What are the recommendations for a patient with Mixed Connective Tissue Disease (MCTD) considering fertility treatment?

Fertility Treatment Recommendations for MCTD Patients

Patients with Mixed Connective Tissue Disease (MCTD) can proceed with assisted reproductive technology (ART) if their disease is stable/quiescent, they are on pregnancy-compatible medications, and antiphospholipid antibody (aPL) status has been assessed, though MCTD with pulmonary hypertension or severe organ involvement poses significant risks requiring multidisciplinary evaluation. 1

Pre-Treatment Disease Optimization

Achieve disease quiescence for at least 6 months before attempting conception or fertility treatments. 2

• Active MCTD at conception increases risks of miscarriage (29.8%), stillbirth (5.3%), preterm delivery (18.9%), fetal growth restriction (18.9%), and small-for-gestational-age infants (27.0%). 3
• Disease activity is the primary adverse factor predisposing to intrauterine death, prematurity, and low birth weight. 1
• Approximately two-thirds of women in remission remain in remission during pregnancy, while active disease at conception persists or worsens in two-thirds of cases. 1

Medication Management Before ART

Switch from teratogenic medications to pregnancy-compatible alternatives at least 3 months before starting fertility treatments. 1

Discontinue These Medications:

• Methotrexate (teratogenic and reduces male fertility causing oligospermia). 1
• Mycophenolate mofetil/mycophenolic acid (teratogenic). 1
• Cyclophosphamide (directly impacts maturing follicles and causes ovarian insufficiency). 1

Pregnancy-Compatible Options:

• Hydroxychloroquine (strongly recommended throughout pregnancy). 4, 5
• Sulfasalazine (safe throughout pregnancy, though may cause reversible oligospermia in males). 1, 4
• Azathioprine (pregnancy-compatible immunosuppressant). 4, 5
• Low-dose prednisone ≤10 mg daily (conditionally recommended). 4, 5, 6
• Certolizumab (preferred TNF inhibitor with minimal placental transfer). 4, 5

Continue necessary immunosuppressive therapies during ovarian stimulation for oocyte/embryo cryopreservation (except cyclophosphamide) to prevent disease flares. 1

Antiphospholipid Antibody Assessment

Test all MCTD patients for antiphospholipid antibodies before proceeding with ART, as this determines anticoagulation requirements. 1

Anticoagulation Protocol Based on aPL Status:

• Negative aPL: Proceed with ART without anticoagulation. 1
• Positive aPL without clinical APS: Use prophylactic low molecular weight heparin (LMWH) or unfractionated heparin during ART procedures. 1
• Obstetric APS (≥3 consecutive losses <10 weeks, fetal loss ≥10 weeks, or delivery <34 weeks due to preeclampsia/growth restriction): Use therapeutic-dose LMWH during ART procedures. 1
• Thrombotic APS: Transition from vitamin K antagonists to therapeutic-dose LMWH (enoxaparin 1 mg/kg subcutaneously every 12 hours), withhold for oocyte retrieval, then resume. 1

Ovarian Stimulation Modifications

Patients with antiphospholipid antibodies or at risk for thrombosis should use ovarian stimulation protocols incorporating aromatase inhibitors to achieve lower peak estrogen levels. 1

• High estrogen levels during standard ovarian stimulation increase thrombotic risk in patients with aPL. 1
• GnRH-agonist trigger with cycle segmentation (freeze-all strategy) eliminates ovarian hyperstimulation syndrome risk and reduces thrombotic complications. 2

High-Risk MCTD Scenarios

MCTD patients with pulmonary hypertension, severe organ involvement, or antiphospholipid syndrome require specialized evaluation before proceeding with fertility treatments. 7

• A case report documented respiratory failure and severe complications following controlled ovarian hyperstimulation in a 25-year-old with MCTD, secondary pulmonary hypertension, and APS, despite successful embryo cryopreservation. 7
• Patients with severe disease-related damage who cannot safely undergo pregnancy may consider ovarian stimulation with oocyte retrieval followed by embryo transfer to a gestational carrier. 1
• MCTD with simultaneous pulmonary and renal involvement is very rare but poses catastrophic risks, including scleroderma renal crisis. 8

Fertility Preservation for Cyclophosphamide Treatment

If cyclophosphamide therapy is required, offer oocyte/embryo cryopreservation before treatment and administer monthly gonadotropin-releasing hormone agonist co-therapy to reduce ovarian insufficiency risk. 1

• GnRH agonist should be administered 10-14 days prior to cyclophosphamide infusion. 1
• For males requiring cyclophosphamide, strongly recommend sperm cryopreservation before treatment initiation. 1
• Cyclophosphamide causes the most damage to postmeiosis spermatids; if sperm is collected after treatment, wait minimum 3 months after completion. 1

Steroid Management During Fertility Treatment

Use low-dose prednisone (≤10 mg daily) or methylprednisolone during fertility treatments if needed for disease control. 5, 6

• Higher steroid usage was associated with live births in MCTD pregnancies, but lower prednisolone dosage (median 7 mg vs. 10 mg) in the live birth group suggests optimal dosing at the lower end. 3
• Avoid fluorinated corticosteroids (dexamethasone, betamethasone) as they cross the placenta extensively. 4, 6
• Doses above 20 mg/day increase risks of gestational diabetes, pregnancy-associated osteoporosis, serious infections, and preterm birth. 6

Mandatory Multidisciplinary Coordination

Coordinate care between rheumatology, reproductive endocrinology/infertility specialists, and maternal-fetal medicine before proceeding with ART. 1

• Medical clearance by rheumatology is required before ovarian stimulation. 1
• Rheumatologists should consult with reproductive specialists regarding ovarian stimulation protocol adjustments to minimize patient risk. 1
• Women with underlying significant medical disease should undergo fertility therapy only in centers where appropriate expertise is readily available. 1

Contraception Requirements

Use effective contraception until disease is optimized and pregnancy-compatible medications are established, as unplanned pregnancies in MCTD carry greater risks than planned pregnancies. 1, 5

• Almost half of pregnancies in the US are unplanned. 1
• Unplanned pregnancies in rheumatic disease patients carry greater risk than planned pregnancies during periods of low disease activity on compatible medications. 1, 5

Critical Pitfalls to Avoid

• Do not proceed with ART during active MCTD disease – disease activity must be quiescent for at least 6 months. 2, 3
• Do not omit aPL testing – failure to identify and treat antiphospholipid antibodies increases thrombotic risk during ovarian stimulation. 1
• Do not discontinue immunosuppression during oocyte retrieval cycles – risk of disease flare outweighs theoretical concerns about medication exposure during fertility preservation. 1
• Do not use standard ovarian stimulation protocols in patients with aPL – aromatase inhibitor protocols with lower peak estrogen are safer. 1, 2
• Do not proceed with ART in patients with pulmonary hypertension without extensive risk assessment – catastrophic complications have been reported. 7