible NSAID use should be limited to 48-72 hours, sufficient for acute inflammatory conditions while minimizing cumulative exposure.

   3. Aspirin is Different: Low-dose aspirin (81mg) for preeclampsia prevention represents a distinct pharmacologic scenario from therapeutic NSAID dosing and is explicitly recommended in high-risk pregnancies.

   4. Document the Conversation: Shared decision-making documentation protects both patient and physician, ensuring informed consent and acknowledgment of alternatives.

   5. COX-2 Selectivity Doesn't Help: Despite theoretical advantages, COX-2 selective agents show similar fetal risks, offering no safety benefit in pregnancy.

   6. Lactation is Generally Safe: Most NSAIDs (ibuprofen, naproxen) transfer minimally into breast milk and are compatible with breastfeeding, providing a postpartum option for mothers requiring anti-inflammatory therapy.

   Medicolegal Considerations

   The 2020 FDA strengthening of NSAID warnings after 20 weeks establishes a clear regulatory standard. Prescribing NSAIDs after 30 weeks requires:

   • Documented medical necessity
   • Consideration and documentation of alternatives
   • Informed consent discussion
   • Fetal monitoring plan
   • Shortest possible duration

   Conclusion

   NSAID prescribing in pregnancy demands individualized risk-benefit assessment incorporating gestational age, indication, alternative options, and patient preferences. While first-trimester risks appear modest with brief exposure, third-trimester use carries well-established fetal risks warranting strict avoidance after 28-30 weeks. The internal medicine physician must balance maternal therapeutic needs against fetal safety, leveraging pregnancy-compatible alternatives whenever possible. When NSAIDs are truly necessary, second-trimester use with the shortest effective duration represents the optimal compromise. Multidisciplinary collaboration with obstetrics and maternal-fetal medicine optimizes outcomes for complex cases.

   Key Takeaways for Clinical Practice

   • Acetaminophen first: Adequate for most pain/fever scenarios
   • Avoid after 28 weeks: Non-negotiable except under specialist care
   • Second trimester safest: If NSAID truly needed, this is the window
   • Document thoroughly: Risk-benefit discussions and alternatives considered
   • Prefer ibuprofen: When NSAID selected, best-studied option
   • Consider alternatives: Corticosteroids, colchicine, biologics often safer for chronic conditions
   • Brief exposure okay: Short first-trimester exposure rarely catastrophic; counsel with perspective

   References

   1. Daniel S, Koren G, Lunenfeld E, et al. Fetal exposure to nonsteroidal anti-inflammatory drugs and spontaneous abortions. CMAJ. 2014;186(5):E177-E182.

   2. Food and Drug Administration. FDA recommends avoiding use of NSAIDs in pregnancy at 20 weeks or later because they can result in low amniotic fluid. FDA Drug Safety Communication. October 2020.

   3. Antonucci R, Zaffanello M, Puxeddu E, et al. Use of non-steroidal anti-inflammatory drugs in pregnancy: impact on the fetus and newborn. Curr Drug Metab. 2012;13(4):474-490.

   4. Østensen ME, Skomsvoll JF. Anti-inflammatory pharmacotherapy during pregnancy. Expert Opin Pharmacother. 2004;5(3):571-580.

   5. Koren G, Florescu A, Costei AM, et al. Nonsteroidal antiinflammatory drugs during third trimester and the risk of premature closure of the ductus arteriosus: a meta-analysis. Ann Pharmacother. 2006;40(5):824-829.

   6. Edwards DR, Aldridge T, Baird DD, et al. Periconceptional over-the-counter nonsteroidal anti-inflammatory drug exposure and risk for spontaneous abortion. Obstet Gynecol. 2012;120(1):113-122.

   7. Dathe K, Hultzsch S, Pritchard LW, et al. Risk estimation of fetal adverse effects after short-term second trimester exposure to non-steroidal anti-inflammatory drugs: a literature review. Eur J Clin Pharmacol. 2019;75(10):1347-1353.

   8. Cleves MA, Savell VH Jr, Raj S, et al. Maternal use of acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), and muscular ventricular septal defects. Birth Defects Res A Clin Mol Teratol. 2004;70(3):107-113.

   9. Bloor M, Paech M. Nonsteroidal anti-inflammatory drugs during pregnancy and the initiation of lactation. Anesth Analg. 2013;116(5):1063-1075.

   10. Flint J, Panchal S, Hurrell A, et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding—Part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. Rheumatology. 2016;55(9):1693-1697.

   exposure to non-steroidal anti-inflammatory drugs: a literature review. Eur J Clin Pharmacol. 2019;75(10):1347-1353.

8. Cleves MA, Savell VH Jr, Raj S, et al. Maternal use of acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), and muscular ventricular septal defects. Birth Defects Res A Clin Mol Teratol. 2004;70(3):107-113.

9. Bloor M, Paech M. Nonsteroidal anti-inflammatory drugs during pregnancy and the initiation of lactation. Anesth Analg. 2013;116(5):1063-1075.

10. Flint J, Panchal S, Hurrell A, et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding—Part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. Rheumatology. 2016;55(9):1693-1697.