Hydroxyurea (Hydroxycarbamide) and Pregnancy in Sickle Cell Disease

Current Guideline Position

• Fitzpatrick's Dermatology lists pregnancy/lactation explicitly as a relative contraindication, noting "Hydroxyurea is a category D agent during pregnancy, and its use should be avoided" - Fitzpatrick's Dermatology, Vol. 1/2, Table 190-8
• Dermatology (2-Volume Set, 5th Ed.) describes it as a "known teratogen; not to be used during pregnancy or lactation"
• Goldman-Cecil Medicine states: "Hydroxyurea should be avoided, including during the breast-feeding period" in special situations

Why It Is Contraindicated

What Happens If Exposed During Pregnancy?

• A 2025 Systematic Review (Al Sulaimani et al., J Obstet Gynaecol Can, PMID 40381805) reviewed 7,227 pregnancies (567 exposed to HU) and found: "Neither teratogenic nor hematologic effects on the fetus were observed" - concluding pregnancy risks may be lower than anticipated.
• A 2023 review (Dong et al., Pharmacotherapy, PMID 36928875) noted that human data shows "inconsistent results of fetal or infant adverse effects" and that the contraindication is based on theoretical animal-model concerns using supraphysiological doses.
• Data presented at ASH 2025 found no adverse pregnancy outcomes among sickle cell patients with accidental hydroxyurea exposure, and noted better live birth rates than prior studies.

Evolving Guidance (2025-2026)

• ASH (draft guidelines, 2025-2026) propose that continuing OR discontinuing HU should be decided on a case-by-case basis with shared decision-making - for both planned conception and unplanned exposure. This is rated as "very low certainty of evidence."
• WHO 2025 global guidelines on sickle cell disease address the issue particularly for low- and middle-income countries, where stopping hydroxyurea may expose patients to dangerous vaso-occlusive crises if safe transfusion alternatives are unavailable.

Management During Pregnancy in SCD

1. Blood transfusion (exchange or simple) - the main alternative; reduces HbS fraction and prevents crises
2. Folic acid supplementation - mandatory (continued throughout pregnancy)
3. Close monitoring by Maternal-Fetal Medicine + Hematology
4. Supportive care for pain crises (hydration, analgesics safe in pregnancy)
5. Prophylactic transfusion - not universally recommended but considered in high-risk cases

Key Takeaway

⚠️ Note: Evolving 2025 data may update recommendations. Always consult current local/national guidelines and a hematologist for individual patient decisions.

Hydroxyurea Continued Unknowingly During Pregnancy - What Actually Happens?

The Reality: More Reassuring Than Expected

ESCORT-HU Cohort - The Largest Real-World Data (ASH 2025)

What Happens Trimester by Trimester?

• Most critical for organogenesis (organ formation)
• Theoretically the highest risk window for teratogenicity
• However, in the ESCORT-HU cohort and a 2025 systematic review of 567 HU-exposed pregnancies - no teratogenic effects on the fetus were observed, even with first-trimester exposure
• Standard practice: stop HU as soon as pregnancy is confirmed

• Risk of structural malformations is largely past after organogenesis (completed by ~10 weeks)
• Later concerns: fetal growth restriction, hematologic effects on the newborn
• Human data shows no consistent pattern of harm

2025 Systematic Review (PMID 40381805)

"Neither teratogenic nor hematologic effects on the fetus were observed in these cases. Pregnancy risks associated with HU are lower than anticipated."

What Should Be Done Once Pregnancy Is Discovered?

Hydroxyurea unknowingly taken during pregnancy
           ↓
1. STOP hydroxyurea immediately upon discovering pregnancy
2. Do NOT panic - human evidence is reassuring
3. Refer urgently to:
   - Hematology
   - Maternal-Fetal Medicine (MFM) / Obstetrics
4. Start alternative management:
   - Blood transfusion (exchange/simple) for SCD control
   - Folic acid supplementation (continue)
   - Close fetal monitoring (detailed anomaly scan at 18-20 weeks)
5. Counsel patient:
   - Animal teratogenicity ≠ proven human harm
   - No clear malformation signal in human studies
   - Ongoing pregnancy is viable
6. Special case - if transfusion NOT safe (e.g. DHTR history):
   - May continue HU under strict hematology supervision
   - Shared decision-making with patient

Why Animal Data Overestimated the Risk

• Animal teratogenicity studies used supraphysiological doses - far higher than therapeutic human doses
• Human pharmacokinetics and placental transfer differ significantly from rodents
• The mechanism (ribonucleotide reductase inhibition) is dose-dependent - therapeutic doses may not reach embryotoxic thresholds

Key Points to Remember

Hydroxyurea Continued Unknowingly Until 28 Weeks - Full Clinical Picture

Context First: Why 28 Weeks Matters

• Organogenesis is long complete (finished by ~10 weeks) - so the structural malformation window has passed
• The fetus has functioning organ systems
• Main concerns shift from teratogenicity to fetal growth, hematological effects, and neonatal outcomes

What the Evidence Actually Shows for Prolonged Exposure

1. No Structural Malformations (Reassuring)

"For live births, there does not appear to be an increase in birth defects when hydroxyurea is used during pregnancy" - SCDIC Registry (Kroner et al., Am J Hematol, 2022, PMC8986611)

"No treatment-related malformations among newborns" - ESCORT-HU cohort (ASH 2025, 246 pregnancies)

2. Risks That ARE Present with Prolonged Exposure

Critical caveat: The SCDIC study had a major limitation - women ON hydroxyurea were inherently sicker and had more severe SCD, which independently increases miscarriage and stillbirth risk. The OR of 2.21 likely reflects disease severity confounding, not pure drug effect.

3. The 9.3% Who Continued Throughout Pregnancy (ESCORT-HU)

• 76% live birth rate - comparable to or better than SCD pregnancies without HU
• Zero maternal deaths
• No congenital malformations

4. An Interesting ASH Observation (Relevant to 28 Weeks)

"Some women choose to stop taking hydroxyurea early in their pregnancy and then start it again during the third trimester (after 29 weeks)" to improve maternal health and fetal outcomes.

What Must Be Done Now (28 Weeks, HU Exposure Discovered)

IMMEDIATE STEPS
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
1. STOP hydroxyurea NOW
   - Organogenesis long past, but reduce further exposure
   - Switch to transfusion-based SCD management

2. URGENT REFERRAL
   - Maternal-Fetal Medicine (MFM) / High-risk Obstetrics
   - Hematology
   - Neonatology team briefing

FETAL MONITORING (from now until delivery)
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
3. Detailed anomaly scan (if not done) - though 28 weeks
   is past standard 20-week scan; still do morphology review

4. Serial growth scans every 2-4 weeks
   - Monitor for fetal growth restriction (IUGR)
   - Measure amniotic fluid (oligohydramnios)

5. Doppler velocimetry (umbilical artery)
   - Assess placental blood flow

6. Biophysical profile / Non-stress tests (NST)
   - From 28-32 weeks onward

NEONATAL PREPARATION
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
7. Alert neonatology team at delivery
8. Check cord blood / neonatal CBC at birth
   - Rule out myelosuppression (low WBC, platelets)
9. Monitor newborn for feeding difficulties, jaundice

MATERNAL MANAGEMENT
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
10. Exchange transfusion or simple transfusion for SCD control
11. Continue folic acid
12. Watch for vaso-occlusive crises (stopping HU may precipitate)

Prognosis Summary

Most Important Message to the Patient

1. The malformation window (first trimester) has long passed - the baby's organs have already formed
2. No malformations have been reported in any large study of HU-exposed pregnancies
3. The pregnancy should not be terminated on account of HU exposure alone
4. Close monitoring from now until delivery is the key management step
5. The biggest ongoing risk is from the sickle cell disease itself, not the hydroxyurea
6. Long-term follow-up of the child's development is advisable since data beyond infancy is limited

⚠️ The data is reassuring but not complete - long-term neurodevelopmental outcomes in children exposed to HU in utero beyond the first trimester are not yet well-studied. Parents should be counseled honestly about this knowledge gap.

HU at 19 Weeks: Stop, Continue, or Reduce Dose?

First - Why 19 Weeks Is a Specific Inflection Point

The Three-Way Decision: Stop / Continue / Reduce Dose

Option 1: STOP Hydroxyurea (Default Guideline Recommendation)

• Transfusion (exchange or top-up) is available and safe
• No history of delayed hemolytic transfusion reaction (DHTR)
• Mild-moderate SCD with manageable disease burden
• Patient preference after counseling

• Position Statement on Management of Pregnancy in SCD (PMC12099178, 2025):

  "If safe to discontinue during pregnancy, stop hydroxyurea when pregnancy confirmed. Consider commencement of red cell exchange or top-up transfusion."

• ASH draft guidelines 2025-2026: recommend discontinuation as the default, with transfusion as bridge

• Switch immediately to transfusion-based SCD management
• Exchange transfusion preferred; top-up acceptable
• Expect VOC risk to increase in weeks following HU withdrawal - have a clear crisis plan
• Folic acid: continue throughout

Option 2: CONTINUE Hydroxyurea (Selective Cases - Evidence-Supported)

• History of delayed hemolytic transfusion reaction (DHTR) - makes transfusion dangerous
• Transfusion not available or not safe (resource-limited settings)
• Very severe SCD with high stroke/ACS risk where stopping is more dangerous than continuing
• Patient has been counseled and chooses to continue

• ESCORT-HU (ASH 2025): 9.3% of women continued HU throughout entire pregnancy - zero malformations, zero maternal deaths, 76% live births
• Dr. Habibi (ASH 2025): "HU may be continued when transfusion is not an alternative, particularly in patients with a history of DHTR"
• 2025 Systematic Review (PMID 40381805): "Pregnancy risks associated with HU are lower than anticipated. Use may be justified considering significant risks of untreated SCD"
• ASH draft guidelines propose continuing HU on a case-by-case basis with shared decision-making

• Organogenesis is over - continuing carries no additional structural malformation risk
• Monitoring for growth restriction and neonatal myelosuppression is key

Option 3: REDUCE DOSE

Honestly - NO clear evidence supports dose reduction as a middle-ground strategy. There is no published trial or guideline that recommends a specific reduced dose for pregnancy. This option has no solid evidence base.

• No dose-response data in pregnancy establishes a "safe" lower dose
• Subtherapeutic dosing means the mother gets inadequate SCD protection without clear fetal benefit
• The SCDIC study couldn't even define safe dose thresholds - dosing data wasn't recorded
• Creates a false sense of safety for both mother and fetus

Decision Algorithm at 19 Weeks

Hydroxyurea at 19 weeks - DECISION TREE
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

Is SAFE transfusion (exchange/top-up) available?
               ↓
        YES ──────────── NO
         ↓                ↓
   STOP HU NOW      History of DHTR?
   + Start           ↓           ↓
   transfusion      YES          NO
                     ↓           ↓
               CONTINUE HU   Can transfusion
               full dose +   be arranged?
               close fetal     ↓        ↓
               monitoring     YES       NO
                            STOP HU  CONTINUE HU
                            + transfuse  full dose

In ALL scenarios:
  ✓ MDT discussion (Hematology + MFM + Neonatology)
  ✓ Shared decision-making with patient
  ✓ 20-week anomaly scan (already due - URGENT)
  ✓ Serial growth scans every 2-4 weeks from now
  ✓ Folic acid continue throughout
  ✓ NSAIDs - STOP NOW (>20 weeks = oligohydramnios risk)

What the Guidelines Actually Say (2025)

Specifically Because She Is at 19 Weeks RIGHT NOW

1. 20-week anomaly scan is DUE NOW - schedule urgently; this is the standard structural survey and is now even more important for documentation
2. NSAIDs must stop at 20 weeks (oligohydramnios) - check her pain management plan immediately
3. Multidisciplinary team meeting - the decision to stop/continue CANNOT be made by a single clinician at this gestational age; requires Hematology + Obstetrics + MFM joint decision

Summary Answer

The answer is never one-size-fits-all - it depends entirely on whether safe transfusion is an option for this specific patient. That single question drives the entire decision.