For a woman with recurrent implantation failure and immunologic abnormalities (elevated natural‑killer cells or autoimmune disease), should tacrolimus be used in IVF, and what dose and monitoring are recommended?

Tacrolimus in IVF for Recurrent Implantation Failure

For women with recurrent implantation failure (RIF) and elevated Th1/Th2 cell ratios (≥10.3-11.8), tacrolimus should be used as it significantly improves implantation and live birth rates, with dosing of 1-4 mg daily starting 2 days before embryo transfer and continuing through early pregnancy.

Patient Selection Criteria

Measure peripheral blood Th1/Th2 cell ratios (CD4+ IFN-γ+/CD4+ IL-4+) to identify candidates for tacrolimus therapy. 1, 2

• The optimal cut-off for patient selection is a Th1/Th2 ratio ≥11.8 when using euploid blastocyst transfers 2
• The original threshold of ≥10.3 has been used successfully in multiple studies 1, 3
• Women with autoimmune disease or elevated natural killer cells who also meet the Th1/Th2 criteria are appropriate candidates 4

Dosing Protocol

Start tacrolimus 2 days before embryo transfer and continue until at least the pregnancy test (minimum 16 days), then throughout pregnancy if conception occurs. 3, 1

Dose Selection Based on Th1/Th2 Ratio:

• 1 mg daily: For Th1/Th2 ratios at the lower end of the elevated range 3
• 2-3 mg daily: For moderately elevated ratios 3, 1
• Up to 4 mg daily: For severely elevated ratios 1

The dose should be determined by the degree of Th1/Th2 elevation, with higher ratios requiring higher doses to adequately suppress the aberrant immune response 3.

Monitoring Requirements

Monitor tacrolimus blood concentrations and maintain target trough levels of 4-8 ng/mL during pregnancy. 5, 1

Laboratory Monitoring Schedule:

• Baseline: Complete blood count, liver function tests, renal function (creatinine), glucose, potassium 5
• During treatment: Tacrolimus trough levels should be measured to ensure therapeutic range 1
• Ongoing: Blood pressure, renal function, glucose, and liver enzymes regularly 5

Tacrolimus concentrations in maternal plasma remain relatively stable during pregnancy when administered on a consistent daily regimen 1.

Expected Outcomes

Tacrolimus treatment achieves clinical pregnancy rates of 50-64% and live birth rates of 35-60% in RIF patients with elevated Th1/Th2 ratios who previously failed multiple embryo transfers. 4, 3

• Implantation rate: 40% 4
• Clinical pregnancy rate: 50-64% 4, 3
• Live birth rate: 35-60% 4, 3
• Miscarriage rate: 6.3% (significantly lower than untreated controls) 3, 2

In contrast, untreated RIF patients with elevated Th1/Th2 ratios have 0% clinical pregnancy rates 3.

Mechanism of Action in RIF

Tacrolimus acts as a calcineurin inhibitor that modulates the endometrial immune environment by suppressing Th1 immunity and promoting Th2 cytokine expression. 2, 4

• Significantly increases expression of leukemia inhibitory factor (LIF), IL-10, and IL-17 in the endometrium 4
• Decreases expression of IFN-γ and IL-4, reducing the IFN-γ/IL-10 ratio 4
• IL-10 levels show significant positive correlation with implantation rates 4
• The Th1/Th2 ratio decreases significantly from pre-pregnancy to first trimester and from first to second trimester under tacrolimus treatment 6

Safety Profile in Pregnancy

Tacrolimus has an established safety profile in pregnancy based on extensive transplant literature and emerging reproductive medicine data. 1, 7

Maternal Safety:

• No significant side effects reported in RIF treatment studies 3
• Obstetric complications are rare: only 2/109 women (1.8%) developed hypertensive disorders of pregnancy 1
• Premature delivery rate: 8.3% (9/109 pregnancies including twins) 1
• Lower incidence of hypertension and preeclampsia compared to cyclosporine 7

Fetal Safety:

• Congenital abnormality rate: 0.9% (1/113 babies), comparable to general population 1
• No significant differences in birthweight or placental weight across different tacrolimus doses 1
• Neuromotor development of babies exposed in utero is comparable to the general population 1
• Tacrolimus crosses the placenta at 30-60% of maternal concentration but shows no significant malformation risk 7

Administration Guidelines

Administer tacrolimus consistently either with or without food, as food decreases absorption by 37%. 5

• Maintain the same timing and food relationship daily to ensure stable blood levels 5
• Continue treatment throughout pregnancy if conception occurs 1, 2
• For women with history of recurrent pregnancy loss in addition to RIF, continue tacrolimus to prevent biochemical pregnancy loss 2

Special Considerations for RIF-Plus-RPL Patients

Women with both RIF and recurrent pregnancy loss (RPL) show delayed immune suppression and require continued tacrolimus throughout pregnancy. 6, 2

• The Th1/Th2 ratio reduction occurs more slowly in RIF-plus-RPL patients compared to RIF-alone patients 6
• Tacrolimus significantly reduces biochemical pregnancy rates in RPL patients 2
• Live birth rates are significantly higher with tacrolimus treatment in this population 2
• Prior severe obstetrical complications can be controlled with tacrolimus administration during pregnancy 2

Contraindications and Precautions

Screen for and monitor potential tacrolimus-related complications including nephrotoxicity, glucose intolerance, and hypertension. 7

• Monitor for diabetes mellitus development (screen for gestational diabetes) 7
• Monitor blood pressure throughout pregnancy for hypertension 7
• Women taking tacrolimus should avoid mycophenolate mofetil, which is contraindicated in pregnancy 7
• Consider Pneumocystis jiroveci prophylaxis with immunosuppressive use 5

Drug Interactions

Be aware that azole antifungals and macrolide antibiotics significantly increase tacrolimus levels through CYP3A4 inhibition. 8

• Reduce tacrolimus dose by 50-75% prophylactically when starting azole antifungals (fluconazole, voriconazole) 8
• Prefer azithromycin over erythromycin or clarithromycin if macrolide therapy is needed 8
• Monitor tacrolimus levels every 2-3 days when starting any antimicrobial agent 8

Breastfeeding Considerations

Tacrolimus is conditionally compatible with breastfeeding according to rheumatology guidelines. 7

• The decision to breastfeed should balance disease control needs with medication exposure 7
• Tacrolimus levels in breast milk are generally low but individual assessment is warranted 7